Familial Mediterranean Fever and Monogenic Autoinflammatory Diseases

Literature and regulatory information update: 1 November 2026.

Hereditary periodic fevers: familial Mediterranean fever (MEFV), cryopyrin-associated periodic syndromes (NLRP3), TNF receptor-associated periodic syndrome (TNFRSF1A) and mevalonate kinase deficiency (MVK); NLRP1-associated autoinflammatory diseases (MSPC, AIADK, JRRP); Behçet-like autoinflammatory diseases of the canonical NF-κB pathway: haploinsufficiency of A20 (TNFAIP3) and haploinsufficiency of RelA (RELA); CARD8-associated inflammatory bowel disease (CARD8)

0. Initial Reference Table

Table data: [1–36].

1. Introduction

Monogenic autoinflammatory diseases are disorders of innate immunity characterised by recurrent or continuous systemic inflammation, without high-titre autoantibodies or antigen-specific autoreactive T cells. The 2014 classification of the International Union of Immunological Societies, reproduced in the Oxford Desk Reference, places them in group VII of primary immunodeficiencies, defining them as diseases marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system [4]. The classic group of hereditary periodic fevers comprises four entities: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD), whose mild form was historically called hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS) [5, 37].

FMF is the most frequent monogenic autoinflammatory disease [10, 38]. The inaugural description is attributed to Sheppard Siegal, who in 1945 reported «benign paroxysmal peritonitis» in the Annals of Internal Medicine, a designation that reflected the self-limited episodes of abdominal pain and fever [39]. In 1972 Goldfinger reported the prophylactic effect of colchicine on attacks [40]. In 1986 Zemer and colleagues showed, in a cohort of 1,070 patients followed for 4 to 11 years, that colchicine prevented amyloidosis: the cumulative rate of proteinuria was 1.7% at 11 years in adherent patients and 48.9% at 9 years in non-adherent patients [41]. In 1997 Livneh and colleagues published the Tel-Hashomer diagnostic criteria [42] and, in the same year, two independent consortia, the French FMF Consortium and the International FMF Consortium, identified the MEFV gene on the short arm of chromosome 16 by positional cloning, naming the encoded protein marenostrin and pyrin, respectively [43, 44].

CAPS were recognised through distinct clinical stages before being brought together into a single spectrum. Muckle and Wells described in 1962 the familial association of urticaria, deafness and amyloidosis [45]; Prieur and Griscelli described in 1981 chronic infantile neurological, cutaneous and articular syndrome (CINCA), also called neonatal-onset multisystem inflammatory disease (NOMID) [46]. In 2001 Hoffman and colleagues identified mutations in the CIAS1 gene (cold-induced autoinflammatory syndrome 1), now NLRP3, in familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS) [47], and in 2002 Aksentijevich and colleagues demonstrated de novo mutations of the same gene in NOMID/CINCA [48].

TRAPS was described in 1982 by Williamson and colleagues in a family of Irish and Scottish ancestry, under the name «familial Hibernian fever» [3, 49]. In 1999 McDermott and colleagues demonstrated germline variants in the extracellular domains of the 55 kDa TNF receptor (TNFR1), proposing the acronym TRAPS [50]. HIDS was described by van der Meer and colleagues in 1984 [51], and in 1999 two groups identified the MVK gene as the cause of the disease [52, 53]. The understanding that these diseases share a final pathway of excessive production of interleukin-1β (IL-1β) led to the development of targeted therapies: anakinra, rilonacept and canakinumab. This article treats FMF as the central entity, with dedicated subsections for CAPS and TRAPS and a discussion of MKD, integrating the recommendations of EULAR (European Alliance of Associations for Rheumatology) and PReS (Paediatric Rheumatology European Society) [9, 10, 38].

NLRP1-associated diseases form the most recent group of inflammasomopathies. In 2013, Soler and colleagues identified, by exome sequencing in a French family, the NLRP1 variant NM_033004.4:c.230T>C p.(Met77Thr) as the cause of corneal intraepithelial dyskeratosis with palmoplantar hyperkeratosis and laryngeal dyskeratosis [54]. In 2015, Mamaï and colleagues described, in a five-generation Tunisian family, multiple self-healing palmoplantar carcinoma (MSPC), with linkage to 17p13 [55], and in 2016 Zhong and colleagues showed that germline gain-of-function variants in NLRP1 cause MSPC and familial keratosis lichenoides chronica (FKLC), proposing a group of inflammasomopathies without fever and with a predisposition to skin cancer [16]. In 2017, Grandemange and colleagues described autoinflammation with arthritis and dyskeratosis (designated NAIAD in the original publication and AIADK in OMIM) [17], and in 2019 Drutman and colleagues associated a homozygous gain-of-function variant with juvenile-onset recurrent respiratory papillomatosis (JRRP) [18]. In 2024 the unifying designation NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) was proposed for cases published under different names [56].

Behçet-like autoinflammatory diseases of the canonical NF-κB pathway were individualised in the last decade and constitute the group of NF-κBopathies, that is, diseases in which the primary defect lies in the regulation of NF-κB signalling rather than in the inflammasome. In 2016, Zhou and colleagues described, in six unrelated families, an early-onset disease resembling Behçet's disease but with autosomal dominant transmission, caused by germline truncating variants of TNFAIP3; they showed that the mutant proteins exert no dominant-negative effect and that the mechanism is haploinsufficiency of A20, hence the designation haploinsufficiency of A20 and the acronym HA20 [23]. Before that, common TNFAIP3 variants were known only as susceptibility alleles for systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and type 1 diabetes, and biallelic somatic variants only in B-cell lymphomas [26, 57]. In 2017, Badran and colleagues identified, in a family with autosomal dominant chronic mucocutaneous ulceration, a RELA splice-site variant that halves the transactivating subunit of NF-κB, establishing haploinsufficiency of RelA, now designated RELA-associated inflammatory disease (RAID) [27]. OMIM organised these entities into a genetic heterogeneity series: familial Behçet-like autoinflammatory syndrome 1 (AIFBL1, 616744) corresponds to TNFAIP3, 2 (AIFBL2, 301074) to ELF4 with X-linked inheritance, and 3 (AIFBL3, 618287) to RELA, the latter with the synonym chronic mucocutaneous ulceration [31]. The initial nomenclature of «monogenic Behçet's disease» was progressively abandoned in favour of gene-based designations, for two reasons: many patients do not meet the international criteria for Behçet's disease, and the phenotype of haploinsufficiency of A20 proved much broader, with autoimmunity, immunodeficiency, atopy and lymphoproliferation, which led to its classification as an inborn error of immunity with complex immune dysregulation and not merely as an autoinflammatory disease [22, 26, 57]. In 2023, the description of RELA variants with an expressed truncated protein and a dominant-negative effect added to this group a form of type I interferonopathy, showing that the same gene can cause disease through two distinct mechanisms [58]. Within the scope of this article, these two entities are included as monogenic autoinflammatory diseases of the canonical NF-κB pathway that share with the periodic fevers recurrent mucosal ulceration, fever and elevation of acute-phase reactants, and that differ from them by the absence of stereotyped attacks, by the burden of autoimmunity and by the preferential response to TNF blockade.

CARD8-associated inflammatory bowel disease entered the group of inflammasomopathies in 2018, when Mao and colleagues, at the National Institutes of Health, described a North American family with Crohn's disease in two generations and a heterozygous CARD8 variant that deprives CARD8 of its ability to restrain the NLRP3 inflammasome [33]. OMIM records the entity as inflammatory bowel disease 30 (IBD30, 619079), with autosomal dominant inheritance and the symbol «?», which denotes a provisional gene-phenotype relationship, and Orphanet assigns it the code ORPHA:714410 (CARD8-related inflammatory bowel disease) [34, 35]. Before that, a frequent CARD8 frameshift variant had been associated with PFAPA syndrome, without a Mendelian pattern [59]. CARD8 is, moreover, an inflammasome sensor in its own right, with an architecture similar to that of NLRP1, whose uncontrolled activation contributes to the cytopenias of DPP9 deficiency [36, 60].

2. Molecular Genetics and Pathophysiology

2.1 Familial Mediterranean fever — MEFV and the pyrin inflammasome

The MEFV gene (16p13.3; OMIM 608107; reference sequence NM_000243.3) encodes pyrin, a protein expressed mainly in neutrophils and monocytes [1]. Pyrin is an intracellular sensor of bacterial inactivation of the GTPase RhoA. Under basal conditions, RhoA activates the kinases PKN1 and PKN2, which phosphorylate pyrin; phosphorylated pyrin binds 14-3-3 proteins and remains inactive. When bacterial toxins inactivate RhoA, pyrin is dephosphorylated, dissociates from the 14-3-3 proteins and oligomerises with the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) and with pro-caspase-1, forming the pyrin inflammasome; active caspase-1 cleaves pro-IL-1β into mature IL-1β [1]. FMF-causing variants act by gain of function: they lower the activation threshold of the inflammasome without activating it constitutively. The B30.2 domain (encoded by exon 10) normally restrains pyrin, and pathogenic variants weaken binding to the 14-3-3 proteins, making pyrin hypersensitive to dephosphorylation; inflammasome activation also suppresses production of the IL-1 receptor antagonist (IL-1Ra), amplifying inflammation [1]. Pyrin also participates in autophagy, functioning as a receptor that recruits ULK1, beclin-1, ATG16L1 and ATG8 proteins for the degradation of components of other inflammasomes, including caspase-1, NLRP1 and NLRP3 [1].

Most pathogenic variants cluster in exon 10 (B30.2 domain), although there are FMF-associated variants elsewhere in the gene, such as NM_000243.3:c.1437C>G p.(Phe479Leu) in exon 5; variants associated with other pyrinopathies lie in other domains. Somatic cases of pyrin-associated disease have been described [1]. No large deletions or duplications of MEFV have been identified, and they are not expected to cause FMF, which is consistent with the gain-of-function mechanism [1].

The mode of inheritance of FMF is a matter of debate. GeneReviews (July 2026 revision) retains autosomal recessive inheritance, explaining families with apparent dominant transmission by an undetected second allele, by pseudodominance in populations with a high carrier frequency, or by a distinct pyrin-associated autoinflammatory disease (PAAD) [1]. ClinGen classifies as definitive the relationships of MEFV with both autosomal recessive FMF and autosomal dominant FMF, emphasising that patients with one or two identified alleles have similar severity and age at onset, share the same common variants, and that up to 25% of patients with FMF have only one heterozygous variant identified; OMIM maintains separate entries for autosomal recessive (249100) and autosomal dominant (134610) FMF [2, 61]. The Oxford Desk Reference refers to FMF as an autosomal recessive disease associated with variants in MEFV [4].

Genotype-phenotype correlation. Variants affecting methionine residue 694 (in transcript NM_000243.3, c.2080A>G p.(Met694Val), c.2082G>A p.(Met694Ile) and c.2081_2083del p.(Met694del)) and the variant p.(Met680Ile) are associated with early onset, higher attack frequency and a greater risk of AA amyloidosis; homozygosity or compound heterozygosity for these variants can lead to end-stage kidney disease [1]. The variant c.2177T>C p.(Val726Ala) is associated with late onset and lower severity, and compound heterozygotes for a severe and a mild variant (for example p.[Met694Val];[Val726Ala]) show intermediate severity [1]. Compound heterozygosity p.[Ile692del];[Val726Ala] (c.2076_2078del with c.2177T>C) has been associated with a severe inflammatory phenotype with markedly raised interleukin-18 (IL-18), neutrophilic dermatoses, anaemia and cytokine storm-like episodes, designated CHIVE-18 [1]. Penetrance is highest in individuals biallelic for codon 694 variants and is modulated by additional genetic and environmental factors [1].

Variants of controversial interpretation. The MEFV (NM_000243.3) variants c.442G>C p.(Glu148Gln), c.1105C>T p.(Pro369Ser), c.2084A>G p.(Lys695Arg) and c.2230G>T p.(Ala744Ser) are frequent in several populations but are now widely considered benign by GeneReviews, which excludes them from carrier frequency estimates [1]. European recommendations state that p.Glu148Gln alone does not support a diagnosis of FMF [38, 62]. Classification may, however, diverge between databases: in a Slovak cohort of 113 patients, the variant p.Lys695Arg was classified as likely pathogenic by ACMG (American College of Medical Genetics and Genomics) criteria and as of uncertain significance in the Infevers database, illustrating the need for expert interpretation [63]. The ISSAID/EMQN (International Society of Systemic Auto-Inflammatory Diseases/European Molecular Genetics Quality Network) guidelines for the genetic diagnosis of autoinflammatory diseases propose a genotype table based on the five-tier classification and a decision tree for the scope and method of testing [64].

Table source: GeneReviews, table 8 [1].

Pyrin-associated autoinflammatory diseases (allelic). Besides FMF, specific MEFV variants cause distinct diseases, with longer episodes and manifestations that are rare in FMF [1, 65]. Autosomal dominant PAAD (variants, in NM_000243.3, c.1118C>T p.(Pro373Leu), c.1432C>T p.(His478Tyr), substitutions of threonine 577 by asparagine, serine or alanine, such as c.1730C>A p.(Thr577Asn), and c.2081_2083del p.(Met694del)) presents with prolonged febrile attacks, evanescent rash, urticaria, conjunctivitis, polyadenopathy, hepatosplenomegaly, profound anaemia, granulomatous colitis and persistent arthralgia. PAANI (c.1748A>C p.(Glu583Ala), exon 9) presents with neuroinflammation (seizures, aseptic meningitis). PAAND (c.726C>G p.(Ser242Arg), c.730G>A p.(Glu244Lys), exon 2), an autosomal dominant disease with neutrophilic dermatosis (OMIM 608068), lacks serositis and may have inflammatory bowel disease-like digestive involvement. PAAHe (c.622A>T p.(Ser208Cys), c.623G>C p.(Ser208Thr)), of autosomal recessive inheritance, combines neutrophilic dermatosis, marked eosinophilia and aseptic osteitis [1].

2.2 CAPS — NLRP3 and the NLRP3 inflammasome

The NLRP3 gene (1q44; OMIM 606416), formerly designated CIAS1, encodes cryopyrin, a protein with a pyrin domain, a nucleotide-binding domain (NACHT) and leucine-rich repeats, expressed predominantly in leucocytes [5, 47]. NLRP3 is the sensor of the inflammasome of the same name: on detecting loss of membrane integrity and other danger signals, it nucleates a complex with ASC and caspase-1, which cleaves pro-IL-1β, pro-IL-18 and gasdermin D, causing cytokine secretion and pyroptosis. Pathogenic variants relieve the autoinhibition that keeps NLRP3 bound to ADP at rest, so the inflammasome forms without an adequate stimulus [8, 66]. In CINCA, variants cluster in exon 3, and somatic mosaicism is frequent [5]. In the series of Aksentijevich and colleagues, only 6 of 13 patients with classic NOMID had a germline variant detectable by sequencing, and in the four with parental DNA available the variants were de novo [48]. Somatic mosaicism may also arise in adulthood: in a British series of eight patients with an intermediate CAPS phenotype and a median age at onset of 50 years, Sanger sequencing was negative and deep amplicon sequencing detected a somatic NLRP3 variant in all; these patients represented 8% of CAPS diagnosed at the centre, in one patient the mutant allele fraction rose from 5% to 45% over 12 years with clinical worsening, and two developed AA amyloidosis [66]. FCAS, MWS and CINCA/NOMID are allelic diseases and form a continuum of severity [5, 8]. Other NLRP3-associated phenotypes include hereditary fleeting keratoendotheliitis (OMIM 148200) and autosomal dominant deafness 34 (DFNA34, OMIM 617772), with or without systemic inflammation [8]. FCAS type 2, associated with NLRP12, is a distinct entity [4].

2.3 TRAPS — TNFRSF1A and endoplasmic reticulum stress

TNFRSF1A (12p13.31; OMIM 191190; NM_001065.4) encodes TNFR1, a membrane receptor expressed on a wide variety of cells, which induces cytokine secretion, expression of adhesion molecules and leucocyte activation. Receptor activation normally triggers its proteolytic cleavage (shedding), releasing the soluble extracellular portion, which acts as a competitive inhibitor of TNF [3, 50]. Pathogenic variants lie predominantly in the extracellular domain and disturb protein folding, frequently by disrupting hydrogen bonds and disulphide bridges; the mutant receptor is neither cleaved nor transported to the surface, accumulates inside the cell and causes endoplasmic reticulum stress, activation of the unfolded protein response and increased mitochondrial reactive oxygen species, which promote the production of pro-inflammatory cytokines [3, 67, 68]. The mechanism is not loss of function: the gene is intolerant of loss-of-function variants and deletions or duplications have never been described in TRAPS [3].

Cysteine variants (for example, in NM_001065.4, c.176G>A p.(Cys59Tyr), c.241T>C p.(Cys81Arg) and c.242G>T p.(Cys81Phe), designated Cys30Tyr, Cys52Arg and Cys52Phe in the old nomenclature) and c.236C>T p.(Thr79Met) (Thr50Met, the most frequent) are associated with severe disease and a greater risk of AA amyloidosis [3]. Two numbering systems coexist in the literature: early work subtracted the 29 amino acids of the signal peptide, whereas HGVS (Human Genome Variation Society) nomenclature starts at the initiating methionine; for example, c.123T>G (p.Asp41Glu) was published as p.Asp12Glu [3]. The low-penetrance variants c.123T>G (p.Asp41Glu), c.224C>T (p.Pro75Leu), c.362G>A (p.Arg121Gln, formerly R92Q), c.370G>A (p.Val124Met) and c.398G>A (p.Arg133Gln, formerly R104Q) are enriched in people with TRAPS-like presentations, but functional studies show that they do not behave like the cysteine variants; carriers have mild or no symptoms, the variant is often inherited from an asymptomatic parent, and asymptomatic people with these variants are not, in general, considered to have TRAPS [3, 68]. Somatic and gonosomal mosaicism for TNFRSF1A variants has been described, including adult-onset TRAPS [3].

2.4 MKD/HIDS — MVK and the mevalonate pathway

Mevalonate kinase catalyses the phosphorylation of mevalonate to 5-phosphomevalonate, the initial step in the synthesis of all isoprenoids [6]. MKD results from biallelic variants in MVK and forms a clinical and biochemical continuum: in mevalonic aciduria enzyme activity is usually undetectable, whereas in HIDS residual activity is 1–10% of that of controls [6]. Most patients with HIDS are compound heterozygous for the hypomorphic allele p.Val377Ile, exclusive to the mild form, and a second severe allele; the p.Val377Ile protein is active, but its maturation is temperature-sensitive, which explains the residual activity and the precipitation of attacks by fever [6]. The inflammatory manifestations are attributed to a transient shortage of geranylgeranyl pyrophosphate [6]; the resulting failure of protein prenylation favours inflammasome activation and IL-1β production [11]. More than 186 pathogenic variants have been described [6].

2.5 NLRP1-associated diseases — epithelial inflammasomopathies

The NLRP1 gene (17p13.2; OMIM 606636; MANE reference sequence NM_033004.4) encodes NLRP1, the most highly expressed inflammasome sensor in human skin [16]. The human protein has a distinctive domain organisation: an N-terminal pyrin domain (PYD), a NACHT domain, leucine-rich repeats (LRR), a FIIND domain (function-to-find domain) and a C-terminal CARD domain [69]. The FIIND undergoes autocleavage, so that the functional protein is formed by two non-covalently associated fragments; activation results from proteasomal degradation of the N-terminal fragment, which releases the C-terminal UPA-CARD fragment, capable of recruiting ASC and caspase-1 [69]. At rest, dipeptidyl peptidase 9 (DPP9) binds the FIIND and sequesters the C-terminal fragment, preventing inflammasome assembly [70, 71]. Stimuli that activate human NLRP1 include enteroviral 3C protease, which cleaves the N-terminal region of the protein in airway epithelial cells, and the ribotoxic stress response mediated by the kinase ZAKα, triggered by ultraviolet B radiation and by ribosome-damaging toxins [72, 73]. Keratinocytes and bronchial epithelial cells express pro-IL-1β and pro-IL-18 constitutively and do not express NLRP3, which explains why NLRP1 gain-of-function diseases manifest mainly as inflammation of epithelial barriers (skin, cornea, conjunctiva, mucosae and airways), unlike CAPS, in which systemic inflammation is driven by myeloid cells [74].

Zhong and colleagues showed that all pathogenic variants then known were gain-of-function alleles: PYD variants (associated with MSPC) and the in-frame deletion in the LRR domain (associated with FKLC) undo the autoinhibition that keeps NLRP1 as an inactive monomer and increase its self-oligomerisation; patients' primary keratinocytes activate the inflammasome spontaneously, and paracrine IL-1 signalling is sufficient to cause skin inflammation and epidermal hyperplasia [16]. The variant p.(Pro1214Arg), in the FIIND, acts by another mechanism: it abolishes binding to DPP9 and releases the inflammasome from its repression [70]. In the three patients of the original AIADK description, serum caspase-1 and IL-18 were raised [17]; the variant p.(Ala59Pro) caused spontaneous IL-1β cleavage in a reconstitution assay and a constitutive increase in IL-18 in the patient's mononuclear cells [75]; and the variant NM_033004.4:c.2264C>A p.(Thr755Asn), identified in JRRP, induced inflammasome oligomerisation and IL-1β secretion in an overexpression system, with raised basal IL-1β in patients' keratinocytes and raised inflammasome-dependent cytokines in serum [18].

The protein designations in the literature (A54T, A59P, A66V, M77T, R726W, T755N, L813P, P1214R) coincide with MANE transcript numbering, confirmed in VariantValidator and ClinVar [77]. The classification of p.(Arg726Trp) as a variant of uncertain significance in ClinVar contrasts with its causal attribution in the original publication and illustrates that the functional and segregation evidence for each variant must be reassessed [17, 77].

The NLRP1 allelic family has two inheritance patterns. MSPC and corneal intraepithelial dyskeratosis are associated with heterozygous PYD variants with autosomal dominant transmission [16, 54, 55]. AIADK has been described with both patterns: homozygosity for NM_033004.4:c.2176C>T p.(Arg726Trp) in a consanguineous family and de novo heterozygosity for p.(Pro1214Arg) [17]; the variant p.(Ala59Pro) segregated dominantly with incomplete penetrance over three generations [75]. JRRP and the phenotype associated with p.(Leu813Pro) result from biallelic variants [18, 78]. Expressivity is variable within the same family: the mother of the patient with p.(Ala54Thr) described by Burlakov and colleagues had only hyperkeratotic lesions on the elbows and raised CRP [76], and the two sisters homozygous for p.(Leu813Pro) had differing severity, attributed in part to additional variants associated with atopy and psoriasis [78]. Common NLRP1 polymorphisms, such as the haplotypes associated with vitiligo and the p.Met1184Val variant associated with asthma severity, are susceptibility factors and not Mendelian causes [74]. Biallelic DPP9 deficiency reproduces part of the picture through loss of NLRP1 repression and constitutes a related inflammasomopathy [79].

2.6 Haploinsufficiency of A20 — TNFAIP3 and the brake on the canonical NF-κB pathway

The TNFAIP3 gene lies at 6q23.3, has OMIM gene number 191163 and encodes tumour necrosis factor alpha-induced protein 3, universally known as A20; the MANE Select reference transcript is NM_001270508.2, with protein NP_001257437.1 [31, 80]. A20 has 790 amino acids and combines two types of enzymatic activity on ubiquitin: an amino-terminal ovarian tumour (OTU) domain, which removes (activating) Lys63-linked polyubiquitin chains from signalling adaptors, and seven zinc finger (ZnF) domains which, conversely, promote Lys48 ubiquitination and proteasomal degradation of those same adaptors [26, 57]. The fourth zinc finger domain functions as a scaffold for binding adaptor proteins (TAX1BP1) and E3 ligases (Itch, RNF11), and the seventh binds linear (Met1-linked) ubiquitin chains, which recruits A20 to the TNF receptor signalling complex where it disrupts the interaction between NEMO and the LUBAC complex [26]. At rest A20 is barely expressed, being induced by immune activation itself: it functions as a negative feedback brake, which explains why reduced dosage has consequences mainly after stimulation [26].

The disease mechanism is haploinsufficiency: a single functional copy is not enough to terminate NF-κB-dependent signalling [22]. Zhou and colleagues demonstrated this in six unrelated families, showing that the truncated proteins were not detectable in patients' cells, that none exerted a dominant-negative effect on co-expression with the normal protein, and that patients' cells had reduced recruitment of A20 to the TNFR1 complex, increased phosphorylation of IKK-α and IKK-β, accelerated degradation of IκB-α, increased nuclear translocation of the p65 subunit and defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 [23]. The functional result is excessive production of TNF-α, IL-1β, IL-6 and IL-8, polarisation of CD4 T lymphocytes towards Th9 and Th17 profiles and an increase in inflammatory CD14+ monocytes [23]. A20 also regulates the NLRP3 inflammasome and necroptosis through NF-κB-independent mechanisms, and modulates interferon signalling, which links this entity both to the inflammasomopathies of the preceding sections and to the type I interferonopathies [23, 26, 57].

Inheritance is autosomal dominant, with high penetrance: in the Japanese nationwide survey, three of 70 heterozygous germline carriers were asymptomatic, corresponding to a penetrance of 95.7%; the two carriers identified with low-level somatic mosaicism (10.06% in a mother and 16.7% in a father) were asymptomatic, so an apparently healthy parent can transmit the variant [25]. Expressivity is highly variable between families and within the same family: in family 27 of that cohort, two siblings with the same frameshift variant had opposite courses: one with fever and lymphadenopathy from 3 months of age, the other with fever and severe neurological disease of adult onset [25]. A second inheritance pattern is now documented: Alsabbagh and colleagues described a homozygous variant in the seventh zinc finger domain, NM_001270508.2:c.2341G>A p.(Glu781Lys), confirmed in VariantValidator, in a patient with lupus-like disease beginning at the age of 4 years; the variant impairs binding to linear ubiquitin and behaves as a functional hypomorph, with a reduced but not absent ability to inhibit NF-κB, so the recessive form is not explained by complete loss [30, 80]. The divergence in mode of inheritance between the two publications is not an error: these are distinct molecular mechanisms in the same gene, and both should appear in the genetic report.

The variant spectrum is dominated by loss of function. In the systematic review of 177 patients, variants affected the OTU domain in 92 cases and a zinc finger domain in 68, and geographical origin, recorded sex and variant type significantly influenced the phenotype [81]. The multicentre international cohort of 185 patients from 41 centres in seven countries identified 89 pathogenic variants, 46 of them novel, and found no clear association between disruption of specific functional domains and age at onset or phenotype; large deletions, by contrast, were associated with neurological disease (p = 0.0054) and developmental delay (p = 0.0245) [24]. About 95% of patients have a sequence variant, about 3% an intragenic deletion or duplication detectable by targeted analysis and about 2% a 6q23 deletion encompassing the gene, detectable by chromosomal microarray [22]. The six variants of the original description illustrate the domain distribution and were all confirmed in VariantValidator against the MANE transcript.

Table sources: [23, 30, 80, 82].

No genotype-phenotype correlations have been established [22, 24]. The impression that missense variants cause milder disease with reduced penetrance has not been demonstrated, and it is precisely among rare missense variants that interpretation is difficult: about 80% are classified as of uncertain significance, and the ACMG/AMP PS3 criterion requires functional studies in isogenic systems [22, 26]. The reference assay consists of overexpressing constructs carrying the normal sequence and the variant in cell lines, stimulating with TNF-α and measuring NF-κB activation by luciferase, p65 phosphorylation, nuclear localisation, IκB-α degradation or IKK-α/β phosphorylation [26]. The variant NM_001270508.2:c.728G>A p.(Cys243Tyr), for example, did not reduce protein levels or increase NF-κB activity in the Japanese assays, illustrating the limits of these systems [83]. Common non-coding TNFAIP3 variants are, on the other hand, susceptibility signals replicated in genome-wide association studies for systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases: they reflect population risk and not a Mendelian diagnosis, and should not be reported as a cause of haploinsufficiency of A20 [57]. As an allelic disease in the somatic sense, acquired biallelic inactivation of TNFAIP3 is frequent in sporadic B-cell lymphomas; it is not present in the germline and confers no hereditary predisposition [22].

2.7 Haploinsufficiency of RelA — RELA and epithelial survival under TNF

The RELA gene lies at 11q13.1, has OMIM gene number 164014 and encodes RelA (also designated p65), the main transactivating subunit of NF-κB; the MANE Select transcript is NM_021975.4, with protein NP_068810.3 [31, 80]. RelA is kept inactive in the cytoplasm by the IκB inhibitory proteins, mainly as a heterodimer with p50 encoded by NFKB1; stimuli that activate the IKK complex (IKK-α, IKK-β and NEMO) lead to phosphorylation, ubiquitination and proteasomal degradation of IκB-α, and the released heterodimer enters the nucleus and binds κB sequences in the promoters of genes of inflammation, immunity and cell survival [27, 29]. The decisive point for the disease is that RelA drives the anti-apoptotic arm of TNF signalling: with half the dose of protein, epithelial and stromal cells exposed to TNF die instead of surviving and regenerating [27].

Badran and colleagues established the mechanism in a two-generation family with chronic mucocutaneous ulceration, identifying the splice donor site variant NM_021975.4:c.559+1G>A (ClinVar VCV000617487, pathogenic), which reduces messenger RNA and protein by 50% [27, 80, 84]. Patients' fibroblasts showed increased cell death and caspase-8 cleavage after TNF, reduced NF-κB activation, decreased IL-6 secretion and lower induction of NF-κB-dependent anti-apoptotic genes; impaired survival was restricted to stromal cells and did not affect lymphocytes [27, 31]. Rela+/− mice reproduce the phenotype: they develop skin ulceration with epidermal loss and a neutrophil and macrophage infiltrate after TNF exposure, and severe dextran sulphate sodium-induced colitis that improves with TNF inhibition; chimera experiments showed that the defect is epithelial and stromal and not in bone marrow-derived immune cells [27]. The location of ulcers on the oral, gastrointestinal and vaginal mucosae, which are rich in microbiota, suggests that microbial stimuli induce local release of TNF that the mucosa can no longer tolerate [31].

There is a second mechanism, which should not be confused with simple haploinsufficiency. Moriya and colleagues described six patients from five families whose heterozygous variants all lie in the 3' segment of the gene and create a premature stop codon: the truncated protein is expressed, has no function and exerts a dominant-negative effect on normal RelA [58]. In these patients there is increased expression of TLR7 and MYD88 messenger RNAs in plasmacytoid dendritic cells and other myeloid cells, with TLR7-dependent excessive secretion of type I and III interferons and an interferon-stimulated gene signature in leucocytes, which defines a form of type I interferonopathy with autoinflammation and autoimmunity [58]. The same principle had been described in three patients with a lupus phenotype and dominant-negative variants, in whom co-expression of the mutant protein with the normal protein strongly activated transcription controlled by interferon alpha consensus sequences, with positivity for antinuclear and anti-double-stranded DNA antibodies in all; these results were released as a preprint without peer review and are cited here from the review that compiles them [29]. Patients with dominant-negative variants had, in these series, more severe disease than patients with simple haploinsufficiency [29, 58].

Fourteen different RELA variants had been described in the 2026 review, all classified as pathogenic or likely pathogenic [29]. Penetrance is incomplete and expressivity markedly variable, even within the same family: five carriers of the variant NM_021975.4:c.1459del included two patients diagnosed with Behçet's disease, two with recurrent oral ulcers only and one without Behçet-like manifestations but with anti-aquaporin-4 antibodies and a diagnosis of neuromyelitis optica [29]. Carriers of the same c.985C>T variant presented, in different series, with a perianal abscess and diarrhoea from the first month of life with a diagnosis of Crohn's disease and immune thrombocytopenia, with fever, arthralgia and bloody diarrhoea from the age of 9 years, or with oral and skin ulcers with lupus nephritis and pericarditis [29].

Table sources: [27, 29, 58, 80, 84, 85].

The numbering of these variants requires care. OMIM assigns the same allelic variant number (164014.0003) to the variant of the Irish family and to that of the Eurasian family, and gives c.1004dupC for the latter, whereas, in transcript NM_021975.4, the original publication and the 2026 review give c.1044dup; conversion in VariantValidator confirms that only c.1044dup produces the published protein consequence, p.(Tyr349LeufsTer13) [29, 31, 80]. As an allelic disease, the somatic ZFTA::RELA fusion, formerly designated C11orf95-RELA, is present in more than 60% of supratentorial ependymomas and has its own Orphanet code; it is a structural rearrangement acquired in the tumour, does not exist in the germline, and a germline RELA variant confers no predisposition to ependymoma nor justifies any oncological surveillance [29].

2.8 CARD8-associated inflammatory bowel disease — the brake on the NLRP3 inflammasome

The CARD8 gene (19q13.33; OMIM gene 609051; MANE reference sequence NM_001184900.3, protein NP_001171829.1; synonyms TUCAN, CARDINAL and NDPP1) encodes a protein with a disordered N-terminal region, a FIIND domain and a C-terminal CARD domain, an organisation that reproduces the C-terminal half of NLRP1 [36]. Alternative transcription start sites and splicing give rise to several isoforms, designated by their approximate molecular mass: T60, T54, T51, T48 and T47 [36]. T48, which starts in exon 6, was the first to be characterised and for years was treated as canonical; T60, which starts in exon 4, is the longest and corresponds to the MANE transcript [33, 36]. This multiplicity of isoforms has direct consequences for variant interpretation, because the same genomic change may be non-synonymous in one isoform and fall in an untranslated or intronic region in another [33].

CARD8 has two opposing functions in the control of inflammation. As a sensor, it follows the NLRP1 model: the FIIND undergoes autocleavage, proteasomal degradation of the N-terminal fragment releases the C-terminal UPA-CARD fragment, and this directly recruits pro-caspase-1, without the need for ASC [36]. Activation of the CARD8 inflammasome produces mainly pyroptosis, with little release of IL-1β, and is triggered by inhibition of dipeptidyl peptidases 8 and 9 (DPP8/9), for example with Val-boroPro (talabostat), by HIV-1 protease, which cleaves the N-terminal region unique to T60, and by the 3C proteases of some picornaviruses; DPP9 binds CARD8 and keeps it inactive [36]. As a regulator, CARD8 binds NLRP3 at rest, through the FIIND, and prevents subthreshold stimuli from triggering oligomerisation of the NLRP3 inflammasome; silencing of CARD8 in human macrophages increases IL-1β secretion, and the mutant forms of NLRP3 in CAPS no longer bind CARD8, escaping this brake [86]. CARD8 also inhibits NF-κB, NOD2 and caspase-9 signalling [36]. There is no mouse orthologue of CARD8, so the study of its variants depends on human cells or humanised mice [33, 60].

In the family described by Mao and colleagues, exome sequencing identified in the three affected individuals (the proband, the mother and the maternal aunt) the heterozygous variant NM_001184900.3:c.130G>A p.(Val44Ile) (NC_000019.10:g.48238462C>T), absent in the father, who was healthy [33]. The variant lies upstream of the T48 initiation codon and alters only the protein sequence of T60; it then had a frequency of 0.0015% in gnomAD (two heterozygotes) [33]. Mutant T60 lost binding to NLRP3 and the ability to inhibit its oligomerisation, gained affinity for the normal T60 and T48 isoforms, with which it forms oligomers that also no longer bind NLRP3, and no longer prevented the deubiquitination and serine dephosphorylation of NLRP3, steps that precede its activation [33]. The effect is thus dominant-negative, and explains the loss of function of one allele despite the presence of a normal allele [33]. The proband's serum IL-1β was raised, and the proband's monocytes and myeloid dendritic cells produced more IL-1β than controls, at rest and after NLRP3 stimulation with ATP or nigericin; the mother and the aunt had the same abnormality [33]. The proband and the mother also carried the MEFV variant p.Arg329His (frequency 0.2%), without increased pyrin inflammasome activity and absent in the aunt with well-defined Crohn's disease, which ruled it out as a contributor to the phenotype [33]. ClinVar classifies c.130G>A as a variant of uncertain significance (VCV000252559, a single submitter, no phenotype specified), in contrast with the causal attribution of the original publication; this divergence, added to the existence of a single family, explains the provisional status of the association [34, 87].

Two frequent CARD8 variants have been studied as susceptibility factors and should not be confused with the Mendelian form. rs2043211, known in the literature by the historical designation p.C10X, creates a stop codon only in the T48 and T51 isoforms; in the MANE transcript it corresponds to NM_001184900.3:c.304T>A p.(Phe102Ile) and, in the T54 isoform, to NM_014959.5:c.154T>A p.(Phe52Ile), both single amino acid substitutions [36]. The allele has a frequency of about 30% in gnomAD (44,288 of 149,018 alleles) and, in some populations, about 9% of people are homozygous, so it is not equivalent to a CARD8 null allele [36, 88]. The associations described with Crohn's disease, rheumatoid arthritis and gout are inconsistent between studies [36]. rs140826611, designated CARD8-FS, corresponds to NM_001184900.3:c.440_441dup p.(Val148LysfsTer26), which generates a truncated protein lacking the FIIND and CARD, unable to bind the NOD domain of NLRP3 [59]. In a Swiss cohort of 82 patients with PFAPA, 13.9% were carriers, compared with 3.2% in the healthy local population (odds ratio 4.96; 95% confidence interval 1.33–18.47) [59]. The frequency in gnomAD is 4.2% of alleles (6,297 of 149,164) and 12.9% in the Japanese population, and ClinVar classifies the variant as benign (VCV001170357) [87–89]. It is a risk factor of moderate effect, without diagnostic value in isolation.

Activation of CARD8 as a sensor has clinical relevance outside intestinal disease. In DPP9 deficiency (Hatipoglu syndrome), loss of the repression exerted by DPP9 releases NLRP1 and CARD8; in humanised mice, deletion of DPP9 in human haematopoietic stem and progenitor cells reproduced pancytopenia through CARD8-dependent pyroptosis, whereas NLRP1 was dispensable for cell death [60]. A de novo DPP9 variant with a dominant-negative effect caused haemophagocytic lymphohistiocytosis-like hyperinflammation in an infant, and the mutant protein was unable to repress either inflammasome [90].

The nomenclature of the three variants was confirmed in VariantValidator (GRCh38), without warnings, and that of the first two also in ClinVar [87].

3. Clinical Spectrum and Manifestations by System

3.1 Familial Mediterranean fever

FMF presents with recurrent, self-limited episodes of serositis lasting one to three days, separated by asymptomatic intervals; onset typically occurs in early childhood [1, 4]. Between 30% and 50% of patients report prodromes (malaise, irritability, myalgia or localised discomfort) hours or days before the attack [1]. Fever may reach 40 °C (104 °F) and, especially in young children, may be the only manifestation [1]. Abdominal pain occurs in about 95% of patients and ranges from mild discomfort to frank peritonitis, and may be mistaken for acute appendicitis [1]. Arthralgia and arthritis affect 50% to 75% of patients, usually as monoarthritis of large joints (knee, ankle, hip, wrist); unlike rheumatoid arthritis, FMF arthritis is neither erosive nor deforming, although attacks may take several weeks to resolve [1]. Pleuritis, as a rule unilateral, occurs in 30% to 45% of patients [1]. Erysipelas-like erythema appears in 10% to 40%: raised, well-demarcated, warm and painful erythematous plaques on the dorsum of the foot, the ankle and the front of the leg, with local oedema and frequently ipsilateral arthritis; histologically there is a perivascular neutrophilic infiltrate without vasculitis [1].

Among less frequent manifestations, acute scrotal swelling affects 2% to 5% of boys, mainly in childhood and adolescence; it results from serositis of the tunica vaginalis, mimics testicular torsion or epididymitis, resolves in 24 to 72 hours without testicular damage or infertility, and Doppler ultrasound with preserved testicular flow helps to avoid surgery [1]. Pericarditis occurs in 1% to 5%, with retrosternal pain relieved by leaning forward, pericardial rub and diffuse ST-segment elevation with PR-segment depression; tamponade and constrictive pericarditis are rare [1]. European recommendations also recognise protracted febrile myalgia and exertional leg pain as manifestations specific to FMF, with specific therapeutic approaches [38, 62]. Chronic arthritis is rare but may require additional therapy [62]. In Japanese patients with onset after the age of 40 years, arthritis and myalgia predominate, with a lower frequency of exon 10 variants [91].

AA amyloidosis. AA amyloidosis is the most serious complication and the main cause of death in untreated FMF; it results from the deposition of fibrils derived from serum amyloid A protein (SAA), an acute-phase reactant produced in a sustained way by subclinical inflammation [1, 92]. It mainly affects the kidney (more than 90% of cases), presenting with proteinuria, nephrotic syndrome and renal failure, and may involve the gastrointestinal tract (malabsorption), the heart and the thyroid [1]. The risk is greater in males, in homozygotes for MEFV NM_000243.3:c.2080A>G p.(Met694Val), in patients with a family history of amyloidosis and when diagnosis is late; before colchicine, a frequency of about 13% was estimated [1, 93]. In the series of 374 patients with AA amyloidosis of various causes followed by Lachmann and colleagues, mortality, amyloid load and renal prognosis correlated with SAA concentration: the risk of death was 17.7 times higher with SAA ≥ 155 mg/L compared with SAA < 4 mg/L, and deposits regressed in 60% of patients with a median SAA below 10 mg/L [92].

Heterozygotes. Most heterozygotes are asymptomatic; those with symptoms generally have milder phenotypes, raised acute-phase reactants or a distinct PAAD [1]. About 25% of patients with a confirmed clinical diagnosis of FMF do not have two variants identified in MEFV [62].

Data from the French PNDS (2022). The HAS PNDS (French National Diagnosis and Care Protocol) for FMF, prepared by the reference centre for autoinflammatory diseases and inflammatory amyloidosis (CeReMAIA) with the FAI²R network, places the median age at onset at 4 years, with 10% of patients symptomatic before 1 year and most before 20 years [12]. Attacks last a median of 48 to 72 hours, but may be limited to a few hours or extend to 4 days in severe forms, and their frequency ranges from one per week to one or two per year [12]. Half of attacks are preceded by prodromes (fatigue, irritability, headache, myalgia, chills), a proportion at the upper limit of the 30% to 50% given by GeneReviews [1, 12]. Abdominal pain begins in the epigastrium, moves to the right iliac fossa and then becomes generalised, and the child lies in flexion or adopts a bent posture; chest pain, more frequent on the left, is accompanied by tachypnoea or a sensation of basal thoracic heaviness radiating to the shoulder; arthralgia affects, in decreasing order, the ankle, the knee and the hip [12]. In children under 1 year, fever may be apparently isolated, which delays diagnosis, whereas some adults do not feel the fever or have only a low-grade fever despite raised CRP [12].

The PNDS gives a frequency of 7% to 10% for ankle pseudo-erysipelas (series of 91 patients by Koné-Paut and colleagues), lower than the 10% to 40% in GeneReviews, and considers it the only pathognomonic skin sign of the disease; it predominates in children and adolescents, with a peak at 13–14 years, appears 24 to 48 hours after prolonged standing, is unilateral in each episode but usually affects both legs over time, regresses in a few days and requires no biopsy, which would show a neutrophilic dermatosis [1, 12]. Dependent vascular purpura, favoured by heat, fatigue and prolonged sitting, is another classic manifestation, and oral or bipolar aphthosis occurs in about 7% of patients, without specificity; perineal lesions should raise suspicion of hidradenitis suppurativa [12]. Inflammation of the tunica vaginalis affects 5% to 10% of boys in the PNDS (2% to 5% in GeneReviews) and is regarded as a marker of attack severity [1, 12]. Between attacks, about half of children do not become completely asymptomatic: they retain fatigue, especially after intense or closely spaced attacks, exertional myalgia localised to the calves, exertional plantar pain and transient ankle oedema that may extend up to the calves [12].

Elevation of CRP during the attack is mandatory for diagnosis and is usually accompanied by moderate neutrophilic leucocytosis and raised SAA, sometimes with a moderate increase in transaminases and bilirubin; outside attacks these markers normalise, but in 50% of untreated patients they only decrease, constituting occult inflammation that is itself a therapeutic target [12]. The PNDS describes four atypical presentations: the chronic inflammatory form, in patients with at least one p.Met694Val allele, without evident attacks but with a chronic pain syndrome, digestive discomfort, myalgia and CRP permanently above 15 mg/L; the rheumatological form, with lower-limb arthralgia, rarely arthritis, and significant biological inflammation, more frequently associated with spondyloarthritis; the form revealed by vasculitis, mainly localised vascular purpura or IgA vasculitis, and more rarely polyarteritis nodosa or Behçet's disease; and protracted febrile myalgia, with intense myalgia preventing mobilisation, purpura, abdominal pain and orchitis, which mimics polyarteritis nodosa and in which skin or muscle biopsy does not contribute to the diagnosis [12]. In adults, the disease may be revealed by sacroiliitis without HLA-B27, by ileitis without histological evidence of Crohn's disease, by an unexplained, prolonged or recurrent inflammatory syndrome, or by AA amyloidosis — nephrotic syndrome or renal failure sometimes already end-stage and, exceptionally, recognised only after kidney transplantation for nephropathy of undetermined cause —, as well as by amyloid goitre, chronic diarrhoea or hepatomegaly with cirrhosis [12].

In the case series cited by the PNDS, IgA vasculitis affects about 3% to 7% of patients with FMF and is complicated by acute intussusception in about 9% of affected children; polyarteritis nodosa, in about 1% to 1.5%, is not usually linked to hepatitis B virus, affects mainly men aged 20 to 40 years and presents in about half of cases with parenchymal infarction or perirenal haematoma, and should be sought in the presence of renal signs, arterial hypertension, central neurological signs or atypical skin lesions, such as subcutaneous nodules; the association with Behçet's disease remains uncertain [12]. Sacroiliitis occurs in 5% to 12% of patients with rheumatological manifestations, and FMF-associated spondyloarthritis is distinguished by the absence of HLA-B27, peripheral predominance over axial involvement, absence of uveitis, a balanced sex ratio and the frequency of enthesitis [12]. Symptomatic coxitis affects fewer than 2% of patients, but is severe in 73% of cases and may require one or two prostheses; it has been described only in p.Met694Val homozygotes and is investigated by computed tomography, magnetic resonance imaging or ultrasound [12]. Chronic liver disease includes non-alcoholic steatohepatitis and so-called cryptogenic cirrhosis, more frequent in p.Met694Val homozygotes; about 15 patients of the French adult reference centre developed severe liver disease, most already cirrhotic [12]. FMF does not increase infectious risk, and COVID-19 was severe only in patients with the usual risk factors or in transplanted patients with AA amyloidosis under immunosuppression, in whom the French centre observed excess mortality; Helicobacter pylori and Clostridioides difficile activate the pyrin inflammasome and may decompensate the disease [12].

3.2 CAPS — FCAS, Muckle-Wells and CINCA/NOMID spectrum

Familial cold autoinflammatory syndrome (FCAS, also familial cold urticaria). Episodes triggered by generalised exposure to cold, with maculopapular or urticarial rash, arthralgia, myalgia, fever, chills and conjunctivitis; late renal amyloidosis is rare [1, 8, 47].

Muckle-Wells syndrome (MWS). Chronic recurrent urticaria, arthralgia, progressive sensorineural hearing loss and reactive renal amyloidosis; the urticarial rash is in fact a mildly pruritic neutrophilic dermatitis, and symptoms are not necessarily precipitated by cold [1, 45, 47].

CINCA/NOMID. This is the severe end of the spectrum and presents from birth [5]. Bone Dysplasias lists as the main clinical findings neonatal-onset urticarial rash, inflammatory arthritis associated with periodic fever, prominent joints with limited mobility (particularly the knee), chronic meningitis, craniofacial dysmorphism (persistently open fontanelles, frontal bossing, prominent eyes), ocular findings (optic atrophy and uveitis), hepatosplenomegaly, lymphadenopathy and laboratory signs of inflammation [5]. The rash appears in the neonatal period and remains persistent and migratory; chronic neutrophilic meningitis may cause intellectual disability and deafness; visual acuity may decrease; joint manifestations begin in childhood and progress to physical disability in the absence of treatment [5].

Radiological findings in CINCA/NOMID. Osteocartilaginous overgrowth plays the main role in joint swelling and limitation, with a limited contribution from synovitis and effusion [5]. The characteristic radiological findings are epiphyseal overgrowth with irregular ossification, especially of the patellae and distal femoral epiphyses; metaphyseal radiolucencies interspersed with irregular «popcorn» calcifications, particularly in the distal femur; polyostotic and asymmetric epimetaphyseal changes, which may become symmetric in late stages; subtle periosteal reaction at the metadiaphyseal junction; and mild bowing of long bones [5]. Overgrowth and premature ossification of the patella, when present, are characteristic of the syndrome [5]. The series illustrated in the atlas show that at 2 years radiographs may be normal despite autoinflammatory symptoms, that metaphyseal radiolucencies appear at around 3 years, and that, after introduction of the IL-1 receptor antagonist, the metaphyseal lesions were partly replaced by bone and the epiphyses became regular [5].

Table sources: [1, 3, 5, 8, 14, 37, 47, 48].

Data from the French PNDS (2013). The PNDS (French National Diagnosis and Care Protocol) for CAPS, prepared by the reference centre for rare paediatric autoinflammatory diseases (CeRéMAI, now CeReMAIA), describes a continuum without validated definitions for the three forms, with FCAS-MWS and MWS-CINCA transitional cases; onset occurs before 1 year in most patients, FCAS has a mainly paroxysmal course, CINCA a chronic course and MWS an intermediate position, and intense chronic fatigue is common to all three [14]. In patients with an identified NLRP3 variant, general manifestations occurred in 42% to 81%, cutaneous in about 90%, articular and muscular in 89%, ocular in 67%, auditory in 74%, central nervous system in more than 90% and abdominal in 44% [14].

In FCAS, the rash usually appears at the end of the day, about 2 hours after exposure to cold (including air conditioning), lasts less than 24 hours, is not triggered by contact with an ice cube and appears as a rule in the perinatal period or before 10 years of age, accompanied by distal oedema, low-grade fever of less than 24 hours, chills, intense thirst and profuse sweating; histologically it is a neutrophilic dermatosis, unlike allergic urticaria [14]. In MWS, the rash lasts on average 1 to 3 days and is more apparent in the evening; fever generally lasts 2 to 3 days, but may extend to 2 to 3 weeks; sensorineural hearing loss affects high frequencies first and is often present by 5 years; headaches occur in the morning, and the neurological picture may include chronic aseptic neutrophilic meningitis, learning difficulties and demyelinating white matter lesions; ocular manifestations include episcleritis, uveitis and papilloedema; male sterility is frequent, there is growth and pubertal delay secondary to inflammation, and digital clubbing, band-like erythema on the backs of the hands and periungual erythema may occur [14]. The variants p.Arg260Trp and p.Val198Met may be associated with either FCAS or MWS, and different phenotypes coexist in the same family, whereas variants typical of FCAS have never been found in severe CINCA, and vice versa [14].

In CINCA, first described in France by Prieur in 1981, progressive cortico-subcortical cerebral atrophy with intellectual disability affects 50% of patients and epilepsy 25%, with episodes of diplegia or hemiplegia and rare demyelinating lesions; deforming arthropathy due to exuberant epiphyseal hypertrophy (mainly knees, but also elbows, wrists and ankles) occurs in 30% to 50% of patients with onset before 1 to 2 years; ocular involvement may progress to keratopathy, non-granulomatous anterior or posterior uveitis with chorioretinitis, retinal dystrophy or vasculitis, optic atrophy and blindness; facial dysmorphism (frontal bossing, depressed nasal root, macrocephaly and protrusion of the eyeballs), male sterility and primary or secondary amenorrhoea are frequent [14]. A family history is rare, variants are as a rule de novo and some patients have somatic mosaicism; according to the data gathered by the 2013 PNDS, life expectancy was generally reduced, with death of at least 20% of patients in childhood from infectious complications or amyloidosis and a high risk of amyloidosis in young adulthood [14]. Macrophage activation syndrome has not been described in CAPS, but the PNDS recommends surveillance by analogy with other autoinflammatory diseases [14].

3.3 TRAPS

TRAPS is characterised by inflammatory episodes that recur every four to six weeks and last between 5 and 25 days, triggered by stress, infections, trauma, hormonal changes or vaccination [3]. The median age at onset is 4.3 years, but onset may be late, especially with mild or somatic variants [3]. In the series of 158 patients from the Eurofever/EUROTRAPS registry and in the review by Cudrici and colleagues, the frequencies of the manifestations were as follows: fever 96%, abdominal pain 70%, arthralgia 69%, myalgia 69%, maculopapular or migratory rash 60%, conjunctivitis 37%, chest pain 33% and periorbital oedema 28% [3, 67, 94]. Migratory myalgia accompanies a rash that progresses distally along the limb during the attack and that is generally not pruritic; fasciitis has been described, and skin biopsies show non-specific perivascular infiltrates of lymphocytes and monocytes [3]. Periorbital oedema, in the context of the other manifestations, distinguishes TRAPS from the other periodic fevers [3]. Gastrointestinal manifestations (serositic pain, diarrhoea, constipation, vomiting, aseptic peritonitis and gastrointestinal bleeding) occur in about 70%; pericarditis in about 30%; lymphadenopathy in about 15%; and headache, seizures, pharyngitis and aphthous stomatitis have been described [3]. Acute-phase reactants may remain slightly raised between attacks [3]. AA amyloidosis is the most serious sequela; when it occurs, it presents with proteinuria and renal failure in 80% to 90% of cases, with intestinal, thyroid, myocardial, hepatic and splenic deposits being less frequent [3].

Data from the French PNDS (2018). The TRAPS PNDS (French National Diagnosis and Care Protocol) describes a ubiquitous disease, reported mainly in Caucasian populations but also in African Americans, Japanese and Mediterranean populations, with no sex difference, a median age at onset of 4 years (range 0.5 to 63 years) and similar symptoms in ancestors or descendants in two thirds of cases [15]. The attack lasts a median of 11 days; fever is present in most patients at least for the first 3 days, may be absent in adults, which makes measurement of inflammatory markers in blood necessary, and persists for more than 15 days in 25%; onset is abrupt with chills in 30%, and a quarter of patients identify a trigger (stress, fatigue, emotion, menstruation, physical exercise and, more rarely, vaccination) [15]. The median frequency is 7 attacks per year (2 to 12), about 10% of adults have a chronic form with daily symptoms, and untreated patients accumulate a median of about 70 symptomatic days per year [15]. Mucocutaneous manifestations affect 80%, with erythematous and oedematous, warm and painful plaques with ill-defined borders, which begin at the root of the limbs and migrate distally, more or less urticarial confluent lesions of the trunk and pseudo-erysipelas; arthritis is asymmetric and non-erosive, and tenosynovitis may occur [15]. Periorbital oedema, initially regarded as a cardinal sign, is reported in only 20% in the PNDS (28% in the Eurofever/EUROTRAPS registry), and cervical lymphadenopathy, less frequent in adults, may be associated with variants of uncertain pathogenicity [3, 15, 94]. Some cases present directly with AA amyloidosis, and questioning then reveals attacks considered minor by the patient, so TRAPS should be sought in unexplained AA amyloidosis; the PNDS estimates that about 10% of patients may develop amyloidosis, mainly with imperfect disease control, and that the residual risk under adequate follow-up and adherence is concentrated in structural cysteine variants [15].

3.4 MKD/HIDS (brief discussion)

MKD is an autoinflammatory disease with a chronic pro-inflammatory state of monocytes and episodes of fever lasting 3 to 7 days, recurring on average every 4 to 6 weeks and accompanied by abdominal pain, vomiting, diarrhoea, cervical lymphadenopathy, hepatosplenomegaly, arthralgia and rash; onset occurs mainly in the first year of life, and episodes are precipitated by vaccination, physical or emotional stress and minor trauma [6]. In mevalonic aciduria there are in addition developmental delay, ataxia, cerebellar atrophy, hypotonia, severe failure to thrive, dysmorphic features and early death [6]. Saudubray's textbook includes MKD in the differential diagnosis of recurrent abdominal pain with fever, rash, arthralgia and an inflammatory syndrome, which may mimic FMF, and of multisystem inflammatory diseases of infantile onset, alongside NLRP3 mutations [95].

The French MKD PNDS (French National Diagnosis and Care Protocol) (2015) quantifies the clinical picture: symptoms begin in the first year in 90% of patients, sometimes in the neonatal period (mistaken for maternal-fetal infection); attacks recur every 2 to every 8 weeks, last 3 to 6 days, are precipitated by stress, vaccines or minor trauma and combine high fever with chills (80%), painful cervical lymphadenopathy (95%), abdominal pain (70%) with splenomegaly, vomiting (55%), diarrhoea (80%), arthralgia (80%) or arthritis of large joints (70%), polymorphic rash (80%), aphthae (50%) and headache (50%); the frequency, as a rule more than 12 attacks per year in the first 10 years, decreases with age [13]. Residual enzyme activity is 1–12% in the HIDS form, with moderate urinary excretion of mevalonic acid (often below 30 mmol/mol creatinine) only during attacks, because the enzyme is temperature-sensitive, and below 1% in mevalonic aciduria, with permanent excretion of 1000 to 56,000 mmol/mol; inflammation results mainly from the transient deficiency of geranylgeranylated proteins, with increased IL-1β secretion, and mevalonate accumulation is toxic to the cerebellum and the lens [13]. In mevalonic aciduria there are in addition a triangular face with frontal bossing, stable psychomotor delay, epilepsy, progressive ataxia, hypotonia, hearing loss and visual loss (cataract, uveitis, optic atrophy, retinitis pigmentosa), and severe forms die before 2 years of age from liver failure, macrophage activation syndrome or severe infection without adequate treatment [13]. In a French series of 50 patients with HIDS, severe bacterial infections, mainly pneumococcal, were described, and the PNDS lists as severity criteria attacks every 2 weeks, severe infections, hepatic complications and macrophage activation, mucosanguineous diarrhoea (colitis), neurological and ophthalmological signs, glomerulonephritis or amyloidosis (rare), growth delay, persistent inflammation between attacks with corticosteroid dependence and intense permanent mevalonaturia; in adults, the inflammatory phenotype tends to attenuate and neurological and sensory disability dominate in severe forms [13]. According to the Steichen rule cited in the PNDS, MKD is unlikely if symptoms began after the age of 5 years or if attacks last more than 15 days without joint pain [13].

3.5 NLRP1-associated diseases

Multiple self-healing palmoplantar carcinoma (MSPC). In the five-generation Tunisian family described by Mamaï and colleagues, with 27 affected individuals and autosomal dominant transmission, the mean age at onset in the 15 patients studied was 8.8 years (range 1 to 25 years) [55]. The disease begins with ulcerated and nodular tumours on the plantar skin, 5 to 50 mm in diameter and 8 to 12 lesions per patient, which grow for about three months and regress after six months, leaving atrophic scars; lesions arise at pressure and friction points and not in sun-exposed areas [55]. Histology of a plantar lesion showed marked hyperkeratosis over an endophytic squamoproliferative tumour, with keratin cysts, microabscesses and a dense inflammatory infiltrate, and near absence of the granular layer, an appearance suggestive of low-grade verrucous carcinoma [55]. Eighty per cent of patients developed conjunctival lesions in the second decade, compatible with conjunctival keratoacanthomas [55]. Five of 15 patients with available records (33%) developed malignant tumours: lung, head and neck, squamous cell carcinoma of the nose and squamous cell carcinoma with bone metastasis; one patient with carcinoma of the calcaneus required bilateral lower-limb amputation [55]. The distinctive feature compared with other multiple keratoacanthoma syndromes is the location in epithelia without hair follicles (palms, soles, conjunctiva and cornea), and most patients have conjunctival or corneal lesions; associations with hidradenitis suppurativa and dyshidrosis have been described in some patients [19]. The corneal intraepithelial dyskeratosis described by Soler and colleagues, with complete bilateral corneal opacification in a 6-year-old proband, palmoplantar hyperkeratosis and laryngeal dyskeratosis, belongs to the same spectrum [16, 54]. FKLC, described in the same work as an allelic disease, was associated with an in-frame deletion in the LRR domain [16].

Autoinflammation with arthritis and dyskeratosis (AIADK). The three patients of the original description (two cousins born to consanguineous parents and a Dutch girl) had diffuse cutaneous dyskeratosis, autoinflammation, autoimmune manifestations, arthritis and increased transitional B lymphocytes; they were identified in a search for genes associated with systemic juvenile idiopathic arthritis [17]. Herlin and colleagues extended the phenotype to inflammatory corneal intraepithelial dyskeratosis, mucosal inflammation, dental anomalies and eczema [75]. In a 6-year-old Peruvian child with de novo p.(Pro1214Arg), the dominant picture was confluent hyperkeratotic plaques that drained purulent material and scarred [56]. In a Turkish boy seen at 17 years, with three rare NLRP1 variants (two of paternal origin and one, NM_033004.4:c.209C>A p.(Ala70Asp), of maternal origin), pustules, ulcers and crusts began at 40 days of life, accompanied by scarring alopecia, microcytic anaemia (haemoglobin 10 g/dL), serum amyloid A of 107 mg/L, CRP of 39 mg/L, a decrease in class-switched memory B lymphocytes and hypergammaglobulinaemia; the patient had previously been diagnosed with atopic dermatitis and psoriasis [96]. In a case with MSPC/AIADK overlap, a child with p.(Ala54Thr) progressed from neonatal hyperkeratotic dermatitis to bilateral keratoconjunctivitis at 18 months, corneal opacification with near-complete loss of vision at 5 years and, at 7 years, an inflammatory crisis with interstitial pneumonitis and respiratory distress syndrome [76]. A paediatric case treated with canakinumab and a PAPASH-like phenotype (pyoderma gangrenosum, acne, hidradenitis suppurativa and pyogenic arthritis) with papulopustular folliculitis in a heterozygous carrier have also been published [97, 98].

Juvenile-onset recurrent respiratory papillomatosis (JRRP). JRRP is characterised by recurrent growth of papillomas in the upper airways, associated with human papillomavirus (HPV) types 6 and 11, and only a small fraction of exposed children develop the disease [18]. The two siblings homozygous for p.(Thr755Asn) had a syndromic form, with mild dermatological changes and raised inflammasome-dependent cytokines in serum [18]. This phenotype suggests an interaction between NLRP1 activation in the respiratory epithelium and HPV infection, with a risk of respiratory distress and airway obstruction [74].

Systemic phenotypes in adults. In a retrospective Turkish cohort of 33 adults with variants in NLR genes other than NLRP3 (2020–2026), ten had NLRP1 variants, which were frequently associated with FMF-like recurrent fever and serositis and, sometimes, with autoimmune manifestations; across the cohort, about one third responded to colchicine and another third required IL-1 blockade [99]. The series is descriptive, single-centre, includes variants of uncertain significance and coexisting MEFV variants, and does not demonstrate causality [99].

The available information comes from family reports and isolated cases, almost always already treated, so there are no natural history data with defined denominators beyond the Tunisian MSPC family [55].

3.6 Haploinsufficiency of A20

Haploinsufficiency of A20 is a systemic immune dysregulation disease that combines, in variable proportions, autoinflammation, autoimmunity, immunodeficiency, atopy and lymphoproliferation; it does not have stereotyped attacks like the classic periodic fevers, and its course is one of relapses and remissions without defined periodicity [22, 26]. The median age at onset lies between 2.8 and 4 years in the largest cohorts, with one extreme in the first week of life and another at 39 years; about 60% of Japanese patients had onset before 5 years, and the delay to genetic testing was, at the median, 7 years in the international cohort and 9.7 years in the French paediatric cohort [22, 24, 25, 100]. More than 180 patients from 97 families had been described when the GeneReviews chapter was published in December 2024, and the current count approaches 200 cases associated with about 100 distinct pathogenic variants [22, 26].

Recurrent, painful mucosal ulceration is the most frequent manifestation and occurs in more than 70% of patients. Oral ulcers (about 68 to 78% depending on the cohort) are more common than genital ulcers (32 to 42%), and genital ulcers without oral ulcers are rare; both may scar, and there are also perianal, cutaneous and gastrointestinal ulcers [22, 24, 25]. Recurrent fever, with episodes of three to seven days without clear periodicity, affects 49 to 85% of patients, and erythrocyte sedimentation rate and C-reactive protein are not always raised; rarely, fever progresses to cytokine storm or secondary haemophagocytic lymphohistiocytosis [22, 25]. Skin involvement (42 to 50%) includes pustular rash, folliculitis, acne, dermal abscesses, vasculitic purpura, urticaria, lupus-like macular rash, psoriasis, erythema nodosum and immunoglobulin A vasculitis; up to 40% develop an eczematoid dermatitis that does not necessarily follow systemic inflammatory activity [22].

Gastrointestinal disease is as frequent as skin disease and sometimes dominant: 39 to 76% of patients, with dull abdominal pain from serositis, gastrointestinal ulcers, small bowel inflammation or colitis, up to severe inflammation with a risk of perforation [22, 25]. In the international cohort, 58.6% had gastrointestinal symptoms and 27.7% documented intestinal ulcers, the latter significantly more frequent in children and in the Chinese cohort (p = 0.002 and p < 0.0001) [24]. The Japanese survey, which performed endoscopy in 35 patients, found ulcers of the colon in 11 of 32, of the ileocaecal region in 7 of 32 and of the terminal ileum in 4 of 32, with discontinuous lesions in most and diffuse lesions with loss of the vascular pattern in three patients, mimicking ulcerative colitis; histology varied between neutrophilic infiltrates and lymphoplasmacytic infiltrates, with granulomas in four of 23 biopsies [25]. Two patients required enterectomy, one for perforation, and one endoscopic dilatation for stricture [25]. Arthralgia and arthritis occur in 31 to 50% of patients, generally as non-erosive inflammatory polyarthritis with synovitis, symmetric or asymmetric, which may involve the axial skeleton; in a minority it is erosive and mimics rheumatoid arthritis or psoriatic arthritis [22, 24].

Autoimmunity is an integral part of the picture and not an incidental comorbidity: more than 70% of patients develop autoantibodies, often fluctuating and sometimes at high titre (rheumatoid factor, antinuclear, antiphospholipid, antithyroid and antiplatelet antibodies) [22, 26]. Autoimmune thyroiditis affects about 14 to 18% of patients and type 1 diabetes mellitus about 2 to 4%; systemic lupus erythematosus was diagnosed in 6 to 9% and membranous nephropathy may mimic class V lupus nephritis, with a «full house» immunofluorescence pattern [22, 25]. Immune cytopenias range from immune thrombocytopenia and autoimmune haemolytic anaemia to autoimmune neutropenia, lymphopenia and pancytopenia, and were recorded in 6 to 56.6% of patients depending on the cohort and the criteria used [22, 24]. Liver disease, probably underdiagnosed, occurs in 10 to 29% and ranges from hepatomegaly and raised transaminases to severe hepatitis that, without treatment, progresses to cirrhosis and liver failure; in two of the three Japanese patients biopsied, histology showed interface hepatitis with a plasma cell infiltrate, compatible with autoimmune hepatitis [22, 24, 25].

Neurological involvement affects 10 to 18.5% of patients and includes vasculitis or vasculopathy of the central nervous system, which manifests as severe headache and cognitive changes and, in some patients, as transient ischaemic attacks, aseptic meningitis, mononeuritis multiplex, chronic inflammatory demyelinating polyradiculoneuropathy and peripheral neuropathy [22]. In the Japanese series, five patients had central nervous system involvement: two with aseptic meningitis (one with raised IL-6 in cerebrospinal fluid), one with acute encephalopathy with seizures, one with dysarthria and severe seizures with lacunar infarction and leucoencephalopathy on magnetic resonance imaging, and one with diplopia and hiccups with white matter lesions [25]. The Italian cohort drew attention to neuropsychiatric symptoms, present in 41% of the 17 patients studied and significantly more prevalent over a lifetime in patients with onset before 5 years (p = 0.004), unlike arthritis, more common with late onset [101]. Vasculopathy, including coronary vasculitis and arterial aneurysms, has been described in 4 to 17% of patients, and ocular inflammation (treatment-resistant anterior uveitis, scleritis, episcleritis, retinal vasculitis with chorioretinal scars and macular fibrosis, as well as dry eye) in 6 to 17%; uveitis was significantly less frequent in children and in the Chinese cohort than in adults and in the North American cohort (p = 0.001 and p < 0.0001) [22, 24, 25].

The immunodeficiency component is the least recognised. About 8 to 9% of patients have recurrent upper and lower respiratory infections in published reviews, but the international cohort recorded recurrent infections in 35.5%, and approximately 25% of patients at the Pittsburgh centre have some immune deficit; 5 to 8% have humoral deficiency with low IgG, IgA or IgM, decreased response to diphtheria and tetanus vaccines and, in some cases, a previous diagnosis of common variable immunodeficiency [22, 24, 26]. A presentation with combined immunodeficiency has been described, in a 27-year-old man of Ashkenazi ancestry with hypogammaglobulinaemia, low B and CD4 T lymphocytes, decreased regulatory cells and reduced, non-functional NK cells [31]. Lymphoproliferation presents mainly as lymphadenopathy (15 to 32%); autoimmune lymphoproliferative syndrome-like disease, with expansion of double-negative T lymphocytes, and lymphoma are rare (about 1 to 2%) and their causal relationship with haploinsufficiency of A20 has not been established [22, 24]. Hierarchical clustering analysis of the international cohort separated two large clusters — a predominantly autoinflammatory phenotype and a predominantly autoimmune phenotype —, the former being more common in children and in the Chinese cohort (p = 0.033 and p = 0.003), which supports the notion of age-dependent evolution: autoinflammatory manifestations predominate in early childhood and autoimmune manifestations in adolescence and adulthood [24, 101]. Other phenotypes described in association with germline TNFAIP3 variants, whose link to the disease has not been clarified, include premature ovarian insufficiency, dental anomalies and atrophic gastritis [22].

3.7 Haploinsufficiency of RelA

Haploinsufficiency of RelA, designated RELA-associated inflammatory disease, has chronic mucocutaneous ulceration as its clinical core: recurrent oral and genital aphthous ulcers, frequently severe, accompanied by rash, joint inflammation and fever [27, 28]. In the review of 43 patients published up to 2026, oral ulcers were present in 60% (26 patients), of whom 14 also had genital ulcers; recurrent fever in 34%, rash in 32%, musculoskeletal manifestations in 30%, abdominal symptoms in 20%, and central nervous system and ocular involvement in 13% each [29]. Cardiovascular (pericarditis) and renal (lupus nephritis) manifestations occurred in 5%, in patients with a lupus phenotype [29].

The mean age at diagnosis was 5.97 years (range 0 to 33 years), 23% of patients were diagnosed before the first year of life and only three in adulthood [29]. The rash is polymorphic: acneiform, pustular, urticarial, vesiculobullous, erythema nodosum, folliculitis, ulcers, vasculitis, atopic dermatitis and malar rash [29]. Abdominal symptoms include pain, diarrhoea (six of the nine patients with digestive involvement) and vomiting, with colitis, oesophagitis and colonic ulcers documented by endoscopy in several patients; one had peritonitis and mesenteric lymphadenitis, and another presented with a perianal abscess and diarrhoea from the first month of life [29]. Neurological involvement was limited, in this case series, to headache in four patients, cognitive confusion in one and aseptic meningitis in another [29]. Ocular manifestations were conjunctivitis in four patients, episcleritis in one and recurrent optic neuritis in one; the latter occurred in a woman with anti-aquaporin-4 antibodies and an initial diagnosis of neuromyelitis optica [29]. Increased intraocular pressure with optic nerve thinning has been described in patients from the Eurasian family [31].

Atypical manifestations define two groups at the margin of the Behçet-like phenotype. The first is that of dominant-negative variants, in which systemic autoinflammation and autoimmunity with a type I interferon signature combine: painful subcutaneous nodules, growth delay, myalgia, stomatitis, recurrent pancreatitis, aortic regurgitation, hypothyroidism, macrocheilitis, diffuse xerosis and autoimmune cytopenias (neutropenia, thrombocytopenia) [29, 58]. In this group, two patients had short stature and delayed puberty and two had recurrent bacterial and fungal infections [29]. The second is that of autoimmune lymphoproliferative-like disease, described in a patient with splenomegaly, lymphadenopathy, thrombocytopenia, anaemia and neutropenia from 5 years of age, diagnosed with autoimmune lymphoproliferative syndrome before genetic testing [29]. An infant with a missense variant had sudden unexplained death at seven days of life, with radiological and histopathological findings of high bone mass; hyperostosis was not found in any other described patient, and the proposed explanation is that reduced NF-κB activity decreases osteoclast survival and, through that route, bone resorption [29].

Two aspects distinguish this entity from haploinsufficiency of A20. The first is the rarity of recurrent infections: only three of the 43 patients had them, although the definitive ClinGen assertion is filed under the designation combined immunodeficiency, so that label should not be read as predicting an infection-prone phenotype [29]. The second is the lower burden of autoimmunity: in the GeneReviews comparison, RELA-associated disease is characterised by oral and genital ulcers without pathogenic autoantibodies or significant autoimmunity, unlike haploinsufficiency of A20 — a generalisation that holds for the case series as a whole but not for the dominant-negative subgroup, in which there are lupus and autoimmune cytopenias [22, 58]. Acute-phase reactants were raised in about one third of patients, and complement C4 was low in two; antinuclear antibody was tested in 19 patients and was positive in seven, three of whom had a diagnosis of lupus [29]. HLA-B*51 was tested in six patients and was negative in all, which reinforces the independence of this entity from polygenic Behçet's disease [29].

3.8 CARD8-associated inflammatory bowel disease

The known phenotype rests on one family with three affected individuals, whose clinical records appear in the supplementary material of the original publication [33]. The proband, a 16-year-old boy, was admitted for abdominal pain and bloody diarrhoea with more than 2 litres of liquid stool per day, of two months' duration; endoscopy showed macroscopic pancolitis and, on histology, oesophagitis, gastritis, duodenitis and terminal ileitis [33]. The disease was refractory to high-dose glucocorticoids, aminosalicylates, azathioprine, infliximab (increased up to 10 mg/kg every four weeks) and two induction doses of vedolizumab, and was complicated by protein-losing enteropathy (serum albumin 1.5–2.5 g/dL), requiring albumin infusions and parenteral nutrition [33]. Initial biopsies showed a severe mononuclear infiltrate, loss of the villous pattern and epithelial cell apoptosis, a picture similar to graft-versus-host disease; after clinical improvement, histology became that of Crohn's disease, with poorly formed granulomas and giant cells in the terminal ileum [33]. The patient developed avascular necrosis of the hip, attributed to glucocorticoids [33].

The proband's mother presented, at around 50 years of age, with abdominal pain, weight loss and diarrhoea, with circumferential thickening of an ileal loop on computed tomography, and responded to prednisone, followed by budesonide for one year and by mesalazine [33]. The maternal aunt developed the disease at 21 years, with proximal and distal ileal strictures without colonic involvement, granulomas in the surgical specimen, and three intestinal resections over about 16 years, without response to aminosalicylates, prednisone or mercaptopurine; she did not receive TNF inhibitors because of a history of treated latent tuberculosis [33]. Expressivity was therefore variable with regard to age at onset (adolescence, third and sixth decades), extent (pancolitis with upper digestive involvement in the proband, stricturing ileal disease in the aunt) and severity, with the ileum affected in all three [33]. The publication describes neither recurrent fever nor extraintestinal manifestations in the three affected individuals, and the aunt had none [33].

Outside this family, there are isolated descriptions. Gennaro and colleagues reported a 7-year-old girl with right lower-limb pain, intermittent rash, active arthritis, sacroiliitis on imaging and raised inflammatory markers, carrying a CARD8 variant of uncertain significance; before adalimumab was started, fever, vomiting, diarrhoea and haematochezia appeared, with faecal calprotectin above 8000 µg/g and colonoscopy compatible with Crohn's disease [102]. The publication does not specify the variant, which prevents comparison of the case with the 2018 family [102]. In carriers of the frequent CARD8-FS variant with PFAPA, the Swiss cohort described more symptoms outside attacks and more aphthous stomatitis than in patients without the variant, and a Japanese study described three children with PFAPA and Kawasaki disease, all carriers, who had inherited it from their mothers, without the mothers having the disease [59, 89]. The sources consulted do not allow estimation of penetrance or of the untreated natural history of the Mendelian disease.

4. Clinical Recognition and Warning Signs

Recognition of hereditary periodic fevers rests on demonstrating a pattern: stereotyped episodes of fever with inflammation of serosae, skin, joints or eyes, elevation of acute-phase reactants during attacks and (complete or partial) normalisation between them, over at least six months, after infection, neoplasia and autoimmune disease have been excluded [37, 93]. Episode duration is the most informative clinical datum: one to three days suggests FMF, three to seven days suggests MKD, more than seven days suggests TRAPS, and hours after exposure to cold suggests FCAS [1, 3, 6, 37]. Response to colchicine is considered a diagnostic hallmark of FMF [1].

Warning signs that should prompt referral to a centre with experience in autoinflammatory diseases are: recurrent episodes of aseptic peritonitis or negative laparotomies; recurrent unilateral pleuritis; recurrent monoarthritis of large joints with spontaneous resolution; erysipelas-like erythema of the ankles; recurrent acute scrotal swelling with preserved Doppler flow; proteinuria in a patient with a history of recurrent fevers; Turkish, Armenian, Arab or non-Ashkenazi Jewish ancestry with parental consanguinity [1]; urticarial rash present from birth, chronic aseptic meningitis, sensorineural hearing loss or uveitis in a child with persistent inflammation [5, 8]; febrile attacks of more than one week with migratory myalgia, rash progressing distally and periorbital oedema [3]; vaccine-triggered fevers in infancy with cervical lymphadenopathy and aphthous stomatitis [6, 37]. In adults with a late-onset CAPS picture, a negative germline test does not exclude the disease, and somatic mosaicism should be sought by deep sequencing [66]. FMF is increasingly diagnosed in populations without a tradition of the disease, through migration and greater clinical awareness, as illustrated by the cases from Romania and the unexpectedly high prevalence in Slovakia [1, 63, 103].

The French PNDS (French National Diagnosis and Care Protocol) documents add practical rules for suspicion. In FMF, the hypothesis should only be raised in a child of Mediterranean ancestry (at least one grandparent on each side) and after at least three stereotyped episodes; since the patient is as a rule seen outside an attack, history-taking, review of admission reports and of tests taken during attacks, the child health record and the family tree are decisive [12]. Outside at-risk populations, a pathogenic MEFV variant is almost never found, even with a suggestive phenotype, so the grandparents' origin should always be asked [12]. For CAPS, the PNDS brings together six orienting elements: recurrent manifestations with spontaneous, partial or complete resolution (low-grade fever or chills with a circadian rhythm, urticarial rash more visible in the evening, arthralgia, myalgia, arthritis, conjunctivitis, uveitis, morning headache); in severe forms, intellectual disability, progressive deafness and blindness, deforming arthropathy, amyloidosis presenting mainly in the kidney, dysmorphism and growth and pubertal delay; first signs before 1 year in MWS, CINCA and most FCAS; triggering by cold in FCAS and in some cases of MWS; familial aggregation in most FCAS and MWS; and very high CRP during attacks and frequently also outside them, because flares are generally daily [14]. In TRAPS, the indication for genetic testing may be supported by the probability score of the Gaslini Institute in Genoa, available online from PRINTO, which combines age at onset with the frequency of five clinical items and, for TRAPS, requires at least one attack lasting 7 or more days; TRAPS and FMF should be sought in any AA amyloidosis without an apparent cause [12, 15].

In NLRP1-associated diseases, the signs that should raise suspicion are keratoacanthoma-like lesions on the palms, soles or conjunctiva, especially if multiple, self-healing and with onset in childhood; corneal dyskeratosis or opacification without a demonstrated infectious cause; hyperkeratotic, pustular or ulcerated dermatosis from the neonatal period, refractory to treatments for atopic dermatitis and psoriasis, with raised acute-phase reactants; arthritis with cutaneous dyskeratosis; and juvenile respiratory papillomatosis with skin changes or parental consanguinity [17–19, 54, 55, 96]. The inflammatory crisis with pneumonitis and respiratory failure described in one of these patients constitutes an emergency sign [76].

In Behçet-like autoinflammatory diseases of the canonical NF-κB pathway, the central warning sign is recurrent orogenital ulceration beginning in childhood, especially before 10 years of age, with or without fever; polygenic Behçet's disease usually begins in adulthood and is generally limited to the mucosae, so a Behçet-like picture in a child should be considered monogenic until proven otherwise [26, 31]. The following should prompt genetic testing: a family history compatible with autosomal dominant transmission of immune dysregulation, even with different manifestations among members; Behçet's disease, inflammatory bowel disease, lupus, juvenile idiopathic arthritis or PFAPA syndrome with an unusually severe or refractory course; accumulation over the years of apparently unrelated immunological diagnoses; unexplained immune cytopenias; and early-onset colitis or intestinal ulcers [26, 29, 100]. In the French paediatric cohort, the most common initial manifestations were oral ulcers and fever (64.7% each), abdominal pain (47.1%) and arthralgia (35.3%), and genital ulcers, present in only 17.6% at onset, reached 52.9% during follow-up: the absence of genital ulcers at the first assessment does not rule out the diagnosis [100]. The authors of that cohort emphasise that haploinsufficiency of A20 should be suspected in children with fever and gastrointestinal inflammation even without oral or genital ulcers, early-onset colitis, the characteristic morphology of the mucosal ulcers and a positive family history being particularly suggestive [100]. A negative family history of disease does not exclude the diagnosis, given de novo variants, parental somatic mosaicism and the variable expressivity that makes carriers with subclinical disease appear healthy [22, 25]. Among patients with a RELA variant, almost half had previously received a diagnosis of a more common rheumatological disease, generally Behçet's disease, which makes this entity a systematically missed monogenic mimic [28]. In haploinsufficiency of A20 there are also specific emergency signs: fever progressing to cytokine storm or haemophagocytic lymphohistiocytosis, abdominal pain with signs of intestinal perforation, severe headache with cognitive changes or a focal deficit suggesting central nervous system vasculitis, and severe hepatitis with liver failure [22, 26].

In CARD8-associated inflammatory bowel disease, the context of suspicion is Crohn's disease with vertical transmission over more than one generation, especially when it is refractory to TNF inhibitors, when initial histology resembles graft-versus-host disease, with marked epithelial apoptosis, or when serum IL-1β is raised [33]. Age at onset does not exclude the hypothesis, because in the described family it ranged from adolescence to the sixth decade [33]. The emergency signs are those of severe Crohn's disease: large-volume bloody diarrhoea, protein-losing enteropathy with hypoalbuminaemia, obstruction from stricture and perforation [33, 104].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 General principles

European recommendations state that FMF is a clinical diagnosis that genetic testing may support but not exclude [38, 62]. GeneReviews establishes the diagnosis in a proband with suggestive clinical findings and biallelic pathogenic variants in MEFV; the identification of two variants of uncertain significance, or of one pathogenic variant and one of uncertain significance, neither establishes nor excludes the diagnosis [1]. Sequencing of MEFV detects about 100% of known pathogenic variants, all missense or small single amino acid deletions in the coding region, which are captured by the exome; deletion and duplication analysis has no yield [1]. In patients with a non-specific picture, a periodic fever panel including MEFV, MVK, TNFRSF1A, NLRP3 and other genes of the differential diagnosis is preferable [1, 64]. In TRAPS, sequencing of TNFRSF1A detects a pathogenic variant in more than 99% of probands, almost exclusively missense variants of the extracellular domain [3]. In CAPS, Sanger sequencing may miss somatic mosaicism, which requires deep sequencing (preferably in myeloid cells) [64, 66]. In MKD, urinary mevalonate by gas chromatography-mass spectrometry is very high in mevalonic aciduria (1 to 56 mol/mol creatinine) but only moderately raised in HIDS (0.005 to 0.040 mol/mol creatinine, even during fever), so the reference tests remain enzyme activity in leucocytes or fibroblasts and sequencing of MVK [6]. The 2024 revision of the SHARE recommendations advises against IgD measurement because of its negligible diagnostic value, and reserves determination of enzyme activity for severe phenotypes in which the result would change management [11].

5.2 Tel-Hashomer criteria (Livneh 1997)

The Tel-Hashomer criteria were constructed from 27 features evaluated in 105 patients with FMF and 106 controls with recurrent episodes of pain in typical locations, using a model of major, minor and supportive criteria [42]. The conservative set requires one major criterion, or two minor, or one minor with five supportive; the simplified set requires one major criterion or two minor; both achieved sensitivity above 95% and specificity above 97% [42]. Major criteria correspond to typical attacks (fever with generalised peritonitis, unilateral pleuritis or pericarditis, monoarthritis, or isolated fever), minor criteria include incomplete attacks and a favourable response to colchicine, and supportive criteria include data such as family history, ethnic origin and exertional leg pain [42, 93]. In the Turkish paediatric population, the Tel-Hashomer criteria showed a sensitivity of 98.8% but a specificity of only 54.6% [105].

5.3 Yalçınkaya-Özen paediatric criteria (2009)

In a study of 170 children with FMF and variants on both alleles and 141 controls with fever and similar presentations, logistic regression selected five criteria: fever, abdominal pain, chest pain, arthritis and a family history of FMF; the presence of two or more of these five criteria diagnosed FMF with a sensitivity of 86.5% and a specificity of 93.6% [105]. For the episode-related criteria, the operational definition requires attacks of 6 to 72 hours and at least three episodes [93].

5.4 Eurofever/PRINTO classification criteria (2019)

The Eurofever group and PRINTO (Paediatric Rheumatology International Trials Organisation) developed evidence-based classification criteria for the four hereditary periodic fevers and for PFAPA syndrome, with a clinical-genetic version and a clinical-only version for each disease [37]. The four sets achieved a sensitivity of 0.94 to 1 and a specificity of 0.95 to 1, and validation in an independent set of 1,018 patients showed accuracy between 0.81 and 0.98 [37]. They are classification criteria, designed for patients with recurrent fevers for at least six months and raised inflammatory markers, after confounding factors have been excluded [37, 93].

Table sources: [3, 37, 63, 93].

5.5 CAPS diagnostic criteria (Kuemmerle-Deschner 2017)

The CAPS diagnostic criteria were developed by an international team of 16 experts, who reduced 33 typical items to 14 and tested them in 284 cases and 837 controls [8]. The best model requires raised inflammatory markers (C-reactive protein or SAA) and at least two of six typical symptoms: urticarial rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81% and specificity 94%, with good performance in all subtypes and regardless of NLRP3 genotype [8]. Initial assessment includes audiometry, ophthalmological examination, lumbar puncture if chronic aseptic meningitis is suspected and skeletal imaging in CINCA/NOMID [5, 8].

5.6 Laboratory assessment and algorithm

During attacks there is elevation of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and SAA, leucocytosis (in TRAPS typically 9,000 to 12,000/mm³ with neutrophils between 7,000 and 9,000/mm³) and thrombocytosis; SAA may reach very high values in TRAPS [1, 3]. Measurement of acute-phase reactants should be repeated outside attacks to document normalisation and detect subclinical inflammation [1]. There is no confirmatory biochemical test for FMF [1].

5.7 Limitations of genetic tests and report content

Coverage and sample type. In FMF and TRAPS, sequencing of the coding regions detects virtually all known variants, and large deletions or duplications are not expected, consistent with gain-of-function or misfolding mechanisms [1, 3]. The proportion of detectable variants is not, however, equivalent to clinical sensitivity: about a quarter of patients with clinically confirmed FMF have only one variant identified, and the diagnosis remains clinical [1, 62]. In CAPS, the main limitation is somatic mosaicism: Sanger sequencing does not reliably detect low allele fractions, and testing should use deep sequencing, ideally in myeloid cells, especially in neonatal disease without a germline variant and in adult-onset disease [48, 64, 66]. In MKD, a result with variants of uncertain significance should be complemented by urinary mevalonic acid during an attack and, when it changes management, by enzyme activity [6, 11]. Periodic fever panels should declare the genes included, the minimum depth of coverage and the mosaicism detection threshold [64].

Report content. The report should state the gene, the transcript with version — MANE Select transcripts: MEFV NM_000243.3, NLRP3 NM_001243133.2, TNFRSF1A NM_001065.4 and MVK NM_000431.4 [106] —, HGVS nomenclature at the DNA and protein levels, zygosity and, in FMF and MKD, the phase of the variants (in trans or in cis, which requires parental testing), the ACMG/AMP classification and the technical limitations [64, 107]. In CAPS, the classic variant R260W is also designated R262W depending on the transcript used, and the ClinVar record of the substitution c.778C>T on the MANE transcript shows a protein annotation (p.Arg260Ter) discordant with the classic designation, whereas another record annotates p.Arg260Trp for c.778_780delinsTGG; given these discrepancies, the report should state the transcript and the DNA-level change, and not only the abbreviated protein designation [108]; in TRAPS, by contrast, the old numbering subtracts the 29 amino acids of the signal peptide (R92Q corresponds to p.Arg121Gln), so both designations should be given when the reference literature uses the old one [3, 108]. In MKD, the hypomorphic allele p.Val377Ile corresponds to NM_000431.4:c.1129G>A, classified in ClinVar as pathogenic/likely pathogenic [108]. For FMF, the Infevers database and the ACMG/AMP classification may diverge, as illustrated by the p.Lys695Arg variant in the Slovak cohort [63].

Variants of uncertain significance and penetrance. Response to colchicine or to IL-1 blockade does not reclassify a variant of uncertain significance as pathogenic, because these therapies are effective in inflammatory disease of various causes; likewise, partial segregation in a family with frequent variants (MEFV NM_000243.3:c.442G>C p.(Glu148Gln)) or low-penetrance variants (TNFRSF1A NM_001065.4:c.362G>A p.(Arg121Gln)) does not demonstrate causality and should be treated as research [1, 3, 107]. In the Eurofever/PRINTO criteria, the distinction between confirmatory and non-confirmatory genotype formalises this uncertainty, and the diagnosis of patients with a non-confirmatory genotype rests on the clinical items [37].

5.8 Diagnosis of NLRP1-associated diseases

There are no validated diagnostic or classification criteria for NLRP1-associated diseases; diagnosis rests on the combination of the epithelial phenotype with the identification of a gain-of-function variant [19, 56]. In the presence of multiple keratoacanthomas, Dobre and colleagues propose a six-step algorithm that begins with biopsy to confirm keratoacanthoma and history-taking to exclude acquired causes (drugs, ultraviolet radiation, immunosuppression), followed by assessment of lesion location, extracutaneous findings and family history and, finally, targeted genetic testing [19]. Because the palmoplantar lesions of MSPC are treated in the early stages as common warts, histology remains necessary, but definitive diagnosis requires characterisation of the NLRP1 variant [19]. Assessment includes slit-lamp ophthalmological examination, laryngoscopy when there is dysphonia or suspected papillomatosis, CRP, serum amyloid A and full blood count, and B-lymphocyte immunophenotyping, which showed increased transitional B lymphocytes in the original AIADK description and decreased class-switched memory B lymphocytes in two later reports [17, 76, 96]. Serum IL-18 and caspase-1 were raised in patients with AIADK, and inflammasome-dependent cytokines were raised in the serum of patients with JRRP, but these assays have no established diagnostic cut-off values [17, 18].

NLRP1 is included in some autoinflammatory disease panels, such as the one used in the Turkish adult cohort, but may not appear in genodermatosis or keratinisation panels; exome sequencing enabled most of the published identifications [18, 54, 96, 99]. The report should state the MANE transcript (NM_033004.4), HGVS nomenclature, zygosity and ACMG/AMP classification, and family segregation is necessary for novel variants, given the incomplete penetrance described [75, 77]. Functional assays demonstrating gain of function (formation of ASC specks, IL-1β secretion by keratinocytes or mononuclear cells, oligomerisation in overexpression systems) have been performed in research laboratories and are not routine clinical tests [16, 18, 75]. The presence of several rare NLRP1 variants in the same patient, as in the Turkish case with three variants, and the coexistence of variants in other autoinflammatory genes complicate interpretation [96, 99]. Negative sequencing does not exclude an epithelial inflammasomopathy, because the phenotype may result from defects in regulators such as DPP9 [79]. Prenatal and preimplantation diagnosis is technically possible once the familial variant has been identified, although there are no specific reports in these diseases.

5.9 Diagnosis of haploinsufficiency of A20

There are no consensus diagnostic criteria for haploinsufficiency of A20, and the diagnosis is molecular: it is established by identifying a heterozygous pathogenic or likely pathogenic TNFAIP3 variant (about 95% of patients) or a heterozygous 6q23 deletion encompassing the gene (fewer than 5%) [22]. The practical consequence is that a compatible clinical picture does not permit the diagnosis without genetic confirmation, and that the diagnosis is not made by Behçet criteria: many patients do not meet the international criteria for that disease, and fewer than half of Japanese patients met them in full [26, 83].

The testing strategy depends on the family history. With no known affected relative, the recommended approach is a multigene panel for inborn errors of immunity that includes TNFAIP3 and the other monogenic causes of Behçet-like disease, or exome or genome sequencing, which simultaneously evaluates more than 500 genes; when there is a documented familial case, targeted testing of TNFAIP3 is sufficient [22, 26]. About 95% of pathogenic variants are detected by sequence analysis, about 3% by targeted analysis of intragenic deletions and duplications (quantitative PCR, long-range PCR, MLPA or gene-targeted microarray) and about 2% by chromosomal microarray, so a negative sequencing result does not close the investigation and requires a search for copy number changes in the 6q23 region [22]. Several splicing variants outside the canonical sites have been identified, which favours genome sequencing or RNA analysis when clinical suspicion is strong [22]. Large deletions are of particular clinical interest because they are associated with neurological disease and developmental delay, probably because they involve contiguous genes [24].

The genetic report should state the gene, the reference transcript with version (NM_001270508.2 is the MANE Select), the HGVS description at the DNA and protein levels, zygosity and the ACMG/AMP class. Interpretation of missense variants is the critical point: common variants, with an allele frequency above 5%, are risk alleles for autoimmune diseases and should not be reported as diagnostic; rare variants, with a frequency below 0.01%, are classified as of uncertain significance in about 80% of cases and require integration of allele frequency, in silico modelling (for example REVEL or AlphaMissense), previous reports, family segregation and functional assays [26]. The reference assay measures suppression of TNF-α-induced NF-κB activation in cell lines expressing the normal construct or the variant; alternatives include measurement of TNF-induced NF-κB activation or of basal A20 levels in the patient's own cells (monocytes, dermal fibroblasts) and the stability of the mutant protein in overexpression assays [23, 26]. These assays have recognised limitations: they do not evaluate non-coding or splicing variants, suffer from overexpression artefacts, do not reproduce regulatory mechanisms or the native cellular context, and ignore A20 functions outside the TNF–NF-κB axis; some results remain inconclusive even after extensive testing, and none of these assays is available as a validated clinical test [26]. Functional data for some variants are deposited in the Infevers database, and ClinGen curations for TNFAIP3 were in preparation at the time of the 2026 review [26].

No non-molecular test establishes the diagnosis. Laboratory assessment serves to measure activity and look for organ involvement: erythrocyte sedimentation rate, C-reactive protein, fibrinogen, full blood count with differential, serum amyloid A and urinalysis for proteinuria; transaminases and faecal calprotectin; quantitative immunoglobulins, vaccine responses (tetanus, diphtheria) and T, B and NK lymphocyte subsets; and an autoantibody panel (antinuclear antibodies, antibodies to extractable nuclear antigens, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, ANCA, antiphospholipid and antithyroid antibodies), given that more than 70% of patients develop them [22, 26]. In the systematic review, C-reactive protein was significantly raised during attacks in 54 of 63 evaluable patients, with a median of 51 mg/L [81]. In the Japanese survey, the mean leucocyte count during attacks was 11,886/μL (range 600–23,380) and the mean C-reactive protein 7.89 mg/dL (range 0.31–19.89), falling to 0.44 mg/dL (range 0–6.42) outside attacks, with nine patients persistently positive [25]. Conventional markers may, however, be normal in patients with a predominantly autoimmune phenotype and even in patients with ongoing organ damage, which justifies the use, when available, of additional markers: S100A8/A9 and S100A12 proteins, IL-18, CXCL9, soluble IL-2 receptor and type I interferon signature [26]. Nineteen of the Japanese patients had the type I interferon signature assessed: it was raised in 16, and the three with normal values had missense variants [25]. In the Italian cohort, the interferon signature was significantly higher in patients with active disease (p < 0.01), which proposes it as an activity biomarker [101]. Activity markers should not be collected during an infection, because they rise non-specifically [26]. Prenatal diagnosis and preimplantation genetic diagnosis are possible once the familial variant has been identified [22].

5.10 Diagnosis of haploinsufficiency of RelA

Diagnosis rests on identifying a heterozygous RELA variant in a compatible phenotype; there are no consensus criteria, nor any biochemical, histological or serological biomarker to confirm it [29]. Behçet-type criteria do not distinguish this entity from idiopathic Behçet's disease — which is why almost half of the patients in the largest series had previously received a more common rheumatological diagnosis —, so molecular testing is indispensable and should be considered in any patient with Behçet's disease, particularly with early onset or a strong family history [28, 29]. In practice, these patients reach the diagnosis through exome sequencing or a panel for inborn errors of immunity that includes the gene, and Sanger confirmation and family segregation studies are necessary both for the ACMG/AMP classification and for counselling [29]. The report should state the MANE Select transcript NM_021975.4 and its version, because more than one numbering for the same variant exists in the literature and in databases [31, 80].

The functional assays that underpinned the characterisation of the disease are research assays and should not be requested as clinical tests: TNF-induced apoptosis and NF-κB activation in the patient's fibroblasts, with measurement of the expression of NF-κB-dependent anti-apoptotic genes; demonstration of the expressed truncated RelA protein, by immunoblot with antibodies directed at the amino terminus and the carboxyl terminus, which reveals two bands with the former and only the normal band with the latter; luciferase assay with reduced transcriptional activation in response to TNF; and quantification of interferon-stimulated genes in leucocytes, raised in the dominant-negative subgroup [27, 58, 85]. The distinction between simple haploinsufficiency and a dominant-negative effect is not academic: location of the variant in the 3' segment of the gene, expression of a truncated protein and a raised interferon signature identify the group with more severe disease and provide the rationale for considering Janus kinase inhibition in patients who do not respond to TNF blockade [58].

5.11 Diagnosis of CARD8-associated inflammatory bowel disease

There are no specific diagnostic criteria. The intestinal phenotype is established by the usual assessment of inflammatory bowel disease (faecal calprotectin, C-reactive protein, full blood count, albumin, upper and lower gastrointestinal endoscopy with serial biopsies and magnetic resonance enterography), and the aetiological diagnosis depends on sequencing of CARD8 by a monogenic inflammatory bowel disease or autoinflammatory disease panel, or by exome [33, 109]. The approach to very early-onset monogenic inflammatory bowel disease described, in 2014, about 50 genetic variants associated with inflammatory bowel disease-like intestinal inflammation, including those of the IL-10 pathway, XIAP and several primary immunodeficiencies, and combines phenotypic and functional assessment with next-generation sequencing [109]. CARD8 was associated with inflammatory bowel disease after that review, so not all panels include it and its presence should be confirmed in the chosen panel or sought in the exome [33].

Interpretation has four main limitations. First, the c.130G>A variant is non-synonymous only in the T60 isoform; annotated on non-MANE transcripts, such as NM_014959, it appears as a 5' untranslated region or intronic change and may be excluded by analysis filters, so the report should use NM_001184900.3 [33, 87]. Second, the only variant with functional and segregation evidence is classified as of uncertain significance in ClinVar; under the ACMG/AMP criteria, a variant of uncertain significance should not underpin predictive or reproductive decisions, and only segregation in more affected individuals, functional studies and new families allow it to be reclassified [34, 87]. Third, the frequent variants CARD8-FS and rs2043211 are found in a large part of the population and should not be reported as a cause of monogenic disease [36, 59]. Fourth, a negative result does not exclude other monogenic causes of inflammatory bowel disease, which should be sought in the same panel or exome [109].

Serum IL-1β and IL-1β production by monocytes or dendritic cells stimulated with NLRP3 activators distinguished affected individuals from controls in the index family, but these are research assays, without validated reference values for clinical use [33]. The report should state the gene, the transcript and its version, the variant in HGVS, zygosity, the ACMG/AMP class and the recommendation for segregation studies in affected relatives.

5.12 Diagnosis according to the French PNDS (FMF, CAPS and TRAPS)

FMF: genetic interpretation and algorithm. The 2022 PNDS (French National Diagnosis and Care Protocol) considers as confirmatory the homozygous or compound heterozygous genotypes combining the four exon 10 variants most frequent in at-risk populations, NM_000243.3:c.2080A>G p.(Met694Val), c.2082G>A p.(Met694Ile), c.2040G>C p.(Met680Ile) and c.2177T>C p.(Val726Ala), which are also those associated with the most typical phenotypes [12]. French reference laboratories study only exon 10 as first line, by Sanger sequencing, and complete gene sequencing can only be requested by an expert centre [12]. In patients with a single pathogenic variant (mainly p.Met694Val) and a suggestive phenotype, complete sequencing almost never finds a second allele; the PNDS calls these genotypes «non-conclusive» and strongly recommends the opinion of an expert centre [12]. The variant c.442G>C p.(Glu148Gln), the most frequent of those that an expert group no longer considers pathogenic, should not be reported according to the 2020 ISSAID/EMQN recommendations, and next-generation sequencing may reveal never-described variants whose pathogenicity remains to be demonstrated [12, 64]. Phasing, theoretically necessary in a recessive disease, rarely changes the conclusion, because the probability of two pathogenic exon 10 variants on the same chromosome is almost nil [12]. In a young child with a non-confirmatory or non-conclusive genotype, the diagnosis should be reassessed against PFAPA syndrome and the physiological susceptibility to infection of that age, and recurrent fever with onset before 1 year or atypical features requires the opinion of an expert centre to look for other autoinflammatory diseases [12]. Except in very severe phenotypes, the PNDS recommends awaiting the genetic result before starting treatment and communicating the diagnosis in an expert centre whenever the genotype is not confirmatory, with a written report sent to the patient and to the doctors the patient designates [12].

Table source: appendix 3 of the PNDS [12].

FMF: clinical criteria in the PNDS. Appendix 2 of the PNDS presents, under the name Tel-Hashomer criteria, a set different from the two Livneh sets described in section 5.2: major criteria (recurrent febrile episodes with peritonitis, arthritis or pleuritis; AA amyloidosis without another cause; favourable response to continuous colchicine) and minor criteria (recurrent isolated febrile episodes; pseudo-erysipelas; FMF in a first-degree relative), with a definite diagnosis with two major criteria or one major and two minor, and a probable diagnosis with one major and one minor [12]. In the simplified version, the major criteria require recurrent typical attacks (at least three, with fever above 38 °C and a duration of 12 to 72 hours) [12]. The Yalçınkaya-Özen paediatric criteria are satisfied by two items in highly endemic populations, but in a mixed population such as the French one, the PNDS requires three, with a specificity of 95% and a sensitivity of 77% [12]. For the 2019 Eurofever/PRINTO criteria, the PNDS specifies that the non-confirmatory genotype includes simple heterozygosity, compound heterozygosity with one pathogenic variant and one of uncertain significance, and biallelic variants of uncertain significance [12, 37].

FMF: severity, comorbidities and SAA. Severity is assessed by the frequency, duration and intensity of attacks — first retrospectively and then prospectively, with the AIDAI if necessary, for at least 6 months —, by CRP outside attacks, which detects both insufficiently controlled FMF and another cause of inflammation, and by the search for persistent complications: renal amyloidosis (proteinuria and creatinine), coxitis, sacroiliitis and liver disease (transaminases) [12]. The usual cardiovascular risk factors are also sought and, in women, iron deficiency, which may cause fatigue and arthromyalgia and precipitate attacks [12]. When amyloidosis is suspected, first-line biopsy is of the labial minor salivary glands, abdominal fat or upper or lower gastrointestinal mucosa and submucosa, with Congo red staining and immunohistochemistry, renal biopsy being second line [12]. The PNDS appendix devoted to SAA recalls that this reactant has kinetics similar to those of CRP, with a half-life of about 10 hours (about 19 hours for CRP), an increase of up to a thousandfold in the acute phase, measurement by nephelometry or turbidimetry in a limited number of laboratories and a result in about one week; raised SAA is not synonymous with amyloidosis, a normal SAA and CRP do not exclude it, what matters for amyloidogenic risk is documenting and quantifying prolonged inflammation, and it should be verified at least once that SAA is normal when CRP is [12].

CAPS: investigations. The 2013 PNDS, which predates the Kuemmerle-Deschner criteria, had no validated criteria and based the diagnosis on a set of clinical and paraclinical arguments, with genetic confirmation when possible [14]. CAPS are accompanied by an inflammatory syndrome with mild neutrophilia, sometimes microcytic anaemia of inflammation and rarely thrombocytosis, without autoantibodies [14]. The public laboratories of the GenMAI network (Trousseau, Cochin and Montpellier) sequence exon 3 of NLRP3 as first line, where almost all variants lie, including the most frequent in France: NM_001243133.2:c.1043C>T p.(Thr348Met), c.592G>A p.(Val198Met), c.1316C>T p.(Ala439Val), c.907G>A p.(Asp303Asn) and the classic variant R260W, whose discrepant ClinVar annotation is described in section 5.7; p.Val198Met has debated pathogenicity, with conflicting classifications in ClinVar, and is at most a low-penetrance variant [14, 108, 110]. Even with sequencing of all coding regions and adjacent intronic regions, no variant is found in 8% (FCAS) to 50% (CINCA) of patients with a typical picture, which may correspond to low-fraction somatic mosaicism, variants in non-coding regulatory regions or involvement of other genes; a negative result does not, therefore, exclude the diagnosis [14]. On skin biopsy, the dermal neutrophilic infiltrate is inconsistent and non-specific (also present in Still's disease and Schnitzler syndrome), the finding of capillaries packed with neutrophils being more suggestive [14].

The initial CAPS work-up proposed by the PNDS includes full blood count, CRP and, ideally, SAA, whose chronic elevation has prognostic value for amyloidosis; lumbar puncture with cytology, glucose, protein and opening pressure if there is chronic headache or papilloedema; brain magnetic resonance imaging for chronic headache; radiographs, ultrasound and possibly magnetic resonance imaging of affected joints; audiometry; ophthalmological examination with visual acuity, slit lamp, tonometry, fundoscopy, optical coherence tomography and retinal angiography; semen analysis in men, at the appropriate time; gynaecological examination for amenorrhoea; neuropsychological assessment if intellectual disability is suspected; and endocrine assessment for growth delay [14]. When measuring cerebrospinal fluid pressure with a manometer and three-way tap, values above 200 mm of water are probably abnormal, 200 to 250 mm constitute a grey zone and above 250 mm are abnormal; anxiety or voluntary apnoea may increase it by about 50 mm, and with a pressure above 250 mm the needle should be withdrawn without collecting more fluid, analysing that contained in the manometer [14]. Screening for amyloidosis includes urea, creatinine and microalbumin/creatinine ratio (or dipstick, with 24-hour proteinuria if positive), chest radiograph, electrocardiogram, echocardiogram and possibly cardiac magnetic resonance imaging; serum amyloid P component scintigraphy, used in other European countries to measure amyloid load, was not available in France; histological diagnosis begins with the minor salivary glands or periumbilical fat and may require renal, hepatic, rectal or, exceptionally, myocardial biopsies [14]. Before treatment, quality of life may be measured with the CHQ, the SF-36 (scored from 0 to 100; above 50 indicates good quality of life) and the FACIT-Fatigue scale (maximum 52, corresponding to good general condition), and liver function and cholesterol should be assessed, given the hepatotoxic and lipid potential of some IL-1 inhibitors [14].

TRAPS: investigations and genetic interpretation. Elevation of acute-phase reactants during the attack is mandatory to raise the diagnosis; the full blood count is generally normal, apart from microcytic anaemia and relative polymorphonuclear leucocytosis or thrombocytosis, normalisation between attacks is usual but not constant, the absence of autoantibodies at significant titre supports an autoinflammatory disease, and regressive serous effusions documented by ultrasound during the attack (arthritis, pericarditis, pleuritis, peritonitis, orchitis) are an additional argument; the role of cytokine and S100A12 measurements remained to be defined in 2018 [15]. Proteinuria should raise suspicion of amyloidosis [15]. The diagnosis must be confirmed by genetic testing, preferably in a GenMAI network laboratory, and the causality of the variant must be demonstrated: family segregation (variant present in affected and absent in healthy individuals) is one of the strongest arguments, and the most certainly deleterious variants are cysteine substitutions, frameshift variants, those creating a premature stop codon and those causing a major conformational change, as a rule with complete penetrance and variable intrafamilial expressivity; nonsense variants and deletions or insertions that greatly alter protein size are rare in TRAPS [15]. The variants NM_001065.4:c.362G>A p.(Arg121Gln) (formerly R92Q) and c.224C>T p.(Pro75Leu) (formerly P46L), found in the general population, are not sufficient to cause the hereditary form and may act as cofactors; p.Arg121Gln is more frequent in multifactorial diseases such as multiple sclerosis and is associated with transient recurrent fevers of childhood that disappear before adolescence, so a diagnosis of TRAPS should not be announced on the basis of the genetic test alone, and the same applies to rare or private variants, for which there is no routine functional test [15]. As in FMF, the diagnosis should be communicated in a reference or competence centre, given the complexity of interpretation and the absence of reliable clinical criteria [15].

Genetic decision tree and activity and damage scales. The GenMAI network proposes a decision tree common to recurrent fevers, reproduced in the TRAPS PNDS:

Table source: appendix 2 of the TRAPS PNDS [15].

The AIDAI is completed by the patient as a monthly diary, recording on each attack day twelve manifestations scored 0 or 1 (fever ≥ 38 °C, general symptoms, abdominal pain, nausea or vomiting, diarrhoea, headache, chest pain, painful lymph nodes, joint or muscle pain, joint swelling, ocular manifestations and rash) and the use of analgesics; a monthly sum (or monthly mean over the observation period) of 9 or more defines active disease, clinical use is free and there is a web application version [15]. For damage, the PNDS recommends looking for reproductive (infertility, amenorrhoea), renal (amyloidosis, proteinuria, renal failure), growth and pubertal, digestive (peritoneal adhesions) and locomotor (joint stiffness, chronic muscle pain, osteoporosis, bone deformities) sequelae, as well as deterioration in quality of life, depression and school or social disengagement, and proposes the ADDI damage index, then preliminary, which scores changes persisting for at least 6 months, even if they later regress [15].

Table source: appendix 5 of the TRAPS PNDS [15]. In the index glossary, proteinuria corresponds to a urinary protein/creatinine ratio persistently above 20 mg/mmol, an excretion above 0.3 g/24 hours or an albumin/creatinine ratio above 15 mg/mmol; moderate renal failure to a glomerular filtration rate of 15 to 60 mL/min/1.73 m² and severe renal failure to less than 15 mL/min/1.73 m², dialysis or transplantation; and severe hearing loss to that requiring a hearing aid or cochlear implant [15].

MKD according to the French PNDS (2015). The screening test is urinary mevalonic acid during an attack (raised only during attacks in HIDS and permanently in mevalonic aciduria): the first morning urine is collected with a temperature above 38.5 °C, preferably on the second day of fever, about 10 mL, which should reach a metabolic biochemistry laboratory within 12 hours or be frozen immediately [13]. IgD is raised in most patients but has low sensitivity and specificity and the PNDS (French National Diagnosis and Care Protocol) considers it of no diagnostic value; IgA is often raised; during attacks there are raised CRP and SAA, leucocytosis, thrombocytosis and anaemia of inflammation, and CRP may remain raised between attacks in severe forms [13]. Genetics confirms the diagnosis in more than 80% of cases; the international recommendations cited require, at a minimum, testing for p.(Val377Ile) in exon 11, p.(Ile268Thr) and p.(Ser272Phe) in exon 9 and p.(His20Pro) in exon 2, and only one variant was found in 12 of 103 patients in a Dutch series and in 5 of 50 in the French series; measurement of enzyme activity in lymphocytes, outside attacks, is reserved for cases in which genetics is inconclusive; the Gaslini score (age at onset, abdominal pain, aphthae, chest pain, diarrhoea, family history) helps to decide on genetic testing when PFAPA is suspected [13]. Initial assessment includes examination with weight, height, development, dysmorphism, hepatosplenomegaly, neurological, joint and skin signs (with photographs if absent on the day of the consultation); full blood count, CRP, SAA, immunoglobulins, liver function, urea, creatinine and urine dipstick; abdominal ultrasound if organomegaly is in doubt; ophthalmology; brain MRI if neurological examination is abnormal; gastrointestinal endoscopy if there is mucosanguineous diarrhoea; renal biopsy if there is proteinuria, haematuria or renal failure [13].

6. Differential Diagnosis

The differential diagnosis should be approached in two stages: during the attack, exclude systemic or localised infections, surgical acute abdomen and neoplasia; in the presence of self-limited recurrent episodes, consider immunodeficiencies, cyclic neutropenia, inflammatory bowel disease and other autoinflammatory diseases, particularly PFAPA syndrome [93]. Acquired causes to consider in the differential diagnosis of TRAPS include viral, bacterial or parasitic infections, neoplasia, Behçet's disease, inflammatory bowel disease and adult-onset Still's disease [3]. Saudubray lists, among the metabolic causes of recurrent abdominal pain with an inflammatory syndrome, hyper-IgD due to mevalonate kinase deficiency, and among the causes of recurrent fever, Fabry disease [95]. Dysplasia epiphysealis hemimelica shows epiphyseal osteocartilaginous overgrowth similar to that of CINCA, but with less pronounced radiological changes and without autoinflammatory manifestations [5].

Table sources: [1, 3–5, 17–19, 22, 26, 29, 31, 33, 37, 54, 55, 79, 109, 111].

The French PNDS (French National Diagnosis and Care Protocol) documents organise the differential diagnosis by dominant presentation. For FMF:

Table source: appendix 4 of the FMF PNDS [12].

In FMF that appears resistant, with sudden worsening despite full adherence, the PNDS directs a search for other causes of inflammation, including inflammatory rheumatism and vasculitis and, after 50 years of age, low-grade myeloid haemopathy and chronic peritonitis or peritoneal mesothelioma [12]. In CAPS, the main differential diagnosis of FCAS and of some MWS is acquired cold urticaria, much more frequent and also common in young children: lesions appear minutes to 1–2 hours after local cold or cold water (swimming), the ice cube test is positive in only about 60% of cases and the cold water immersion test slightly more, there is no conjunctivitis, and general signs, when present, are dyspnoea, abdominal pain, presyncope or syncope; it is one of the rare potentially fatal physical urticarias, through sudden immersion in cold water or ingestion of an iced drink or ice [14]. The CAPS PNDS adds other autoinflammatory diseases (NLRP12-associated periodic syndrome, Schnitzler syndrome, TRAPS, Still's disease), urticarial vasculitides, especially hypocomplementaemic, and cryoglobulinaemias; infections with intermittent expression (chronic sinusitis, dental abscess, endocarditis, chronic meningococcaemia, tuberculosis, brucellosis, borreliosis, rickettsiosis, HIV, hepatitis B and C, leptospirosis) and parvovirus B19, whose rash may recur for months; neoplasia (histiocytoses, lymphomas, particularly anaplastic and angioimmunoblastic, leukaemias, neuroblastoma, Castleman disease); cyclic neutropenia with documented repeated infections; multiple sclerosis in forms with regressive paralysis or white matter demyelination; and factitious or drug-induced fever [14]. In TRAPS, the PNDS recalls that common abdominal causes rarely recur over years, that functional abdominal pain is not accompanied by an inflammatory syndrome, that FMF has much shorter attacks, that MKD has more diarrhoea, aphthae and cervical lymphadenopathy, that PFAPA syndrome has short and highly stereotyped attacks with pharyngitis, aphthae and lymphadenopathy, and that Still's disease and Castleman disease generally cause continuous rather than recurrent inflammation; in recurrent fever with digestive and locomotor involvement, inflammatory bowel disease should be sought by endoscopy with biopsies and faecal calprotectin [15]. The same PNDS mentions TRAPS-like presentations associated with variants of TNFRSF11A, a gene of the same receptor family [15].

In NLRP1-associated diseases, the differential diagnosis is organised around multiple keratoacanthomas and epithelial dyskeratoses. MSPC is distinguished from the other familial keratoacanthoma syndromes by onset between 1 and 25 years, lesions at pressure and friction points and not in sun-exposed areas, conjunctival keratoacanthomas, the ulcerated and nodular appearance, the size of 5 to 50 mm and transformation into metastatic squamous cell carcinoma, which in MSSE has only been observed after radiotherapy [55]. The absence of chromosomal fragility and a normal karyotype rule out DNA repair syndromes, and the absence of sebaceous and visceral neoplasms rules out Muir-Torre syndrome [19, 55]. In corneal dyskeratosis, the 4q35 duplication of HBID should be excluded, which was done by quantitative PCR in the family of Soler and colleagues [54]. Forms with pustular and ulcerated dermatosis are mistaken for atopic dermatitis and psoriasis, and the combination of raised acute-phase reactants, B-lymphocyte abnormality and resistance to topical therapies should lead to genetic testing [96]. DPP9 deficiency shares the mechanism but is associated with pancytopenia and growth delay [79]. In adults with recurrent fever and serositis without biallelic MEFV variants, rare NLRP1 variants found on panels require cautious interpretation, because causality is rarely demonstrated [99].

In Behçet-like autoinflammatory diseases of the canonical NF-κB pathway, the differential diagnosis is organised along two axes. The first is the distinction from polygenic Behçet's disease, with which they all share orogenital ulceration: in favour of the monogenic forms are onset in the first decade, a family history compatible with dominant transmission (or X-linked in the case of ELF4), failure to meet the international Behçet criteria, association with Crohn-like intestinal inflammation or colitis, immune cytopenias and systemic autoimmunity, and HLA-B*51 negativity [26, 29, 31]. The second axis is the distinction between the NF-κBopathies themselves. Haploinsufficiency of A20 is distinguished from RELA-associated disease by the burden of autoantibodies and clinically significant autoimmunity, by thyroiditis and hepatitis, and by the existence of a humoral immunodeficiency component; RELA-associated disease, in its simple haploinsufficiency form, is concentrated on mucocutaneous ulceration and has rare infections [22, 29]. ELF4-associated disease shares the oral ulcers but has no described genital ulcers and is associated with recurrent mucosal fungal infections; otulipenia is distinguished by panniculitis and lipodystrophy [22]. Mosaic trisomy 8-associated autoinflammatory disease mimics the picture with oral and genital ulcers and fever, but adds dysmorphism, platelet defects and an increased risk of haematological neoplasia, and is identified by karyotype and microarray and not by sequencing [22]. On the side of the periodic fevers covered in the preceding sections, familial Mediterranean fever is the diagnosis most frequently considered first in children with recurrent fever and abdominal pain, and a negative MEFV panel in a patient with mucosal ulcers and colitis should lead to investigation of the NF-κBopathies, as illustrated by the case described in section 10.4 [100, 112]. The acquired causes to exclude are the same: infection, neoplasia, systemic lupus erythematosus, juvenile idiopathic arthritis, recurrent aphthous stomatitis, PFAPA syndrome and inflammatory bowel disease [22]. A practical observation closes the differential diagnosis: for TNFAIP3 variants of uncertain significance found on panels requested for recurrent fever in adults, causality is rarely demonstrated, and the same caution that applies to rare NLRP1 variants applies here [26, 99].

In CARD8-associated inflammatory bowel disease, the main differential diagnosis is polygenic Crohn's disease, from which it is distinguished only by the family history of vertical transmission, by the refractoriness to TNF inhibitors and the response to IL-1 blockade described in the index family, and by identification of the variant [33]. In young children, the monogenic forms of the IL-10 pathway and XIAP deficiency have earlier onset, perianal disease or haemophagocytic lymphohistiocytosis and their own functional tests [109]. Haploinsufficiency of A20 and RELA-associated disease may also present with Crohn-like inflammatory bowel disease, but are accompanied by orogenital ulcers [22, 29]. In children with periodic fever, PFAPA remains a non-Mendelian disease, even in carriers of CARD8-FS, and is diagnosed by clinical criteria [37, 59].

7. Treatments and Risk Management Strategies

7.1 Objectives and principles (EULAR 2016 and EULAR/PReS 2024)

The 2016 EULAR recommendations for FMF comprised 18 recommendations and were updated in 2024 (2025 publication) into a set of four overarching principles and twelve recommendations, with a level of agreement above 9/10 for all statements, an emphasis on treatment adherence, a set of priorities and quality indicators [10, 38]. The aim of treatment is complete control of unprovoked attacks and minimisation of subclinical inflammation between attacks, to prevent AA amyloidosis [38, 62]. Colchicine should be started as soon as the clinical diagnosis is made; persistence of attacks or of subclinical inflammation is an indication to increase the dose; adherent patients who do not respond to the maximum tolerated dose are considered resistant and have an indication for alternative biological therapy, preferably IL-1 blockade [38, 62]. In established AA amyloidosis, treatment should be intensified with the maximum tolerated dose of colchicine, combined with biologics when necessary [38, 62]. Asymptomatic homozygotes for MEFV NM_000243.3:c.2080A>G p.(Met694Val) should be assessed and followed closely, and in asymptomatic biallelic individuals with risk factors for amyloidosis (country of origin, family history, persistently raised inflammatory markers, especially SAA) treatment should be considered [38, 62].

In France, practice follows the national diagnosis and care protocols (PNDS, French National Diagnosis and Care Protocols) of the Haute Autorité de Santé for FMF (2022), CAPS (2013) and TRAPS (2018), whose therapeutic recommendations, doses and divergences from international guidelines are brought together in section 7.15 [12, 14, 15].

7.2 Colchicine

Nature and role. Colchicine is an alkaloid and has been the first-line treatment of FMF since 1972 [40, 62, 113]. Beyond symptom control, its main purpose is the prevention of amyloidosis [1, 41].

Regulatory status and presentation. In the United States, Colcrys® colchicine tablets (0.6 mg) have had an indication approved by the FDA (Food and Drug Administration) since 29 July 2009 for FMF in adults and children aged 4 years or older [113]. Not all colchicine formulations include this indication. In the European Union, the only colchicine with centralised EMA authorisation (Colchicine Agepha Pharma, July 2026) is indicated for secondary prevention of atherothrombotic events in coronary disease, so use in FMF relies on nationally authorised medicinal products [114]; the tablets used in Europe are as a rule 0.5 mg and in the United States 0.6 mg, which explains the two equivalence columns of the following table [62].

Table sources: [38, 62, 113]. GeneReviews gives, based on the EULAR/PReS update, 0.6 to 1.8 mg/day as a single or divided dose [1]. A randomised non-inferiority trial in children showed that once-daily dosing is not inferior to twice-daily dosing [62], and the US label allows administration in one or two doses [113]. During periods of physical or emotional stress a temporary dose increase may be justified, and during attacks the usual dose may be maintained and non-steroidal anti-inflammatory drugs added [38, 62]. Exertional leg pain is treated with non-steroidal anti-inflammatory drugs, and in protracted febrile myalgia glucocorticoids may lead to resolution of symptoms [38, 62]. In paediatrics, a range of 0.03 to 0.07 mg/kg/day is also cited [93].

Adjustment for renal and hepatic function. The Colcrys® label recommends caution in moderate and severe renal impairment and in dialysis: with creatinine clearance below 30 mL/min, treatment should be started at 0.3 mg/day, and in dialysis the total starting dose should be 0.3 mg/day, with increases only under close monitoring; in severe hepatic impairment dose reduction should be considered [113]. European recommendations indicate regular monitoring of liver enzymes, with colchicine reduction if they exceed twice the upper limit of normal, and monitoring for signs of toxicity and of creatine kinase in patients with decreased renal function [38, 62].

Adverse effects and interactions. Gastrointestinal effects (cramps, nausea, diarrhoea, abdominal pain, vomiting) occur in up to 20% of patients, generally in the first 24 hours, and are usually mild and reversible with dose reduction; if severe, they may herald more serious toxicity [113]. Myelosuppression, leucopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anaemia have been described, as well as neuromyotoxicity and rhabdomyolysis, especially in renal impairment, in the elderly and with statins, fibrates or ciclosporin [113]. Mild, clinically silent leucopenia occurs in about 10% of children treated with 0.5 to 2 mg/day [93]. Colchicine is a substrate of P-glycoprotein and CYP3A4: co-administration with potent inhibitors (clarithromycin, ketoconazole, itraconazole, ritonavir and other protease inhibitors) has caused fatal interactions, is contraindicated in renal or hepatic impairment and, in the absence of an alternative, requires limiting the maximum daily dose in FMF to 0.6 mg (which may be given as 0.3 mg twice daily) [113]. Overdose, accidental or intentional, may be fatal in adults and children; severe toxicity occurs with ingestions above 0.1–0.2 mg/kg [93, 113].

Resistance and intolerance. About 5% to 10% of patients do not respond to or do not tolerate colchicine; in the anakinra trial, refractoriness was estimated at 10% to 20% [62, 115]. The 2021 Delphi consensus defined resistance as persistent activity on the maximum tolerated dose, with recurrent clinical attacks (on average one or more per month over three months) or persistent laboratory inflammation between attacks, and emphasised the need to assess adherence before concluding resistance [116]. Adherence is insufficient in more than half of patients [93]. Intolerance manifests mainly as gastrointestinal symptoms that prevent the effective dose from being reached, and is distinct from toxicity (severe gastrointestinal involvement, myelosuppression, neuromyopathy) [62, 116]. In stable patients, without attacks for more than five years and without elevation of acute-phase reactants, dose reduction may be considered after specialist advice [38, 62].

7.3 Interleukin-1 inhibitors

Mechanisms. Anakinra is the recombinant form of the human IL-1 receptor antagonist, which competitively inhibits the IL-1R1 receptor; canakinumab is a human monoclonal antibody that neutralises IL-1β; rilonacept is a soluble decoy receptor («IL-1 Trap») [62, 117–120].

Canakinumab (Ilaris®). Approved by the FDA on 17 June 2009 for CAPS and, on 23 September 2016, for TRAPS, HIDS/MKD and FMF [121, 122]. In the European Union it has been authorised since 23 October 2009 and the current SmPC includes CAPS (MWS, CINCA/NOMID and severe forms of FCAS), TRAPS, HIDS/MKD and FMF (in combination with colchicine, if appropriate) from 2 years of age [114, 118]. The CLUSTER trial randomised patients with genetically confirmed colchicine-resistant FMF, MKD or TRAPS to canakinumab 150 mg or placebo every four weeks; at week 16, complete response was 61% versus 6% in FMF, 35% versus 6% in MKD and 45% versus 8% in TRAPS, rising to 71%, 57% and 73%, respectively, with escalation to 300 mg; the eight-week interval maintained control in 46%, 23% and 53% [123]. Infections were the most frequent adverse events (173.3, 313.5 and 148.0 per 100 patient-years), with few serious infections [123]. In CAPS, 34 of 35 patients (97%) had a complete response after 150 mg, and in the randomised withdrawal phase 81% of patients on placebo relapsed, compared with none on canakinumab [124].

Anakinra (Kineret®). In the United States, the CAPS indication is restricted to NOMID (approved on 21 December 2012), alongside rheumatoid arthritis and DIRA [117, 122]. In the European Union, where it has been authorised since 8 March 2002, the SmPC includes all CAPS (NOMID/CINCA, MWS and FCAS) and FMF (in combination with colchicine, if appropriate), in adults, adolescents, children and infants from 8 months of age weighing 10 kg or more [114, 125]. In the NOMID study, 18 patients treated with 1 to 2 mg/kg/day all responded rapidly, with median SAA falling from 174 to 8 mg/L and improvement of cochlear and leptomeningeal lesions on magnetic resonance imaging; withdrawal caused relapse within days [126]. In the randomised trial in 25 patients with colchicine-resistant FMF, the mean number of attacks per month was 1.7 with anakinra and 3.5 with placebo, and six patients on anakinra (none on placebo) had fewer than one attack per month [115].

Rilonacept (Arcalyst®). Approved by the FDA on 27 February 2008 for CAPS (FCAS and MWS) from 12 years of age, and later for maintenance of remission of DIRA and for recurrent pericarditis [122, 127]. In the European Union, the 2009 authorisation (Rilonacept Regeneron, formerly Arcalyst) was withdrawn in 2012, and a later application was withdrawn in 2025, so the drug is not marketed in the EU [114]. In the two phase III trials in 47 adults with CAPS, rilonacept reduced the composite symptom score by 84% compared with 13% with placebo [119]. In colchicine-resistant or intolerant FMF (14 patients, alternating design), it reduced attack frequency (median 0.77 versus 2.00 per month), without altering their duration [120]; this use is off-label.

In severe renal impairment (creatinine clearance below 30 mL/min), including dialysis, administration of anakinra on alternate days should be considered [117, 125]. The European SmPC for anakinra recommends, in severe CAPS, assessment of the central nervous system, inner ear (magnetic resonance imaging or computed tomography, lumbar puncture, audiometry) and eyes three months after initiation and then every six months until the effective dose is found, becoming annual once clinical control is achieved [125].

Adverse effects and precautions of IL-1 blockade. All three drugs are associated with an increased risk of serious infections; they should not be started during active infection and should be suspended in the event of serious infection [117, 121, 127]. Before initiation, latent tuberculosis should be screened for, the vaccination schedule updated (including pneumococcal and inactivated influenza vaccines) and live vaccines avoided during treatment [1, 117, 121, 127]. Combination with TNF inhibitors is not recommended because of an increase in serious infections [117, 121, 127]. Injection-site reactions are the most frequent adverse effect of anakinra (71% in rheumatoid arthritis trials) and of rilonacept [117, 127]. Anakinra may cause neutropenia, so a neutrophil count is recommended before initiation, monthly in the first months and then quarterly; amyloid deposits at the injection site and systemic amyloidosis due to IL-1 receptor antagonist protein have been described in patients with NOMID treated with high doses at the same site, so rotation of injection sites is recommended [117, 125]. With canakinumab and anakinra, hypersensitivity reactions and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) have been described in patients with autoinflammatory diseases [117, 121]. Rilonacept may increase serum lipids, so the lipid profile should be monitored [127]. In CAPS, the most frequent adverse effects of canakinumab (more than 10%) were nasopharyngitis, diarrhoea, influenza, rhinitis, nausea, headache, bronchitis, gastroenteritis, pharyngitis, weight gain, musculoskeletal pain and vertigo; in TRAPS, HIDS/MKD and FMF they were injection-site reactions and nasopharyngitis [121].

7.4 Specific treatment of TRAPS

IL-1 blockade is considered first-line treatment and is, in general, more effective than TNF inhibition; about 90% of patients respond [3]. Canakinumab has an approved indication at the doses in the preceding table [118, 121]. Among TNF inhibitors, etanercept (soluble receptor) is the most effective and may be used in refractory cases, whereas anti-TNF monoclonal antibodies have been associated with severe paradoxical reactions and should be avoided [3]. Etanercept has no approved indication in TRAPS and GeneReviews does not define its dose, so it should follow a specialist centre protocol, based on the SHARE recommendations and the practical guide of Soriano and colleagues [3, 128, 129]. Patients with infrequent attacks may require treatment only during attacks [3]. Corticosteroids (for example prednisone 1 mg/kg/day) may be useful during attacks, but are not sufficient for long-term treatment and do not prevent amyloidosis; non-steroidal anti-inflammatory drugs bring no benefit in most patients; colchicine has a poor response [3]. Retinal infarctions and optic nerve damage require follow-up by an ophthalmologist and low vision services, and may not reverse with therapeutic optimisation [3]. IL-1 inhibitors and etanercept prevent AA amyloidosis [3].

7.5 Specific treatment of CAPS

CAPS respond consistently to IL-1 blockade, which should be started early to prevent organ damage; the 2021 EULAR/ACR (American College of Rheumatology) points to consider for IL-1-mediated diseases include five overarching principles, 14 statements on diagnosis, 10 on therapy and 9 on long-term monitoring, with surveillance schedules specific to inflammation-induced organ damage [8, 9]. Bone Dysplasias reports that treatment with an IL-1 receptor antagonist markedly improves the clinical and laboratory findings of CINCA and, possibly, the final outcome, and may prevent severe cartilaginous overgrowth of the knee [5]. In patients with FCAS, prevention of cold-induced attacks with anakinra was demonstrated by Hoffman and colleagues [1].

7.6 Treatment of MKD (brief discussion)

IL-1 blockade is the mainstay of treatment: canakinumab has FDA and EMA approval for HIDS/MKD, with dose escalation frequently required; anakinra is used off-label, continuously or on demand at the onset of an attack [11, 118, 121, 123]. Statins and bisphosphonates are not recommended, because inhibition of HMG-CoA reductase aggravates isoprenoid depletion; in mevalonic aciduria simvastatin worsened symptoms [6, 11]. Allogeneic haematopoietic stem cell transplantation is an option in severe refractory forms; in a multicentre series, seven of nine patients achieved complete remission and two died of transplant complications [6, 11]. Saudubray also reports improvement with corticosteroids, colchicine or ciclosporin in a minority and reduced attack frequency with etanercept in some patients [6].

The 2015 French PNDS (French National Diagnosis and Care Protocol), which predates the approval of canakinumab for MKD, considered all treatments off-label and proposed: in less severe forms, corticosteroid on the first day of the attack only, oral betamethasone (Célestène®) 10–15 drops/kg or prednisolone (Solupred®) 1–2 mg/kg, with complete efficacy in 24.4% and partial efficacy in 37.8% in a Dutch series and complete in 24% and partial in 67% of 39 patients in the Eurofever registry; non-steroidal anti-inflammatory drugs appear to have little efficacy; on-demand anakinra, in a prospective study of 11 patients, reduced the duration and severity of attacks by more than half, without controlling inflammation between attacks [13]. As maintenance treatment, statins are neither effective nor recommended, colchicine serves mainly for frequent aphthae, and biological therapies are reserved for severe forms or after failure of anti-inflammatory drugs and corticosteroids, with IL-1 inhibitors as first line (grade C): in Eurofever, anakinra was effective in 24 of 27 patients (6 complete remissions) and etanercept in 11 of 17, mostly with partial responses [13]. Before IL-1 blockade, the PNDS requires weight and BMI, complete pneumococcal vaccination, updating of the schedule, annual influenza vaccine, varicella vaccine at least 3 weeks beforehand if there is no immunity, exclusion of tuberculosis, HIV and hepatitis B and C, full blood count, ESR, CRP, SAA, transaminases and cholesterol; live vaccines are contraindicated during biological therapy and, if indispensable, require minimum intervals of 2 days after the last anakinra dose, 3 weeks after etanercept and 5 months after canakinumab; neutropenia below 1500/mm³ limits anti-IL-1 agents, anakinra clearance falls by 50% in moderate renal impairment and by more than 70% with creatinine clearance below 30 mL/min (reduce the dose or space the injections), pregnancy is discouraged under biological therapy, and local reactions to anakinra are attenuated with lidocaine cream and ice [13]. Under prolonged systemic corticosteroid therapy (more than 14 days with 2 mg/kg/day or 20 mg/day of prednisone or more), live vaccines are contraindicated during treatment and for up to 1 month afterwards [13]. The proposed follow-up is six-monthly at the centre under biological therapy and annual without it, with full blood count, CRP and SAA at least annually, liver and renal function and urine dipstick six-monthly, urinary protein/creatinine ratio annually, ophthalmology annually, annual cognitive and neurological assessment in mevalonic aciduria, lipids six-monthly under anti-IL-1 therapy, the AIDAI score (12 items; 9 or more indicates active disease) and quality-of-life scales [13].

Table 7.6a — Divergences and inconsistencies of the French MKD PNDS (2015) [13]

7.7 Investigational therapies

Tocilizumab (anti-IL-6) was evaluated in two randomised trials in colchicine-resistant FMF: neither met its primary endpoint, but the drug reduced attack frequency and acute-phase reactants and improved secondary parameters [62]. Janus kinase (JAK) inhibitors, such as tofacitinib, induced clinical and laboratory remission in case series of six patients, on the basis of JAK1/TYK2 regulation of IL-1β-mediated inflammation [1, 62]. The evidence for both classes remains limited compared with IL-1 blockade [1]. In CAPS, direct oral NLRP3 inhibitors are in phase 2: the VTX2735 trial (NCT05812781) included 7 patients with CAPS and ended in 2024, and results were released only in a sponsor press release (mean 85% reduction in the key symptom score and a fall in inflammatory markers), with no peer-reviewed publication identified; the DFV890 trial in FCAS (NCT04868968) was completed with 4 participants [130, 131]. None of these drugs is authorised, and no ongoing phase 3 trials in FMF, TRAPS or MKD were identified in the ClinicalTrials.gov registry consulted [130].

7.8 Risk management: surveillance

Table sources: [1, 3, 8, 38, 62, 125].

7.9 Pivotal trials and limitations of comparisons between drugs

Limitations of comparison. The trials differ in design (historical cohort, randomised withdrawal, alternating design within individual patients, parallel trial), in population (resistant FMF, defined before the 2021 Delphi consensus, CAPS of variable severity), in duration and in endpoint: «complete response» in CLUSTER, mean number of attacks per month with anakinra, individual median of attacks with rilonacept and relapse after withdrawal in the Lachmann trial. An individual median in an alternating design is not comparable with a group mean in a parallel trial, and complete response percentages at 16 weeks are not equivalent to prevention of amyloidosis, which has only been directly demonstrated for colchicine in an observational cohort [41, 115, 116, 120, 123]. The tocilizumab trials, negative on the primary endpoint, should be read alongside the positive ones [62]. For these reasons, the EULAR/PReS and EULAR/ACR recommendations do not rank the IL-1 inhibitors against each other on the basis of indirect comparisons [9, 10].

7.10 Comparative regulatory status: United States and European Union

Regulatory information distinguishes peer-reviewed publication, sponsor press release, CHMP opinion (a recommendation, not an authorisation) and an authorisation decision by the FDA or the European Commission; an authorisation does not guarantee marketing, reimbursement or access in each country, and access in Portugal (INFARMED) and Brazil (ANVISA/CONITEC) was not verified in this update. There have been no new indications in the diseases of this article in the last 12 months: the latest European Commission decision on Ilaris® dates from 30/04/2026 and the recent revisions of the US labels for Ilaris® (08/06/2026) and Kineret® (03/04/2026) maintain the autoinflammatory indications described below [114, 117, 121, 122].

Extrapolation of evidence and off-label use. Extrapolation refers to evidence — for example, applying to PAAD or to FMF with a single variant the results of CLUSTER, which required genetic confirmation, or estimating the effect of anakinra in TRAPS from case series [3, 123]. Off-label use depends on the label, age and jurisdiction: anakinra in FMF is within the indication in the EU but not in the US; canakinumab in NOMID/CINCA is within the indication in the EU but not in the US; canakinumab below 2 years of age and anakinra below 8 months or 10 kg are off-label uses in the EU [114, 117, 118, 121, 125]. In pregnancy, continuation of colchicine rests on the EULAR/PReS recommendations and not on a specific label indication, and data on IL-1 inhibitors come from retrospective series [38, 62, 132].

7.11 Treatment of NLRP1-associated diseases

There is no FDA- or EMA-approved therapy for NLRP1-associated diseases, nor any guidelines or consensus addressing them; all the evidence comes from case reports, and all the systemic drugs mentioned are used off-label [19, 76, 96]. In MSPC, oral retinoids (etretinate or acitretin) halted the progression of palmoplantar tumours, but also prevented their spontaneous regression to scarring; in resistant cases, the tumours were surgically excised, and the conjunctival lesions were all removed surgically [55]. In the original AIADK description, patients responded favourably to IL-1 blockade and acitretin [17, 96]. In the case with MSPC/AIADK overlap, the crisis with pneumonitis and respiratory distress did not respond to high-dose methylprednisolone (20 mg/kg/day for 5 days) or to rituximab (375 mg/m² weekly, four administrations), but resolved with high-dose intravenous anakinra (5 mg/kg four times daily), with discontinuation of invasive ventilation after five days; anakinra was then switched to the subcutaneous route at 10 mg/kg/day and later 5 mg/kg/day, and the addition of ruxolitinib (25 mg/m²/day) normalised CRP and ferritin within two weeks, with control maintained at three years and no adverse effects recorded [76]. In the Turkish adolescent with ulcerated dermatosis, monthly intravenous immunoglobulin for three years and anakinra (200 mg/day for six months) had no effect, and baricitinib (4 mg/day) produced improvement by the second month and extensive healing by the sixth month; an interruption due to unavailability of the drug in the country caused a flare at 22 months, and stability was regained by the 25th month [96]. A paediatric case treated with canakinumab has also been reported [97].

Janus kinase inhibitors were chosen in these reports because they inhibit signalling of a broader set of cytokines than IL-1 blockade, including the pathways downstream of IL-18 and interferon; the isolated response to baricitinib and the partial response to anakinra within the same spectrum suggest heterogeneity between patients, without permitting comparison between drugs [76, 96]. The US baricitinib label carries a boxed warning for serious infections, mortality, malignancies, major adverse cardiovascular events and thrombosis, and requires screening for tuberculosis and viral hepatitis and a full blood count before initiation; the ruxolitinib label requires a full blood count every 2 to 4 weeks until the dose is stabilised and lipid assessment 8 to 12 weeks after initiation [134, 135]. Acitretin is teratogenic: it is contraindicated in pregnancy and requires effective contraception during treatment and for at least three years after discontinuation [133]. For NLRP1-associated JRRP, the sources consulted do not describe the patients' treatment. No inhibitors targeting NLRP1 or the DPP9 pathway in clinical trials were identified; pharmacological inhibition of NLRP1 is referred to as a research prospect [19, 74]. Photoprotection is sensible, given that ultraviolet B radiation activates NLRP1 in keratinocytes through ribotoxic stress, but there is no clinical evidence of its effect in these diseases [73].

7.12 Treatment of haploinsufficiency of A20

There are no society guidelines or consensus documents for haploinsufficiency of A20, nor any drug with an FDA- or EMA-approved indication for this disease; all use is off-label and the evidence is observational, without a controlled trial [22, 26, 81]. The practice described by the centre with the largest case series is organised around three decisions: treat all patients, including those with mild disease, because treatment prevents morbidity; choose the drug according to the dominant phenotype and biomarkers; and avoid abrupt withdrawal of immunosuppression, which may precipitate severe flares [26]. The frequency of use in published series reflects this heterogeneity: in the systematic review of 177 patients, the most used treatments were corticosteroids and non-steroidal anti-inflammatory drugs (32 patients), TNF inhibitors (29), colchicine (28) and methotrexate (14) [81]. In the Japanese survey, 45 of the 54 patients (83.3%) received anti-inflammatory treatment and nine were followed without treatment; colchicine was used in 37 patients (68.5%), considered effective or associated with improvement in 20 (54.1%), and systemic corticosteroids in 38 (70.4%), with efficacy in 57.9% [25].

Mild disease with an autoinflammatory predominance (recurrent fever, serositis, mucosal disease and raised acute-phase reactants) may achieve remission with colchicine monotherapy; in the French paediatric cohort colchicine was effective as monotherapy in 40% of patients [26, 100]. Mucosal disease also responds to phosphodiesterase 4 inhibitors, of which apremilast has an approved indication for the oral ulcers of Behçet's disease — an approval for Behçet's disease and not for haploinsufficiency of A20, although the ulcers are the same; roflumilast, generic and cheaper, does not have this indication but has shown efficacy in small studies [26]. Colchicine and phosphodiesterase 4 inhibitors can be combined with relatively low risk and minimal laboratory monitoring, and both should be started at a low dose with slow titration to limit gastrointestinal effects [26].

In patients who fail these options or who have severe disease threatening an organ, the choice of targeted agent is guided by phenotype and biomarkers. Patients with markers of inflammasome-dependent myeloid activation (IL-18, S100 proteins) or raised serum amyloid A are preferably treated with IL-1 blockade, and patients with raised type I interferon-stimulated genes with Janus kinase inhibitors [26]. In the autoinflammatory phenotype that fails colchicine, the first choice of the Pittsburgh centre is IL-1 inhibition, because of its favourable adverse effect profile; anakinra has a rapid onset of action and a short half-life, and patients are started on 1–2 mg/kg/day with titration up to 5–8 mg/kg/day, as in other autoinflammatory diseases [26]. Daily injection and injection-site reactions at high doses frequently lead to a switch to canakinumab for maintenance, with a lower injection burden, but some patients respond better to anakinra, particularly those with central nervous system disease and severe mucocutaneous disease; with central nervous system involvement, a combination of lower-dose anakinra with canakinumab may be necessary [26]. Rilonacept is a useful alternative in severe mucocutaneous disease, but cannot be combined with anakinra because of mechanistic competition [26]. With prolonged use of anakinra, concerns have been raised about cutaneous or systemic amyloidosis [26].

TNF inhibition is the alternative with the best observational record, especially in gastrointestinal and joint disease and also in large-vessel vasculitis [26]. In the Japanese survey, molecular targeted drugs were given to 24 of the 54 patients (44.4%), with biologics preferred as first choice; among them TNF-α inhibitors were the most used, with a complete response rate of 59.5% and a median duration of efficacy of 1.63 years (range 0.17–9.83) [25]. In the French paediatric cohort, TNF inhibitors had the highest efficacy (adalimumab 60%, infliximab 100% in a small number of patients) [100]. The international cohort of 185 patients concluded that TNF and IL-1 inhibitors were effective in most, with thalidomide and Janus kinase inhibitors reserved for refractory cases, and 51.5% of patients had minimal disease activity at the last assessment [24]. GeneReviews warns, however, that severe paradoxical reactions to anti-TNF monoclonal antibodies may occur [22]. Secondary failure is the main long-term problem: it was the most frequent reason for discontinuation in Japan, observed with ten drugs across seven patients, between two months and several years after initiation; anti-adalimumab antibodies were present in one patient with secondary failure and anti-infliximab antibodies in two, and infliximab was discontinued because of an infusion reaction in three patients [25].

In patients with a predominantly autoimmune phenotype, initial management follows the evidence-based recommendations for each manifestation — methotrexate for seropositive rheumatoid arthritis, mycophenolate with a calcineurin inhibitor for class V lupus nephritis, azathioprine for autoimmune hepatitis —, but many do not respond and move on to biologics; lupus-like disease and inflammatory liver disease have been associated with raised interferon genes and response to Janus kinase inhibitors [26]. Supportive treatments include colchicine and phosphodiesterase 4 inhibitors for persistent mucosal disease, hydroxychloroquine or topical Janus kinase inhibitors for skin disease, methotrexate for peripheral arthritis, and azathioprine, calcineurin inhibitors or sirolimus for liver disease and refractory cytopenias [26]. Thalidomide remains in use in other centres and other countries, was effective in combination with a biologic in two Japanese patients and was used as background treatment, with exclusive enteral nutrition, in four Chinese children [25, 136]. Patients with humoral immunodeficiency or a common variable immunodeficiency phenotype receive immunoglobulin replacement therapy [26]. In disease refractory to a single agent, combinations of biologics have been used: a TNF inhibitor with an IL-1 inhibitor in severe autoinflammation with intestinal disease, and an IL-1 inhibitor with a Janus kinase inhibitor or with interferon alpha receptor blockade in persistent autoinflammation with a raised interferon signature [26]. Anifrolumab, an interferon alpha receptor inhibitor, has been used sporadically with favourable results in patients with a raised interferon signature and was effective in one Japanese patient, but it is not a first-line treatment [25, 26]. Allogeneic haematopoietic stem cell transplantation is an option in severe and refractory disease: one patient has been described in drug-free remission for more than two years after transplantation, and relatives considered as donors should be tested for the familial variant before collection [22, 26].

Flares are treated with short courses of corticosteroids or, in patients who respond to IL-1 blockade, with short on-demand courses of anakinra [26]. Perioperative management and management of intercurrent infections follows an explicit principle: do not universally suspend immunosuppression, but weigh the risk case by case, taking into account the half-life and potency of the drug, the severity of the underlying disease and the invasiveness of the procedure, with a high threshold for suspension in patients with organ- or life-threatening disease [26]. Anakinra can be safely continued even in septic shock, provided the infection is treated, and its withdrawal may trigger a profound rebound effect, with severe autoinflammation or cytokine storm syndrome, because of its short half-life; long-acting TNF inhibitors can be briefly suspended with lower risk [26]. If immunosuppression has to be suspended, patients should be monitored closely, and high-dose IL-1 blockade, pulsed corticosteroids or interferon blockade may be justified [26]. Regarding vaccines, the American College of Rheumatology recommends not giving live attenuated vaccines to patients on continuous biological agents, unless the drug can be interrupted for at least one dosing interval (typically 1 to 4 weeks) before and after vaccination; as many patients with haploinsufficiency of A20 do not tolerate prolonged interruptions, the decision should weigh risk and benefit case by case [22]. In patients with a history of post-vaccination flares, a short course of anakinra (or, less often, low-dose corticosteroid) before the vaccine may reduce that risk; without such a history, empirical use is not recommended, because most patients do not have post-vaccination flares and those that occur are generally mild [26]. In pregnancy, colchicine, azathioprine and hydroxychloroquine are generally continued; TNF inhibitors are recommended in patients with active disease, with consideration of suspension in the third trimester if remission has been achieved, to reduce placental transfer; IL-1 inhibitors are frequently continued, anakinra being considered relatively safe because of its very short half-life; mycophenolate, methotrexate and thalidomide are known teratogens and should be avoided; Janus kinase inhibitors are avoided or contraindicated in pregnancy; and corticosteroid use has been associated with an increased risk of cleft lip with or without cleft palate and with growth restriction, so the decision requires weighing against the risk of uncontrolled inflammation [22]. In the registries consulted on 1 November 2026, no interventional clinical trial with haploinsufficiency of A20 as the condition studied was identified, nor any formal investigational therapy specific to the disease; haematopoietic stem cell transplantation is described as an option to consider and not as a research programme, and this negative search does not demonstrate the absence of ongoing development [22, 140].

7.13 Treatment of haploinsufficiency of RelA

There is no published guideline or consensus for RELA-associated inflammatory disease, and treatment is empirical, derived from reports and small series, without a randomised trial or controlled study [29]. TNF inhibition is the therapy with a mechanistic rationale and the best documented effect: the index patient depended on anti-TNF therapy to maintain remission, and in the murine model TNF-dependent ulceration and colitis improve with TNF blockade [27]. In the largest series, of four families and 23 affected individuals, benefit was observed with glucocorticoids, colchicine and TNF inhibitors [28]. The review of 43 patients allows the accumulated experience to be ordered: most patients with acute symptoms respond to glucocorticoids; for chronic mucocutaneous ulcers or a previous diagnosis of Behçet's disease, anti-TNF therapies were effective (etanercept, infliximab, adalimumab, golimumab), whereas azathioprine, methotrexate and colchicine were only partially effective in some patients [29]. Among published patients, five required no treatment, which is consistent with incomplete penetrance [29]. A patient with Crohn's disease and a Behçet phenotype did not respond to glucocorticoid, colchicine or azathioprine, had serious complications with infliximab and adalimumab, and responded to apremilast; two members of the Eurasian family had fewer flares with colchicine [29, 31]. In the dominant-negative subgroup, one patient responded to infliximab, another to tocilizumab followed by adalimumab, and a third, with Crohn's disease, immune thrombocytopenia and autoimmune neutropenia refractory to rituximab and tacrolimus, responded to allogeneic haematopoietic stem cell transplantation [29, 58]. No trial specific to this disease was identified in the registries; the type I interferonopathy demonstrated in the dominant-negative subgroup provides the rationale for considering Janus kinase inhibition or blockade of the interferon pathway in patients who do not respond to anti-TNF therapy, but this is a mechanistic rationale and not a tested therapy [58, 140].

The most relevant practical implication concerns therapeutic orientation rather than diagnosis: identifying a RELA variant in a patient labelled as having Behçet's disease shifts the treatment rationale towards TNF blockade, even though in some patients the molecular diagnosis does not change the regimen already in place [28, 29]. The absence of data on pregnancy, breastfeeding, vaccination and the perioperative period in this entity makes it necessary to transpose the general recommendations for autoinflammatory diseases and for the drugs used, which is an extrapolation and should be explained to the patient [22].

7.14 Treatment of CARD8-associated inflammatory bowel disease

There is no guideline, consensus or trial for CARD8-associated inflammatory bowel disease, and no drug has an approved indication for this condition [33, 34]. The basis of treatment is that of Crohn's disease, according to the 2024 recommendations of the European Crohn's and Colitis Organisation (ECCO), which stratify the choice between glucocorticoids, immunomodulators and advanced therapies by severity, extent and disease behaviour [104]. The rationale for IL-1 blockade comes from a single patient: the proband of the index family did not respond to glucocorticoids, azathioprine, infliximab at a dose above the label dose or vedolizumab, and improved rapidly with anakinra, with a fall in faecal calprotectin, a reduction in stool volume to less than 500 mL/day and normalisation of albumin; he was then maintained on canakinumab every four weeks, the dose of which was increased from 3 to 4 mg/kg because of persistent microscopic inflammation in the left and transverse colon, combined with vedolizumab, with formed stools, normal growth and normalisation of serum IL-1β and calprotectin [33]. Treatment with the anti-IL-1β antibody normalised serum IL-1β, IL-6 and TNF-α, but not the inflammasome hyperactivation of monocytes stimulated ex vivo, which is compatible with an effect downstream of the defect [33]. The response of the mother and the aunt to IL-1 blockade was not tested [33]. In the girl described by Gennaro and colleagues, the combination of methotrexate and adalimumab was effective [102].

IL-1 blockade is thus an off-label option, to be considered in disease refractory to conventional therapies and TNF inhibitors, with the level of evidence of a case report [33]. Combination of an IL-1 inhibitor with a TNF inhibitor is not recommended, because of the increased risk of serious infections [117, 121]. Tuberculosis screening, vaccination updating and infection surveillance follow the rules for IL-1 blockade and for inflammatory bowel disease biologics [117, 121, 138, 141]. Prolonged exposure to glucocorticoids should be limited, as shown by the proband's avascular necrosis [33, 104].

7.15 Therapeutic recommendations of the French PNDS (FMF, CAPS and TRAPS)

Framework. The PNDS (French National Diagnosis and Care Protocols) are written by the reference centres according to the method published by HAS in 2012, serve as a reference for the treating physician in establishing the care protocol with the consulting physician of the Health Insurance Fund (exemption from co-payment for a long-term condition «not on the list») and identify the medicinal products used outside the marketing authorisation (MA) [12, 15]. Prescription outside the MA is possible in the absence of a suitable alternative, when the indication has been the subject of a temporary recommendation for use by ANSM or when the prescriber considers it indispensable in the light of scientific data; the patient must be informed of the off-label nature, of the risks, constraints and benefits and of the reimbursement conditions, the prescription must state «prescription outside the MA», and the decision is justified in the clinical record; reimbursement may be granted by derogation and for a limited time after a temporary recommendation and an HAS opinion [15]. The CAPS PNDS grades recommendations according to ANAES (2000): grade A, scientific proof established by high-powered randomised trials or meta-analyses; grade B, scientific presumption from lower-powered trials, non-randomised comparative studies or cohorts; grade C, case-control studies; grade D, biased or retrospective comparative studies or case series [14].

FMF — treatment of the attack. Treatment of the attack is only symptomatic, with rest and suspension of school or work activity for as long as symptoms last; first line combines an antipyretic analgesic (paracetamol) and a non-steroidal anti-inflammatory drug, uses the parenteral route if there is nausea or vomiting and uses anti-inflammatory drugs with caution in kidney disease; if pain persists, step 2 analgesics are used and, if necessary, morphine, bearing in mind the risk of dependence with repeated and prolonged use (doses in the following table) [12]. The PNDS does not recommend «on-demand» anakinra for the attack (used in some centres, but without a randomised trial, more expensive than analgesics, injectable, to be stored at 4 °C and liable to impair adherence to colchicine), systemic corticosteroid therapy, or a transient increase in the colchicine dose, because of lack of proof of efficacy and an increased risk of adverse effects, since colchicine does not treat the attack; intravenous colchicine is proscribed because of the risk of fatal overdose and is no longer available in France [12].

FMF — colchicine. In France colchicine has an MA in FMF under the designation «treatment of periodic disease» and should be prescribed for life to any patient, except in the case of an exceptional contraindication, to prevent attacks and amyloidosis; the combination with tiemonium and opium should not be used [12]. The adult starting dose is 1 mg/day orally, adjusted in non-responders in steps of 0.5 mg at minimum intervals of 3 months up to the minimum effective dose, without exceeding 2.5 mg/day; in AA amyloidosis 1.5 mg/day is used from the outset, regardless of clinical response, and in end-stage renal failure on dialysis a very low dose (0.5 mg/day) is maintained, with monitoring for diarrhoea and neuromyopathy [12]. In children, the starting dose depends on age and not on weight: 0.5 mg/day before 5 years and 1 mg/day thereafter; up to 10 years it is adjusted in steps of 0.25 mg without exceeding 2 mg/m²/day, and after 10 years in steps of 0.5 mg, according to digestive tolerance, up to the maximum adult dose [12]. Colchicine has a narrow therapeutic index; renal and, to a lesser extent, hepatic impairment increase toxicity; it has no antidote and is not dialysable, so packs should be kept out of the reach of children and precautions are required in patients at suicidal risk; renal and hepatic function are assessed 1 to 2 times per year, the dose is adjusted in the elderly, and combinations with inhibitors of the ABCB1 transporter (P-glycoprotein) or CYP3A4 are formally contraindicated in renal or hepatic impairment [12]. The PNDS proposes writing on each colchicine prescription the warning «do not combine with certain treatments or antibiotics, in particular macrolides and pristinamycin; inform your doctor or pharmacist of this treatment» [12]. Among the drugs that interfere with ABCB1 it lists erythromycin, clarithromycin, ciclosporin, tacrolimus, verapamil, statins, fexofenadine, H2 antagonists, fenofibrate, some cytostatics, tricyclics, digoxin, antiretrovirals, corticosteroids and ketoconazole; among CYP3A4 inhibitors, grapefruit juice, vitamin K antagonists, amiodarone, diltiazem, verapamil, azoles, HIV protease inhibitors, erythromycin, clarithromycin, josamycin and telithromycin; when the combination is unavoidable, its duration should be shortened, the colchicine dose reduced and signs of overdose monitored (diarrhoea, vomiting, muscle weakness, paraesthesia of the fingers, pallor of the lips and palms, recent hair loss) [12].

Table source: appendix 6 of the PNDS, adapted from the FDA recommendations [12]. The adult maxima correspond, with 0.5 mg tablets, to the 0.6 mg/day and 1.2 mg/day of the Colcrys® label (0.6 mg tablets) [113].

FMF — assessment, intensification and reduction. The aim is complete absence of unprovoked attacks and resolution of subclinical inflammation, assessed by CRP below the laboratory limit measured at least 10 days after the end of the last attack [12]. Response is reassessed every 6 to 12 months by the frequency and severity of residual attacks (severe attack: more than two sites, more than 72 hours, pain with a visual analogue scale score above 5 or pain not relieved by step 1 and 2 analgesics), by days of absence from school or work, by the impact on daily life, by complications (growth delay, anaemia, symptomatic splenomegaly, persistent arthritis, joint destruction, liver disease, amyloidosis) and by CRP; toxicity (number and consistency of stools, nausea, creatine kinase and liver tests interpreted in the light of CRP), adherence (missed doses per week and management of packs) and the patient's beliefs about the drug are also assessed [12].

Table source: [12].

Before concluding resistance, the PNDS applies an eight-point checklist (Hentgen and colleagues, 2020): confirm the diagnosis, including genetics; confirm that the symptoms are inflammatory, with biomarkers collected during attacks; exclude common causes of fever and pain, especially H. pylori and C. difficile infections, treated with antibiotics excluding macrolides; look for triggering personal, social or psychological problems and offer behavioural stress management; ensure adherence to the full dose for at least 3 to 6 months and, if the maximum dose has not been reached, increase it in steps of 0.5 mg (0.25 mg before 5 years) every 3 months; improve tolerance (limit lactose, divide the daily dose, add antidiarrhoeal and antispasmodic agents); with sudden worsening despite full adherence, look for inflammatory rheumatism, vasculitis and, after 50 years of age, low-grade myeloid haemopathy and chronic peritonitis or peritoneal mesothelioma; and document attacks prospectively for 3 to 6 months [12]. For the hair colchicine assay, a lock the thickness of a pencil is cut close to the scalp, at the top and back of the head, tied with a thick thread about 1 cm from the root to identify the proximal end, without adhesive tape, and stored and transported between 15 °C and 25 °C to the pharmacology and toxicology laboratory (in France, that of Raymond-Poincaré hospital, in Garches) [12].

IL-1 inhibitors do not have an MA as first line, but should be considered in contraindication (hepatocellular insufficiency, chronic kidney disease with a glomerular filtration rate below 30 mL/min) or true intolerance to colchicine, and in insufficient response to maximum doses [12]. Under an IL-1 inhibitor, colchicine is maintained at 1 mg/day (0.5 mg/day before 5 years), unless the switch was prompted by toxicity, complete intolerance or contraindication, an exceptional situation [12]. In persistent arthritis or associated chronic inflammatory rheumatism, the addition of non-steroidal anti-inflammatory drugs, local glucocorticoids or TNF inhibitors is considered, looking for the diseases statistically associated with FMF (spondyloarthritis, inflammatory bowel disease), with discussion at a national multidisciplinary meeting and a rheumatology or gastroenterology opinion; TNF inhibitors are the most used option in associated spondyloarthritis, and coxitis requires close rheumatological follow-up and discussion of specific treatment with the expert centre [12].

FMF — AA amyloidosis and the kidney. Colchicine alone at the maximum dose (2.5 mg/day, if renal function is normal) may cause a nephrotic syndrome to regress or disappear; if it persists, an IL-1 inhibitor is added, maintaining colchicine at 1 mg/day [12]. With a glomerular filtration rate below 30 mL/min, and in agreement with nephrology, colchicine is suspended or limited to 0.5 mg/day and, if CRP remains raised, replaced or supplemented by anakinra, a short-acting inhibitor, at a dose of 100 mg/day subcutaneously in non-dialysed patients and 100 mg on dialysis days in haemodialysed patients; after kidney transplantation anakinra is maintained for a few months, colchicine is resumed, usually at 1 mg/day, as soon as renal function allows, verifying the absence of inflammation, and anakinra is weaned over 3 months [12]. Any other source of inflammation, even minimal, should be sought and treated, because it maintains the amyloidogenic situation: intercurrent or chronic infections (particularly tuberculosis), spondyloarthritis and inflammatory bowel disease, which may require TNF inhibitors, and obesity, with nutritional intervention and regular physical activity [12]. Nephroprotective measures have not been evaluated specifically in FMF amyloidosis: angiotensin-converting enzyme inhibitors or AT1 receptor antagonists are proposed for albuminuria above 300 mg/24 hours, with great caution because of frequent hypotension (amyloidosis, adrenal insufficiency, hypovolaemia from capillary leak, other antihypertensives) and with suspension in the event of diarrhoea or dehydration, because of the risk of acute kidney injury, especially on diuretics; the protein restriction usual in chronic kidney disease should not be systematic, and nephrotic syndrome requires a protein intake above 1.2 g/kg/day; sodium is limited in significant oedema, but adjusted to losses in chronic diarrhoea or adrenal insufficiency, and fluid restriction is only required in hyponatraemia; nephrotoxic agents (non-steroidal anti-inflammatory drugs, aminoglycosides, platinum salts) and iodinated contrast media without prior hydration are avoided; and diabetes, smoking and dyslipidaemia, frequently aggravated by nephrotic syndrome, are controlled [12].

FMF — non-pharmacological measures, therapeutic education and vaccination. Psychological support should be offered in adolescence, to optimise adherence, when the disease has a strong social or family impact or is poorly controlled, when there is a psychological component to the somatic manifestations and, if necessary, at the time the diagnosis is communicated [12]. Joint rehabilitation is necessary in chronic involvement, manual lymphatic drainage of the lower limbs may prevent exertional myalgia and pseudo-erysipelas, and remote working one or two days a week may be offered, especially in hot periods [12]. The adult therapeutic education programme, available since 2022 at the adult reference centre, covers triggers (sleep deprivation, stress, violent physical exertion), warning signs and signs of poorly controlled disease, the risk of amyloidosis and testing for proteinuria every 6 to 12 months, adherence, the schedule of consultations and vaccines, adverse effects and the risks of discontinuation, the prohibition on increasing colchicine on one's own during attacks, the main interactions (macrolides, statins, ciclosporin, St John's wort, grapefruit juice), management of pregnancy and the harmlessness of colchicine for male and female fertility, pregnancy and breastfeeding; for children, the individualised reception plan (PAI) at school, adaptation of sports activities and transition consultations are added [12]. On colchicine, vaccination recommendations are those of the general population, without increased risk with live or inactivated vaccines; on a biologic (IL-1 or TNF inhibitors), whose introduction is rarely urgent, the schedule should be completed beforehand (including the human papillomavirus vaccine in both sexes) and the 13-valent pneumococcal conjugate vaccine added (age-based schedule, or one dose in the unvaccinated) followed by one dose of 23-valent polysaccharide vaccine, the varicella vaccine in non-immune individuals (two doses 4 to 8 weeks apart) and the annual influenza vaccine; during treatment, annual influenza, diphtheria-tetanus-poliomyelitis every 10 years, papillomavirus vaccine in three doses (even before 14 years) with catch-up up to 26 years, and pneumococcal polysaccharide vaccine every 5 years [12]. The pneumococcal schedule of the PNDS (French National Diagnosis and Care Protocol) is out of date: in France, the PCV13 + PPV23 sequence was replaced in July 2023 by a single dose of high-valency conjugate vaccine in at-risk adults, and the July 2026 revision prefers PCV21 (Capvaxive®), as a single dose, in at-risk adults aged 18 to 64 years and in all adults aged 65 years or older, and PCV20 (Prevenar 20®), as a single dose, in at-risk children and adolescents aged 15 months to 18 years, abandons PCV13, PCV15 and PPV23 in at-risk children and does not address revaccination; the schedule for patients on biologics follows the current vaccination calendar [143]. In the US, the CDC recommends PCV15 or PCV20 in at-risk children and PCV15 (followed by PPSV23), PCV20 or PCV21 in at-risk adults aged 19 to 49 years and in all adults aged 50 years or older, so the polysaccharide vaccine still has a place in the US schedule [144, 145].

CAPS. In the 2013 PNDS, the only maintenance treatments with demonstrated efficacy are IL-1 inhibitors, which should be offered long term in MWS (grade A) and CINCA (grade B), to avoid attacks and try to prevent amyloidosis (grade D), and in severe FCAS not limited to cold urticaria (grades A and C), regardless of whether an NLRP3 variant has been identified; patients without a variant should be discussed collegially in a reference centre (grades B and D) [14]. Treatment should begin as early as possible, in an experienced centre, because it improves neurosensory and neurological lesions when started in time (grade B), but does not act on sequelae or on hypertrophic arthropathy, and passage across the blood-brain barrier limits the effect on the central nervous system; before 4 years of age it requires particular care because of the risk of infection with encapsulated bacteria [14]. Anakinra (half-life 4 to 6 hours), then used outside the MA in France, was prescribed at starting doses of 0.5 to 2 mg/kg/day in children from 12 months of age and of 100 to 200 mg/day in adults, by daily subcutaneous injection, with higher doses according to severity (about 3.5 mg/kg/day in MWS and 6 to 10 mg/kg/day in two injections in CINCA); the high doses sometimes necessary before 6 months are reserved for exceptional cases with the agreement of a reference centre, neurological improvement requires increasing the dose and monitoring headache, papilloedema and meningeal inflammation by lumbar punctures, the dose ceiling has not been defined and discontinuation is followed by relapse (grade B) [14]. Canakinumab (half-life 28 to 30 days), with an MA in CAPS since 2009 after a randomised trial in MWS (grade A), was prescribed from 4 years of age and 15 kg: 2 mg/kg (15 to 40 kg) or 150 mg (more than 40 kg and adults), subcutaneously every 8 weeks, the dose being doubled, keeping the interval, if there was no improvement 7 days after the first injection; caution is recommended above 65 years, it has the status of an exceptional medicinal product and the first prescription is hospital-based, by rheumatology, internal medicine, dermatology or paediatrics [14]. Rilonacept (half-life 6 to 7 days), approved by the FDA in 2008 and by the European centralised procedure in 2009, was not available in France; gevokizumab, a long half-life anti-IL-1β antibody, was then in trials [14]. The ages and indications of these labels changed later (section 7.10).

Injection-site reactions are very frequent (up to 90% in the first weeks with anakinra and 50% with rilonacept); the PNDS proposes anaesthetic cream (EMLA®) at least 1 hour beforehand, product at room temperature, ice on the skin before injection (without systemic risk, because the ice test is negative in CAPS), slow injection over 5 minutes and topical corticosteroids for intense reactions, and advises against mixing lidocaine with the drug; an anaphylactic or anaphylactoid reaction requires permanent discontinuation (grade D) [14]. In published studies, serious infections occurred in 1.8% of patients on anakinra compared with 0.6% on placebo over 6 months, mainly cellulitis, pneumonia and osteoarticular infections, with a particular risk of Streptococcus pneumoniae; in the US rilonacept trial two adults died, one from pneumococcal meningitis and the other from myocardial infarction; minor infections were more frequent (34% versus 27%), and in infants under 6 months on high doses antibiotic prophylaxis should be discussed [14]. IL-1 inhibitors are contraindicated in acute infection, latent or active tuberculosis (screening by history, tuberculin skin test, interferon-γ release assay if necessary and chest radiograph) and active neoplasia, and not advised in chronic infection, severe depression, neutropenia below 1,000/mm³, progressive ischaemic heart disease, hepatic dysfunction and neoplasia in remission for less than 5 years; they should not be combined with each other or with TNF inhibitors, and cytochrome P450 substrates, such as warfarin, require monitoring [14]. The pre-treatment work-up includes the disease work-up according to the form (audiometry, ophthalmology, lumbar puncture, brain magnetic resonance imaging), screening for tuberculosis, full blood count, ESR, CRP, SAA, transaminases, bilirubin, gamma-glutamyltransferase, total, LDL and HDL cholesterol, triglycerides, urea, creatinine and dipstick or microalbumin/creatinine ratio, possibly semen analysis and, if the history justifies it, protein electrophoresis, HIV and hepatitis B and C serology [14]. Under treatment, serious infection requires suspension until cure, cancer requires interruption, liver abnormalities require reduction or suspension according to severity, neutropenia below 1,000/mm³ requires interruption, refractory depression requires suspension, dyslipidaemia or weight gain requires dietary and lipid-lowering measures, thrombotic cardiovascular disease requires case-by-case discussion and macrophage activation syndrome requires interruption [14]. Before the biologic, the PNDS recommends complete pneumococcal vaccination (conjugate up to 5 years and polysaccharide from 2 years, repeated every 3 to 5 years), updating of the rest of the schedule, annual influenza vaccine and, in those seronegative for varicella-zoster virus, varicella vaccine at least 4 weeks beforehand, vaccination of household contacts if the patient cannot be vaccinated, prophylaxis within 48 hours of an exposure and a booster before transition to adult care; live attenuated vaccines are not advised during treatment, except after case-by-case consideration, and when indispensable at least 2 days should be allowed after the last anakinra injection, 6 weeks after that of rilonacept and 5 months after that of canakinumab, and 4 weeks before the next injection [14].

Colchicine, classic immunosuppressants and TNF inhibitors are ineffective or of little efficacy in CAPS and are not recommended (grade B); nor are H1 antihistamines, because their apparent efficacy corresponds to spontaneous regression of attacks (grade B); high-dose corticosteroids are sometimes necessary for severe neurological or neurosensory manifestations, especially when IL-1 inhibitors are contraindicated or fail (grade B); thalidomide gave partial control with poor tolerance (grade C); and intravenous immunoglobulins should be avoided in severe forms, because they may provoke a significant meningeal reaction [14]. Organ-specific symptomatic treatments include ocular antihistamines and topical corticosteroids, emollients and short-term topical corticosteroids, analgesics, non-steroidal anti-inflammatory drugs with a proton pump inhibitor and intra-articular corticosteroid injections, and ophthalmological treatments, antidepressants or anxiolytics as needed; in amyloidosis with renal failure, the aim is complete control of inflammation, with a normal SAA, below 10 mg/L [14]. Non-pharmacological measures comprise avoiding cold and temperature changes (air conditioning) when they are triggers, psychological support, physiotherapy, orthoses, occupational therapy and prosthetic surgery in severe arthropathies, hearing aids, ocular surgery (glaucoma, cataract), ventriculoperitoneal shunting in threatening intracranial hypertension, systematic screening and early intervention for cognitive deficits (psychomotor therapy, speech therapy, special education), treatment of the complications of amyloidosis (dialysis, kidney, liver or heart transplantation) and, in multiple disability, adaptation of the home and vehicle and assistive devices [14].

TRAPS. Treatment of the attack is symptomatic, with rest and suspension of activities [15]. Non-steroidal anti-inflammatory drugs and paracetamol act on fever but little on the other symptoms, and are combined with step 2 or 3 analgesics if the pain is intense [15]. «On-demand» corticosteroids are effective on all symptoms and on attack duration and are sufficient for more than half of patients: 0.5 to 1 mg/kg/day of prednisolone equivalent orally, not exceeding 60 mg/day, as a single morning dose from the first day and for 2 to at most 10 days, with abrupt discontinuation without tapering and repetition at the next attack; if more than 6 courses per year are needed (more than one every 2 months), an alternative is discussed to avoid the effects of repeated corticosteroid therapy [15]. «On-demand» anakinra, outside the MA, is an option in patients with well-identified attacks and completely asymptomatic intervals, because it limits the periods of immunosuppression: it is proposed in the event of contraindication to or adverse effects of corticosteroids and of overly frequent attacks (more than 6 per year), after verifying the absence of intercritical inflammation, at a dose of 2 mg/kg/day not exceeding 100 mg/day, as a daily subcutaneous injection started on the first day of the attack and maintained for 3 to 7 days; if it is needed more than once a month or if CRP or SAA remain above normal between attacks, maintenance treatment is discussed [15].

No maintenance treatment was fully validated in 2018, so the indication should be discussed within the reference centre network and the patient should be included in the national prospective cohort (JIRcohorte) [15]. Colchicine, prescribed by analogy with FMF, benefits only 20% to 50% of patients, mainly carriers of p.Arg121Gln, with no effect in structural cysteine variants; the PNDS reserves it for minor variants (NM_001065.4:c.362G>A p.(Arg121Gln) and c.224C>T p.(Pro75Leu)), at 1 mg/day after 5 years and in adults and 0.5 mg/day before 5 years, with the FMF precautions and reassessment at 6 months by the AIDAI [15]. Classic immunomodulators (methotrexate, azathioprine, mycophenolate mofetil, ciclosporin, cyclophosphamide, thalidomide, chlorambucil, intravenous immunoglobulins, dapsone) have no demonstrated efficacy and should not be offered [15]. As maintenance treatment, anakinra (outside the MA) is used at 2 mg/kg/day, up to 100 mg/day, as one subcutaneous injection, and may be progressively increased, if intercritical inflammation persists, up to 4 mg/kg/day in children or 200 mg/day in adults; canakinumab (European MA, without defined reimbursement in France in 2018) is given subcutaneously every 8 weeks — 150 mg above 40 kg, 2 mg/kg between 15 and 40 kg, 4 mg/kg between 7.5 and 15 kg — and, if inflammatory signs persist, the injections are progressively brought closer together down to every 4 weeks and only then is the unit dose increased, up to a maximum of 4 mg/kg or 300 mg every 4 weeks [15]. There are no comparative data between the two drugs, which appear equally effective; the indication and choice are made at a multidisciplinary meeting of the reference centre or the FAI²R network, also because of reimbursement difficulties [15]. Etanercept gives frequently transient improvement, with loss of response, and is reserved for the rare patients who fail the previous options; adalimumab and infliximab should not be used, because of disappointing efficacy and the risk of paradoxical reactions, particularly with the c.236C>T p.(Thr79Met) genotype (formerly T50M) [3, 15]. Given the uncertainty, the options should be explained to the patient by an experienced physician and adapted to the patient's wishes and complaints [15].

Before an IL-1 inhibitor, the TRAPS PNDS requires exclusion of intercurrent infection, a history of recurrent serious bacterial infections, chronic viral infection (HIV, hepatitis B and C), liver abnormalities (transaminases, bilirubin, gamma-glutamyltransferase), latent tuberculosis (tuberculin skin test and/or interferon-γ release assay, chest radiograph if in doubt), significant neutropenia or leucopenia and pregnancy, and updating of vaccines, with annual influenza, pneumococcal vaccine according to the immunocompromised schedule, varicella in non-immune individuals and live vaccines at least 3 weeks before initiation; prolonged corticosteroid therapy is not indicated, and the vaccination schedule under biologics follows the recommendations of the Haut Conseil de la Santé Publique [15]. Non-pharmacological measures include psychological support in the same situations as in FMF, non-drug pain management (pain clinic, hypnosis and self-hypnosis, cognitive behavioural therapy), regular physical activity, adapted by medical prescription and guided by a health sports educator when exertion triggers attacks, and joint rehabilitation; therapeutic education includes self-care skills (management of analgesics and on-demand corticosteroid therapy, self-injection, transport and storage of biologics) and testing for proteinuria every 6 to 12 months [15]. AA amyloidosis is an indication for maintenance treatment to lower inflammatory markers, preferably with an IL-1 inhibitor [15].

Divergences between the PNDS and the other sources cited. The guideline is the dose reference in each jurisdiction and the label serves for comparison; the following divergences should be made explicit when one or other source is applied.

8. Reproductive Options and Family Counselling

8.1 FMF

FMF is caused by biallelic MEFV variants; the parents of a proband are usually heterozygous, and each sibling has, at conception, a 25% chance of being affected, a 50% chance of being heterozygous and a 25% chance of inheriting neither variant [1]. In populations with a high carrier frequency or consanguinity, a parent may also be biallelic, in which case the risk to siblings rises to 50%, creating pseudodominance [1]. The offspring of a biallelic proband inherit one variant; their risk of being affected depends on the genetic status of the reproductive partner, whose testing should be considered, particularly if there is consanguinity or shared ancestry [1]. If only one parent is a carrier, a de novo variant, parental mosaicism or uniparental isodisomy should be considered [1]. Testing for the familial variants should be offered to asymptomatic siblings, so that treatment can be started early; systematic screening of asymptomatic heterozygotes is not recommended unless there is a family history of amyloidosis or symptoms [1]. Once the familial variants are known, prenatal diagnosis and preimplantation genetic testing are possible [1].

For population counselling, the Oxford Desk Reference reproduces the empirical estimates of Lazarin and colleagues, obtained by expanded carrier screening: FMF carrier frequency of 1 in 64.2 across all populations, 1 in 13.2 in Ashkenazi Jews, 1 in 24.5 in the Middle East, 1 in 74.5 in southern Europe, 1 in 99.5 in north-western Europe and 1 in 136.6 in Hispanic individuals; in Ashkenazi and Middle Eastern populations FMF is among the most frequent recessive conditions, although neither the ACMG nor ACOG (American College of Obstetricians and Gynecologists) recommended population screening for it [149]. These estimates include variants now considered benign and should be interpreted with that caveat [1].

Pregnancy and lactation. Colchicine should not be stopped during conception, pregnancy or lactation, and current evidence does not justify amniocentesis because of colchicine exposure; in men colchicine need not be stopped before conception, and it may be reduced or temporarily interrupted in the rare cases of azoospermia or oligospermia proven to be drug-related [38, 62]. Information on IL-1 inhibitors in pregnancy is limited; retrospective analyses suggest that anakinra and canakinumab are effective in pregnant women with FMF and other autoinflammatory diseases, with low fetal risk, and no pattern of congenital anomalies has been identified with IL-1 or TNF inhibitors [1, 132]. Corticosteroids in pregnancy are associated with an increased risk of cleft lip with or without cleft palate [1].

Position of the French PNDS. The 2022 PNDS couples the disclosure of the diagnosis with genetic counselling that informs about the risk to relatives and offspring and proposes a family enquiry of relatives with symptoms, without screening of asymptomatic relatives, considering that there is no indication for prenatal diagnosis; it thus diverges from GeneReviews, which recommends offering testing to asymptomatic siblings and allows prenatal diagnosis and preimplantation testing once the familial variants are known [1, 12]. Regarding fertility, before colchicine the spontaneous miscarriage rate was estimated at 25% to 30% and female infertility at 30%, attributed to tubo-ovarian adhesions from peritoneal fibrosis; these figures have presumably fallen with maintenance treatment, but recent data are scarce [12]. A Turkish study cited by the PNDS found infertility in 14.6% of patients, versus 8.6% in the general female population, associated with a higher number of attacks, early onset, homozygous or compound heterozygous p.Met694Val and p.Met680Ile genotypes, late diagnosis and treatment, poor adherence and non-response to colchicine; the causes described include tubal factor and ovarian insufficiency of poorly understood mechanism [12]. Pregnancy may suppress, worsen or not alter attacks; abdominal attacks may increase the risk of miscarriage, and a comparative series showed a higher risk of preterm delivery, without differences in Apgar score, malformations or perinatal mortality [12]. Colchicine is continued at the usual dose during pregnancy, without an increase in miscarriages or malformations (miscarriages were even less frequent than in untreated patients) and without an indication for systematic amniocentesis; the French reference centre on teratogenic agents (CRAT) disagrees with the pregnancy hazard pictogram printed on the packs [12]. Obstetric follow-up does not differ from usual, but the PNDS proposes visits every 2 months with a full blood count and CRP; FMF does not increase thrombotic risk nor, with normal renal function, the risk of pre-eclampsia, whereas renal amyloidosis makes the pregnancy high-risk (worsening renal function, pre-eclampsia, fetal growth restriction, preterm delivery) and requires joint follow-up by nephrology and obstetrics [12]. During breastfeeding, colchicine should be taken at the time of a feed, because the peak in milk occurs approximately 2 hours after the dose, preferably at night, when feeds are further apart; the combination of colchicine with tiemonium methylsulfate and opium (Colchimax®) is contraindicated during breastfeeding [12]. In men, fertility is preserved in the great majority and sperm quality on colchicine is not altered in the available studies; in the event of infertility on colchicine, the drug may be stopped for at least three months and semen analysis repeated, controlling the disease with an IL-1 inhibitor during that period; testicular vaginalitis and testicular amyloidosis have also been implicated [12]. As for IL-1 inhibitors, data in pregnancy are scarce but reassuring; two cases of renal agenesis on anakinra have been described in patients with other risk factors, without causality being excludable; the PNDS prefers anakinra, because of its short half-life and more abundant data, suggests not administering canakinumab from 22 weeks, because of transplacental passage of IgG from the 30th week, and allows breastfeeding on IL-1 inhibitors [12].

8.2 CAPS

CAPS show autosomal dominant inheritance, with a 50% risk for each child of an affected individual [5, 8]. In severe forms (CINCA/NOMID) the variants are often de novo and somatic mosaicism is common [5, 48]. In patients with somatic mosaicism acquired in adulthood, the variant is, as a rule, not present in the germline [66]. The recurrence risk for siblings of a proband with a de novo variant depends on the possibility of parental gonadal mosaicism.

The CAPS PNDS (2013) recommends that disclosure be organised by a reference or competence centre, with information on transmission, a family enquiry of cases without screening of asymptomatic relatives and renewal of genetic counselling when the wish to have children arises [14]. It considers that preimplantation diagnosis cannot be recommended, because the phenotype varies unpredictably within the same family, and that requests for termination of pregnancy for medical reasons should be examined case by case, according to the severity of the parental disease and the foreseeable repercussions of the disease or treatment on the fetus [14]. Sterility is frequent in MWS and CINCA and should be screened for (semen analysis, assessment of amenorrhoea), and requests for medically assisted reproduction should be considered [14]. At the time of the PNDS, pregnancy and breastfeeding on IL-1 inhibitors were advised against, with effective contraception until five half-lives after the last dose; this position predates the series of exposed pregnancies and the recommendations of the TRAPS (2018) and FMF (2022) PNDS, described in sections 8.1 and 8.3 [12, 14, 15, 132].

8.3 TRAPS

TRAPS shows autosomal dominant inheritance; most patients have an affected parent, but the proportion of de novo cases is unknown [3]. Each child has a 50% chance of inheriting the variant [3]. If the variant is not detected in the parents, a de novo variant or parental mosaicism (somatic and germline) should be considered; the latter has been described and may be associated with a mild parental phenotype; the family history may appear negative because of reduced penetrance, variable expressivity or late onset [3]. Predictive testing in asymptomatic adults requires prior identification of the familial variant, and DNA banking is recommended for probands without a molecular diagnosis [3]. For low-penetrance variants, counselling should emphasise that most carriers do not develop disease [3, 68]. The family described by Zegarska and colleagues, in which a 33-year-old man with renal AA amyloidosis transmitted a novel in-frame insertion in TNFRSF1A to three symptomatic daughters, illustrates the value of cascade diagnosis [150].

The TRAPS PNDS (2018) gives a risk of 1/2 for the offspring of an affected parent and proposes a family enquiry of relatives with symptoms, without screening of asymptomatic relatives; it does not recommend systematic genetic screening before procreation or in the siblings of an affected child, because the life expectancy of a child with TRAPS today does not differ from that of the general population, but parents should be able to recognise the signs of the disease quickly for early diagnosis and treatment [15]. Presymptomatic diagnosis is generally advised against and, in France, prohibited in minors outside a framework requiring the opinion of a personal protection committee; it may be discussed in families with highly disabling TRAPS or with renal amyloidosis, and the relevance of prophylactic treatment in an asymptomatic carrier remains without a consensus answer; prenatal and preimplantation diagnosis are exceptionally indicated, given that targeted therapies limit morbidity and mortality [15]. In the absence of amyloidosis, fertility does not appear to be altered in either sex, with or without IL-1 inhibitors; in the event of infertility, amyloidosis is excluded first and the usual causes are then sought [15]. In pregnancy, the course is unpredictable, abdominal attacks favour contractions and miscarriages, non-steroidal anti-inflammatory drugs are contraindicated in the third trimester (premature closure of the ductus arteriosus), and corticosteroids and colchicine may be continued, consulting the CRAT in case of doubt; when IL-1 inhibitors cannot be stopped, anakinra is preferred and canakinumab avoided, particularly after 22 weeks; breastfeeding is possible, because the protein nature of the drugs makes absorption by the infant unlikely; and in the newborn exposed in utero, live vaccines (BCG, rotavirus, measles-mumps-rubella, yellow fever) are contraindicated in the first 3 to 6 months, because of possible transient immunosuppression [15].

8.4 MKD

MKD is autosomal recessive, with a 25% recurrence risk for siblings; carrier detection is by genetic testing, and prenatal diagnosis is possible by molecular or enzymatic analysis [6]. The French PNDS reserves prenatal diagnosis for exceptional cases with early death, proposes study of symptomatic relatives without screening of asymptomatic ones, describes no alterations in fertility, asks for joint follow-up of pregnancy by the specialist, the obstetrician and, if there is renal involvement, the nephrologist, and assesses case by case whether to continue anti-IL-1 treatment in pregnancy [13].

8.5 NLRP1-associated diseases

Counselling depends on the phenotype and zygosity. In MSPC and in the heterozygous forms of AIADK, each child of a carrier has a 50% chance of inheriting the variant, but the incomplete penetrance and variable expressivity described make it impossible to predict severity, and a carrier parent may have only subtle lesions [55, 75, 76]. With de novo variants, such as p.(Pro1214Arg), the recurrence risk for siblings is low, although parental germline mosaicism cannot be excluded [17, 56]. In recessive AIADK and in JRRP, the siblings of an affected individual have a 25% risk, and parental consanguinity was described in the family with recessive AIADK [17, 18]. Cascade testing allows asymptomatic carriers to be identified and dermatological and ophthalmological surveillance to be directed; in minors, it is justified by the childhood onset of the lesions and of corneal opacification [55, 76]. Prenatal and preimplantation diagnosis are technically possible once the familial variant has been identified.

8.6 Haploinsufficiency of A20

Inheritance is autosomal dominant and each child of an affected individual has a 50% chance of inheriting the variant [22]. Many patients have an affected parent; some have a de novo variant, in which case molecular evaluation of both parents is necessary to calculate the recurrence risk [22]. A proband may appear to be an isolated case because the disease is not recognised in relatives, because of intrafamilial variability, reduced penetrance, early death of a parent before symptom onset or late onset in the carrier parent, so de novo occurrence is confirmed only after the absence of the variant in both parents has been demonstrated [22]. If the proband's variant is not detectable in the leucocyte DNA of either parent and biological parentage has been confirmed, the recurrence risk for siblings is estimated at 1%, because of the possibility of parental gonadal mosaicism; leucocyte analysis does not detect all somatic mosaicism and does not detect mosaicism restricted to the germline, and a parent with somatic and gonadal mosaicism may be only mildly affected [22]. The Japanese survey confirmed this possibility in practice, with low-level somatic mosaicism in peripheral blood in a mother (10.06%) and a father (16.7%), both asymptomatic [25]. When the parents have not been tested but appear clinically healthy, siblings are still considered at increased risk, because of reduced penetrance, variable expressivity and gonadal mosaicism [22].

Intrafamilial variability is considerable among relatives with the same variant, and interfamilial variability is considerable among unrelated individuals with the same variant, which prevents severity from being predicted from the genotype and must be made explicit in counselling [22]. For this reason, and because the disease is highly penetrant, it is recommended to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives: this identifies early those who would benefit from an initial evaluation identical to that of a symptomatic patient and from treatment or scheduled surveillance [22]. Relatives with a confirmed variant and subclinical or clinical manifestations should be considered for treatment, and asymptomatic or preclinical relatives should be screened periodically, with attention to mild but clinically relevant manifestations and, in adults, to the risk of lymphoma [26]. Testing in minors is justified by this direct medical reason: newborns and young children may remain asymptomatic until late childhood and still be at risk of severe disease [26]. When haematopoietic stem cell transplantation is being considered, relatives who are candidate donors should be tested for the familial variant [22]. Predictive testing in asymptomatic relatives requires prior identification of the germline variant in the family [22]. The optimal time to determine genetic risk and discuss the availability of prenatal and preimplantation diagnosis is before pregnancy, and counselling should be offered to affected or at-risk young adults, including conception and pregnancy counselling with regard to maternal medication [22, 26]. The autosomal recessive form described with a hypomorphic variant in the seventh zinc finger domain changes the calculation in that particular family, with a 25% risk for siblings of a homozygous patient and heterozygous carriers without classic A20-type disease, which reinforces the need to record the mechanism, and not only the gene, in the report [30].

8.7 Haploinsufficiency of RelA

Inheritance is autosomal dominant and the risk to the offspring of an affected individual is 50% [31]. Penetrance is incomplete and expressivity is markedly variable even within the same family, as shown by the five Irish carriers of the same variant, with phenotypes ranging from isolated oral ulcers to early-onset Behçet disease and recurrent optic neuritis, and by the five published patients who did not require treatment [29, 85]. Among the patients in the review, four were index cases and six were diagnosed through a positive family history, which shows the yield of cascade testing [29]. In the Turkish case, the mother had had oral ulcers only in adolescence and testing revealed no RELA variant, while the father declined testing: investigation of the parental origin remained incomplete, a frequent situation that prevents de novo occurrence from being asserted [29]. Counselling should distinguish the two mechanisms: with variants in the 3' segment that produce an expressed truncated protein with a dominant-negative effect, the disease described is more severe and includes autoimmunity and an interferon signature, which is relevant information for relatives carrying the same variant, although the correlation does not allow an individual prognosis [29, 58]. Prenatal diagnosis and preimplantation genetic diagnosis are technically possible once the familial variant has been identified. One point to be clarified explicitly in counselling is oncological: the somatic ZFTA::RELA fusion of supratentorial ependymomas is an event acquired in the tumour, and a germline RELA variant does not confer a predisposition to ependymoma nor justify oncological surveillance [29].

8.8 CARD8-associated inflammatory bowel disease

The inheritance described is autosomal dominant, and each child of a carrier has a 50% probability of inheriting the variant [33, 34]. Penetrance is not known: the three carriers in the index family were affected, but the variant was also found in two individuals in gnomAD, without clinical information [33]. Because the association is provisional and the variant is classified as of uncertain significance, there is no basis for offering predictive testing of asymptomatic relatives, prenatal diagnosis or preimplantation genetic diagnosis; testing of relatives is valuable mainly as a segregation study, in affected individuals, and should be presented as such [34, 87]. Detection of the common variants CARD8-FS and rs2043211 does not justify Mendelian recurrence counselling or cascade testing [36, 59]. In minors, testing is justified only in the presence of symptoms.

9. Special Considerations: Population Diversity and Epidemiology

FMF predominates in eastern Mediterranean populations: Jews (particularly non-Ashkenazi), Arabs, Greeks, Italians, Armenians and Turks [1, 4]. GeneReviews gives the following estimates: in the Turkish population, a prevalence of 1:400 to 1:1,000 and a carrier frequency of up to 1:8 to 1:10; in Armenians, 1:500 to 1:1,000 and carriers up to 1:9; in Arab populations, 1:1,000 to 1:2,600 depending on the population and carriers up to 1:9; in non-Ashkenazi Jews, 1:250 to 1:1,000 and carriers up to 1:9 [1]. Orphanet data indicate point prevalences of 175/100,000 in Turkey and 200/100,000 in Armenia, 2.5/100,000 in Sweden and 0.23/100,000 in Japan [7]. Founder variants have been identified in Ashkenazi Jews (NM_000243.3:c.2177T>C p.(Val726Ala)), in Sephardic Jews (p.Met694del, p.Val726Ala) and in Druze (p.Met694Ile, p.Val726Ala); p.Met680Ile is frequent in Armenians and p.Phe479Leu in Greeks [1]. In Ashkenazi Jews, the empirical FMF carrier frequency (1 in 13.2) was the second highest among the conditions screened [149].

FMF is increasingly diagnosed in southern Europe and East Asia [1]. In Slovakia, a country with no tradition of the disease, a cohort of 113 patients showed a predominance of the p.Met694Val (52% of alleles) and p.Lys695Arg (29.9%) variants, with a median diagnostic delay of 11 years and amyloidosis in 4.5% [63]. In Japan, FMF has a more atypical phenotype, and patients with onset after 40 years have fewer exon 10 variants and more musculoskeletal manifestations [91]. In Romania, a child homozygous for p.Met694Ile without classic ancestry has been described [103].

CAPS have an estimated prevalence of 2.8 per million in France, the only estimate validated by Orphanet; MWS accounts for approximately 200 cases and HIDS for approximately 200 published cases [7]. For MKD, the French PNDS estimates fewer than 100 patients in France, based on a published national cohort of 50 patients, with the first cases described mainly in the Netherlands and northern France, but also in Asia and the Mediterranean basin [13]. This estimate underestimates late-onset disease due to somatic mosaicism [66]. TRAPS has an estimated prevalence of approximately 1 per million, with more than 200 individuals with a pathogenic variant described by 2020 [3, 150]. MKD has a prevalence of less than 1 per million according to Orphanet, with approximately 300 cases of MKD and 30 of mevalonic aciduria registered; the 2024 review indicates 5 per million in the Netherlands and 6.2 per million in German children up to 16 years of age, and a higher frequency in people of northern European ancestry, consistent with a founder effect [7, 11].

The French PNDS provide their own estimates, from experts and not from population studies published in the documents. For FMF, the overall frequency in France is estimated at approximately 1 in 5,000, i.e. 5,000 to 10,000 patients, out of approximately 100,000 worldwide; carrier frequency may reach 1 in 5 in Sephardic Jews and Armenians, and the disease affects to a lesser degree Kurds, Druze, Lebanese, Italians, Greeks, Ashkenazi Jews and Japanese [12]. For CAPS, the prevalence is 1 in 360,000 inhabitants in France, a value equivalent to Orphanet's 2.8 per million, and, counting undiagnosed cases, 150 to 200 patients; two thirds of French patients have MWS or CINCA, whereas in the United States FCAS appears to predominate, and almost all patients initially described were of European origin, with increasing identification in Asia [7, 14]. For TRAPS, the PNDS indicates 1 to 9 cases per million (approximately 1 per million in the summary), with no difference between sexes [15]. The PNDS do not include data from Portugal or Brazil.

NLRP1-associated diseases have no prevalence estimates; Orphanet classifies the entity ORPHA:352662 among rare diseases without population data [20]. The largest published family is Tunisian, with 27 individuals affected by MSPC over five generations [55]; patients of French, Algerian, Dutch, Peruvian, Slavic and Turkish origin have also been described [17, 54, 56, 76, 96]. In the Turkish cohort of adults with variants in NLR genes, NLRP1 was the second most represented gene, with ten of 33 patients, in a reference centre and without a population denominator [99]. The sources consulted contain no data from Portugal or Brazil.

Haploinsufficiency of A20 has no population prevalence estimate. GeneReviews recorded approximately 200 published patients, and the most recent count associates them with approximately 100 distinct pathogenic variants [22, 26]. There is, however, an indirect estimate that has changed the perception of the rarity of the disease: analysis of population databases indicates that the collective prevalence of individually rare TNFAIP3 null variants (allele frequency below 0.01%) classified as “pathogenic very strong” by the ACMG criteria may reach approximately 1 in 14,000, which would correspond to approximately 500,000 carriers of potentially causal variants worldwide; this estimate was released in a conference abstract, measures variant frequency and not diagnosed disease, and suggests that the disease is greatly under-recognised [26]. Published cohorts cover East Asia, Turkey, Europe and the United States: the systematic review gathered 177 patients from 65 articles published between 2016 and August 2023, 108 of them female; the Japanese national survey estimated 72 patients with pathogenic TNFAIP3 variants in the country, with 54 from 37 families analysed in detail (53 Japanese and one Vietnamese); the international multicentre cohort gathered 185 patients from 112 families at 41 centres in seven countries, including the United States, Asia, Europe, South and Central America and New Zealand; the French paediatric cohort gathered 17 patients from 11 unrelated families; the Italian cohort 17 individuals from six families; and Chinese series describe additional cases [24, 25, 81, 100, 101, 136]. These are counts of identified patients and not population rates, and they reflect selection bias towards the Behçet-like phenotype, which is tested more often [26]. Comparison between cohorts shows differences that are not explained by recruitment alone: intestinal ulcers were significantly more frequent in children and in the Chinese cohort than in adults and in the North American cohort, and uveitis significantly less frequent [24]. In Japan, HLA typing of 31 patients identified HLA-A26 in five, B27 in one, B51 in six and B52 in four, which shows that Behçet disease risk alleles may coexist with the monogenic variant without explaining it [25]. RELA-associated inflammatory disease has little more than four dozen published patients: eight cases before 2023, 23 affected individuals from four families added that year, six patients from five families in the dominant-negative group and isolated cases since then, for a total of 43 in the 2026 review; the origins described include Eurasian (seven patients), European (six), Japanese, Irish and Brazilian (five each), Canadian (four), Algerian (two) and one case each of French, Moroccan and Turkish origin [28, 29, 58]. Converting these counts into rates per 100,000 inhabitants would be spurious, and the true frequency is probably higher than the number of cases, because the families were found by sequencing patients already referred to immunology centres for Behçet-like disease, because penetrance is incomplete and because almost half of those affected previously had a common rheumatological diagnosis [28, 29]. The sources consulted contain no prevalence, cohort or case data from Portugal or Brazil for either entity; the international cohort includes patients from South and Central America without breakdown by country [24]. Both diseases fall within the scope of ERN RITA, and the patient resources indicated by GeneReviews are the Autoinflammatory Alliance, the PRINTO Eurofever project and registry and the National Institute of Arthritis and Musculoskeletal and Skin Diseases [22, 151].

CARD8-associated inflammatory bowel disease has no prevalence estimate: the Mendelian evidence rests on one North American family and isolated descriptions, and Orphanet publishes no epidemiological data for ORPHA:714410 [33, 35, 102]. The common variants have a known population distribution: CARD8-FS is present in 4.2% of alleles in gnomAD, in 3.2% of Swiss controls and in 12.9% of the Japanese population, and rs2043211 in approximately 30% of alleles [59, 88, 89]. These figures measure variant frequency and not disease frequency. The sources consulted contain no data from Portugal or Brazil. The relevant European reference network is ERN RITA, and patients with inflammatory bowel disease have the European Federation of Crohn's & Ulcerative Colitis Associations (EFCCA), which brings together the national associations [151, 152].

Data gaps. In the core sources consulted (GeneReviews, Orphanet, European recommendations and key articles), no population prevalence studies of FMF, CAPS, TRAPS or MKD were identified in Brazil, Portugal, Latin America or sub-Saharan Africa; no targeted geographical search was carried out, and this absence does not demonstrate that such studies do not exist. Hospital series, such as the Slovak cohort, describe diagnosed patients and do not estimate population prevalence [63]. In Latin America, the available literature is limited to case reports, such as the first case of NLRP3-associated autoinflammatory disease described in Ecuador [153]. The FMF carrier frequency in North American Hispanic populations (1 in 136.6) should not be extrapolated to Latin American populations [149].

10. Illustrative Clinical Case

10.1 FMF in a non-endemic population (published report)

A 5-year-old Romanian girl, with no relevant family history and of an ethnic origin not classically associated with the disease, was seen with fever, left upper quadrant pain and urinary complaints; ultrasound showed mild splenomegaly and an accessory spleen, with leucocyturia, CRP of 161 mg/L and ESR of 25 mm/h, and she was treated for urinary tract infection despite a negative urine culture [103]. Over the following year she had recurrent episodes of fever and abdominal pain, initially every one to two months and then fortnightly, with CRP between 80 and 180 mg/L during attacks and 20 to 30 mg/L in the intervals, and one self-limiting episode of shoulder arthralgia; cultures, serologies (Borrelia, EBV, CMV, parvovirus B19, SARS-CoV-2, HIV, hepatitis B and C), immunoglobulin profile, antinuclear antibodies, HLA-B27 and abdominal CT were normal, except for the splenomegaly [103]. Approximately 12 months after onset, the suspicion of autoinflammatory disease led to application of the Eurofever/PRINTO clinical criteria, 6 of 9 of which were met: attacks lasting one to two days, abdominal pain and absence of aphthous stomatitis, urticarial or maculopapular rash and lymphadenopathy [37, 103]. Colchicine 1 mg/day was started and the genetic panel revealed homozygosity for MEFV NM_000243.3:c.2082G>A p.(Met694Ile), confirming FMF [103]. Over the next six months she had only one mild attack, without fever, with CRP of 60 mg/L, and acute-phase reactants, including SAA, normalised between attacks [103]. The course of CRP before and after colchicine is illustrated in figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC11774843/figure/F1/).

Teaching points. The case shows that the absence of typical ancestry does not exclude FMF, that the Eurofever/PRINTO clinical criteria allow colchicine to be started before the genetic result, that baseline inflammation between attacks (CRP of 20 to 30 mg/L) is the therapeutic target to eliminate in order to prevent amyloidosis, and that the dose of 1 mg/day at this age lies within the 0.5 to 1.0 mg/day range recommended by EULAR for children aged 5 to 10 years [38, 62, 103]. Homozygous p.Met694Ile is associated with a severe phenotype, which justifies annual monitoring of proteinuria and SAA and testing of siblings [1].

10.2 NLRP3-associated disease in Latin America (published report)

An Ecuadorian boy presented with recurrent fever from 6 months of age, with urticarial rash, arthralgia and abdominal pain; at 7 years he had a seizure, and magnetic resonance imaging showed demyelinating brain lesions [153]. Genetic testing identified a de novo NLRP3 variant, and the patient responded to canakinumab; this was the first case of NLRP3-associated autoinflammatory disease reported in Ecuador [153]. The case meets the Kuemmerle-Deschner criteria (raised inflammatory markers with urticarial rash and musculoskeletal symptoms) and illustrates central nervous system involvement outside the classic neonatal context [8, 153].

10.3 NLRP1-associated disease with MSPC/AIADK overlap (published report)

Burlakov and colleagues described a girl of Slavic ethnicity, born to non-consanguineous parents, with hyperkeratotic dermatitis from birth [76]. At 18 months bilateral keratoconjunctivitis appeared, attributed to herpesvirus and treated with antivirals and topical corticosteroids, which progressed to bilateral vascularised corneal opacification and almost complete loss of vision by 5 years [76]. At 7 years she had diffuse hyperkeratosis, alopecia areata with fragile hair, nail dystrophy, hypertrophic gingivitis, plantar hyperkeratotic lesions, mild arthritis of the ankles and elbows, bilateral phthisis bulbi, mild anaemia (haemoglobin 110 g/L), CRP of 34.5 mg/L and reduced class-switched B lymphocytes [76]. Genetic testing identified the heterozygous variant NM_033004.4:c.160G>A p.(Ala54Thr), previously described in MSPC, also present in the mother, who had only hyperkeratotic lesions on the elbows and CRP of 50 mg/L [76, 77]. Shortly after admission, the patient had an attack with fever, CRP of 227 mg/L, ground-glass pulmonary opacities and respiratory distress syndrome requiring invasive ventilation, with no infection demonstrated; she did not respond to methylprednisolone or rituximab, and improved immediately with high-dose intravenous anakinra, coming off ventilation after five days [76]. Because CRP and ferritin remained elevated after 90 days of anakinra, ruxolitinib was added, with laboratory normalisation within two weeks and no inflammatory activity three years later, while the skin lesions and the irreversible eye damage persisted [76]. Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC11067529/) shows the pulmonary involvement before and after anakinra, the vascularised corneal opacification, the hypertrophic gingivitis, the follicular hyperkeratosis and the alopecia [76]. The case illustrates the diagnostic delay of epithelial inflammasomopathies, the variable penetrance in the family and the potential for severe systemic attacks; the intravenous anakinra doses and the combination with ruxolitinib are individual management decisions from a report and not a validated regimen [76].

10.4 Haploinsufficiency of A20 with onset in early childhood (published report)

Salehzadeh and Babazadeh Khoei described a 5-year-old girl, of Caucasian origin and with consanguineous parents, followed in north-eastern Iran [112]. From the second year of life she had febrile episodes every 20 days, lasting approximately three days, during which eye redness and pain, swelling of the upper and lower eyelids, abdominal pain, oral aphthae, diarrhoea, perianal swelling and pain and dysuria appeared [112]. The relevant history was a term delivery complicated by neonatal respiratory distress syndrome and a brief febrile seizure in early childhood, treated with phenobarbital for four months, without recurrence [112]. On examination during the episodes she had periorbital oedema, aphthae, abdominal tenderness and a swollen, painful perianal region resembling haemorrhoidal inflammation [112]. Laboratory evaluation showed leucocytes 8.62 × 10⁹/L, haemoglobin 10.6 g/dL, platelets 391 × 10⁹/L, erythrocyte sedimentation rate of 14 mm in the first hour and weakly positive C-reactive protein, with normal immunoglobulins, complement, nitroblue tetrazolium test, coeliac disease serology and urinalysis and negative antinuclear antibodies [112]. Ophthalmological and gastrointestinal investigation, including imaging and faecal calprotectin, was negative, and the panel of the 12 most common MEFV allelic variants was negative, which ruled out the initial hypothesis of familial Mediterranean fever and PFAPA syndrome [112]. Colchicine and intermittent courses of prednisolone produced no relevant improvement [112]. Whole-exome sequencing identified a likely pathogenic TNFAIP3 variant, described by the authors on transcript NM_001270507.2 as c.759del p.Asp253fs; conversion in VariantValidator confirms the same position and consequence on the MANE Select transcript, NM_001270508.2:c.759del p.(Asp253GlufsTer9) [80, 112]. Additional variants were detected in PIK3R1, HBB and SERPINA1, considered by the authors as possible modifiers and not as the primary cause, and a variant of uncertain significance in VPS37A; Sanger confirmation in the patient and parents was planned but had not been performed at the time of publication, a limitation the authors themselves point out [112]. On the basis of the molecular diagnosis, treatment was escalated to infliximab 5 mg/kg at weeks 0, 2 and 6 and then every eight weeks; colchicine was stopped and corticosteroids tapered, with significant clinical improvement [112]. The case illustrates the typical course: periodic fever with bipolar aphthosis and perianal symptoms in the second year of life, initial hypotheses of familial Mediterranean fever and PFAPA, insufficient response to colchicine and redirection of treatment after the genetic diagnosis. The infliximab regimen corresponds to that of the label for paediatric Crohn disease and is here an off-label use; the dose and interval in this report are individual management and not a validated regimen for haploinsufficiency of A20 [112, 139].

10.5 Haploinsufficiency of RelA diagnosed after the label of Behçet disease (published report)

Karaçayır and colleagues described a 14-year-old Turkish adolescent girl with recurrent fever, oral aphthae and arthralgia from 5 years of age [29]. She had three healthy siblings, there was no parental consanguinity or family history of autoimmune, autoinflammatory or immunodeficiency disease, and her mother had had oral ulcers only in adolescence [29]. On admission she had no uveitis or genital ulcers, and on examination she had an aphtha of approximately 0.5 cm on the inner surface of the upper lip, with a negative pathergy test [29]. Full blood count, biochemistry, urinalysis, complement C3 and C4 and immunoglobulins were normal, the erythrocyte sedimentation rate was 6 mm/h and C-reactive protein was slightly elevated (6.75 mg/L, for a reference value below 5 mg/L); HLA-B*51 was negative, antinuclear antibodies were positive with a speckled pattern (3+) and the extractable nuclear antigen profile was negative [29]. Colchicine reduced the frequency and severity of the oral aphthae [29]. At 12 years a 2 × 1 cm ulcer appeared on the right labium majus, which progressed to an abscess during follow-up, with neutrophil-predominant leucocytosis, erythrocyte sedimentation rate of 34 mm/h and C-reactive protein of 265 mg/L; blood cultures and abscess swabs were negative, and perineal magnetic resonance imaging showed a peripherally enhancing collection in the vulvar region, adjacent to the distal portions of the vagina and urethra, with restricted diffusion, consistent with an abscess [29]. Upper gastrointestinal endoscopy and colonoscopy were normal [29]. With the diagnosis of Behçet disease, a glucocorticoid (1 mg/kg/day) and azathioprine (2 mg/kg/day) were added to colchicine, together with local care, with resolution of the genital abscess and tapering of the corticosteroid within two months [29]. Up to 16 years she continued to have recurrent genital ulcers, relieved by systemic corticosteroid therapy; because of the severity and resistance of the ulcerative lesions, persistent fever and the frequent need for corticosteroids, azathioprine was replaced by methotrexate, with a good response to the combination with colchicine and remission maintained at one year of follow-up [29]. Because of the early onset and severe phenotype, whole-exome sequencing was performed, which identified the heterozygous frameshift variant NM_021975.4:c.1303dup, published as p.Thr435fs and confirmed in VariantValidator as p.(Thr435AsnfsTer12), not previously described and classified as likely pathogenic by the 2015 ACMG criteria [29, 80]. Exome sequencing of the mother, who had had oral ulcers in adolescence, revealed no RELA variant, and the father declined genetic testing, so the origin of the variant remained undetermined [29]. The authors note that the molecular diagnosis did not change the treatment of this patient, who was already in remission on methotrexate and colchicine, and that anti-TNF therapy would be considered in the event of frequent relapses; the explicit limitation of the report is the absence of functional validation of the novel variant [29].

10.6 Refractory Crohn disease in a family with a CARD8 variant (published report)

Mao and colleagues described a 16-year-old adolescent boy, living in Ohio, admitted with abdominal pain and bloody diarrhoea of more than 2 litres per day, of two months' duration [33]. Endoscopy showed pancolitis, and histology showed oesophagitis, gastritis, duodenitis and terminal ileitis; the colon had scattered areas of superficial erythema and lenticular ulceration, mainly in the rectosigmoid (figure 1B of the original publication, consulted: https://www.jci.org/articles/view/98642/figure/1) [33]. The initial biopsies resembled graft-versus-host disease, with epithelial apoptosis and crypt loss, and later biopsies showed chronic active ileitis with poorly formed granulomas and giant cells (figure 1C–G) [33]. The disease did not respond to glucocorticoids, aminosalicylates, azathioprine, infliximab up to 10 mg/kg every four weeks or two doses of vedolizumab, and was complicated by protein-losing enteropathy and the need for parenteral nutrition [33]. Exome sequencing identified the heterozygous variant CARD8 NM_001184900.3:c.130G>A p.(Val44Ile), also present in the mother and the maternal aunt, both with Crohn disease, and absent in the healthy father (figure 1A) [33]. Anakinra, chosen on the basis of the histological appearance, led to rapid improvement, with a fall in faecal calprotectin (figure 1J); the patient then switched to canakinumab every four weeks, combined with vedolizumab, and the dose was increased from 3 to 4 mg/kg because of residual microscopic inflammation, with clinical remission, normal growth and normalisation of albumin [33]. He developed avascular necrosis of the hip attributed to the previous glucocorticoids [33]. The management in this report is not routine treatment: the ECCO recommendations do not include IL-1 blockade in Crohn disease, and its use in this family is off-label [33, 104].

11. Prognosis and Long-Term Follow-up

The prognosis of FMF has been transformed by colchicine and IL-1 inhibitors, which have drastically reduced the incidence of AA amyloidosis [1]. With prolonged treatment, complication rates and mortality approach those of healthy age-matched controls [93]. Rare complications include destructive arthritis, peritoneal adhesions, infertility and vasculitis [93]. In AA amyloidosis, the course is dominated by renal dysfunction; median survival after diagnosis was 133 months in the series of Lachmann and colleagues, and patients with SAA persistently below 4 mg/L had a more favourable course [92]. In FMF, proteinuria without nephrotic syndrome may stabilise or regress with colchicine, whereas nephrotic syndrome or uraemia progressed in all patients in Zemer's series [41]. Disease activity instruments, such as the AIDAI, help in deciding on treatment optimisation [1, 93].

In CAPS, IL-1 blockade induces rapid remission, normalises CRP and SAA, and may improve cochlear and leptomeningeal lesions in NOMID [124, 126]. Established deafness and ocular and bone lesions may not reverse, which justifies early treatment and auditory, ophthalmological and neurological surveillance [8, 9, 125]. In TRAPS, adequate treatment prevents amyloidosis in most cases, but retinal and optic nerve lesions may be irreversible [3]. In MKD/HIDS, the long-term course is relatively benign, and symptoms tend to diminish with age; many patients with mevalonic aciduria die in infancy from respiratory failure [6].

Follow-up should be multidisciplinary (rheumatology, paediatrics, nephrology, medical genetics, otorhinolaryngology and ophthalmology in CAPS), at the intervals described in section 7.8, with monitoring of treatment adherence and reassessment of genetic counselling at reproductive age [1, 3, 10]. Information for patients and families can be supplemented by organisations such as the Autoinflammatory Alliance and the PRINTO Eurofever registry [1]. In Europe, the relevant network is ERN RITA (European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory, Autoimmune and Paediatric Rheumatic Diseases), which has a specific autoinflammatory disease stream and counts the FMF & AID Global Association among its partner patient organisations [151].

Prognosis according to the French PNDS. In FMF with AA amyloidosis and end-stage renal failure, mean survival on dialysis was 20 to 50 months depending on the cohort, and a single study showed no benefit of biologics on the survival of haemodialysis patients; peritoneal dialysis may worsen hypoalbuminaemia; renal transplantation improves prognosis and overall survival, which nevertheless remains below that of patients transplanted for other causes, with similar graft survival [12]. In CAPS, the 2013 PNDS estimated amyloidosis in approximately 25% of untreated patients with forms of intermediate severity, then incurable and fatal within about a decade, and a reduced life expectancy in CINCA [14]. In TRAPS, the prognosis is generally good, amyloidosis being the main risk [15]. The socio-occupational impact may be considerable: 37% of patients with untreated FCAS had lost their job or were unemployed, and sequelae may require occupational redeployment or invalidity [14].

Surveillance according to the French PNDS.

Transition and organisation of care in France. In FMF, transition requires a joint paediatric and adult medicine consultation (internal medicine or rheumatology), with a detailed clinical, laboratory and treatment history and an inventory of complications, therapeutic education sessions before and after, follow-up every 6 months in the first years and discussion of tobacco, cannabis, other drug and alcohol use, sexuality and contraception, vaccination status and educational and occupational pathway, according to the 2021 recommendations of the FAI²R network; young people should be reassured that colchicine has no effect on fertility [12]. The French organisation is based on the reference centre for autoinflammatory diseases and inflammatory amyloidosis (CeReMAIA), with a paediatric coordinating site at Le Kremlin-Bicêtre and constituent sites in Versailles (Le Chesnay), Montpellier (children and genetic counselling) and, for adults, at the Tenon and Pitié-Salpêtrière hospitals in Paris, on the RAISE paediatric reference centre and on a network of paediatric and adult competence centres that includes the overseas territories, coordinated by the FAI²R network (rare autoimmune and autoinflammatory diseases) [12, 15]. Difficult treatment decisions go through national multidisciplinary consultation meetings (FAI²R or CeReMAIA), genetic diagnosis through the laboratories of the GenMAI network (Montpellier, Cochin and Trousseau) and follow-up of patients on biologics through the national prospective JIRcohorte cohort [12, 15]. The patient associations are the Association Française de la Fièvre Méditerranéenne Familiale et des autres Fièvres Récurrentes Héréditaires (AFFMF, with the mai-patient application, which includes the AIDAI) and, at the time of the CAPS PNDS, the AMWS-CINCA association; the network is completed by the Alliance Maladies Rares, EURORDIS, the Fédération des Maladies Orphelines, the Maladies Rares Info Services helpline and the national directory of therapeutic education programmes [12, 14, 15]. Severe, disabling or expensively treated forms may qualify for an “off-list” long-term condition (affection de longue durée), with full reimbursement, periodically reassessed by the national health insurance with the centres; for patients with disability, the Maison Départementale des Personnes Handicapées may grant allowances for a disabled child or adult, a compensation benefit, an invalidity card (disability rate above 80%) and a parking card, and the Orphanet booklet «Vivre avec une maladie rare en France» brings together the available forms of assistance [14, 15]. This national organisation is linked to the European network ERN RITA [151].

11.1 NLRP1-associated diseases

The prognosis of MSPC is determined by the risk of invasive squamous cell carcinoma: in the Tunisian family, 33% of patients with available records developed malignant neoplasms, one of them with bone metastasis and bilateral amputation [55]. In forms with corneal dyskeratosis, opacification may lead to loss of vision in early childhood [54, 76]. In AIADK, the course described ranges from chronic skin inflammation to life-threatening systemic attacks, and reports treated with IL-1 blockade or JAK inhibitors describe control for two to three years [76, 96]. There are no published surveillance protocols for these diseases; the table combines the findings of the series with the general intervals for autoinflammatory diseases and with the monitoring requirements of the labels, and intervals without a specific source are marked as extrapolation.

Sources for the table: [1, 3, 8, 18, 19, 54, 55, 76, 125, 133–135].

11.2 Haploinsufficiency of A20

With adequate treatment, the prognosis is good and no significant reduction in life expectancy is expected; GeneReviews cautions, however, that the disease is often refractory and that deaths have been described [22]. The systematic review of 177 patients recorded five deaths at the time of publication of the respective articles, and the description of 16 patients in the first cohort included a patient with mucosal and gastrointestinal ulceration from the first week of life, with intestinal perforation and small-vessel vasculitis of the central nervous system, who died at 8 years [31, 81]. In the international cohort, 51.5% of patients had minimal disease activity at the last assessment, which gives a measure of the control achievable and also of what is lacking [24]. The complications that determine prognosis are hepatitis progressing to cirrhosis and liver failure when untreated, intestinal perforation, central nervous system vasculitis, cytokine storm with haemophagocytic lymphohistiocytosis, treatment-resistant uveitis with visual loss and renal disease; the risk of lymphoma, although of unquantified magnitude, justifies specific attention in adults [22, 26]. Secondary failure of targeted drugs is the most important practical limitation of long-term follow-up, and abrupt withdrawal of immunosuppression may precipitate severe flares [25, 26].

The recommended follow-up is multidisciplinary, coordinated by rheumatology with the family doctor as a second point of reference, and should be at least annual, more frequent in patients with systemic inflammation or organ involvement [22, 26]. The threshold for requesting subspecialist assessment should be low: gastroenterology for inflammatory bowel disease-like symptoms, neurology for aseptic meningitis or polyradiculoneuropathy, ophthalmology for symptoms of ocular inflammation, endocrinology for thyroid disease or type 1 diabetes, nephrology for nephritis, haematology for cytopenias, immunology for immunodeficiency and cardiology for coronary vasculitis [22].

Sources for the table: [22, 26, 101].

11.3 Haploinsufficiency of RelA

There are no long-term prognostic data or published surveillance protocol for RELA-associated inflammatory disease. The available information is that most patients respond to glucocorticoids in acute episodes and that TNF inhibitors maintained remission in the most severely affected patients, including the index patient, who was dependent on that treatment; five of the 43 published patients did not require treatment, and one patient with refractory autoimmune cytopenias went into remission after allogeneic haematopoietic stem cell transplantation [27, 29, 58]. The adverse outcomes described are visual loss due to raised intraocular pressure with optic nerve thinning, recurrent optic neuritis, colitis with ulcers and stricture, lupus nephritis with pericarditis in the dominant-negative subgroup and, in one infant, sudden unexplained death with high bone mass; none of these outcomes has been quantified in terms of risk [29, 31]. The surveillance below transposes that of autoinflammatory diseases and haploinsufficiency of A20 to the organs actually described in this entity, and intervals without a specific source are marked as extrapolation.

Sources for the table: [8, 22, 27–29, 31, 58, 125, 138, 139].

11.4 CARD8-associated inflammatory bowel disease

There are no long-term prognostic data or specific surveillance protocol. In the index family, the disease caused repeated bowel resections in an adult woman and, in the adolescent, refractory disease that remitted only with IL-1 blockade, with clinical remission maintained during the published follow-up [33]. Surveillance follows that of Crohn disease and, when IL-1 inhibitors are used, that of autoinflammatory diseases treated with these drugs.

Sources for the table: [1, 3, 8, 33, 38, 62, 104, 117, 121, 125, 138, 139].

12. Summary and Final Considerations

Hereditary periodic fevers share a final pathway of inflammasome activation and IL-1β production, but differ in genes, modes of inheritance, attack duration and organ manifestations. FMF, caused by gain-of-function variants in MEFV with recessive inheritance (and apparently dominant transmission in some families), produces attacks of one to three days with peritonitis, pleuritis, monoarthritis and erysipelas-like erythema; its diagnosis is clinical, supported by the Tel-Hashomer, Yalçınkaya-Özen or Eurofever/PRINTO criteria and by biallelic variants, p.Met694Val, p.Met694Ile, p.Met694del and p.Met680Ile being markers of severity and of risk of amyloidosis. Continuous colchicine, at doses adjusted to age and renal function, prevents attacks and AA amyloidosis; resistance, defined after adherence has been confirmed, is an indication for canakinumab or anakinra. CAPS, due to gain of function of NLRP3 with dominant inheritance, form a spectrum from FCAS to CINCA/NOMID, with sensorineural deafness, chronic meningitis and arthropathy due to epiphyseal overgrowth; somatic mosaicism is a relevant cause of negative germline tests. TRAPS, due to variants in the extracellular domain of TNFRSF1A, causes attacks lasting more than a week with migratory myalgia and periorbital oedema; it responds to IL-1 blockade and, as second line, to etanercept, and anti-TNF monoclonal antibodies and overinterpretation of low-penetrance variants such as p.Arg121Gln should be avoided. MKD is part of the differential diagnosis, with attacks of three to seven days triggered by vaccines and a response to canakinumab. Doses of colchicine and IL-1 inhibitors differ between FDA and EMA labels, and drug availability varies between regions, rilonacept being absent from the European market. In the sources consulted, no prevalence studies were identified in Brazil, Portugal or Latin America. No new authorisations have appeared in these diseases in the last 12 months, and oral NLRP3 inhibitors remain in phase 2, with results released mainly in sponsor press releases. The French HAS PNDS (FMF 2022, CAPS 2013, TRAPS 2018) add operational rules — confirmatory, uncertain and inconclusive genotype, therapeutic trial of colchicine, criteria for control, intensification and reduction, corticosteroid therapy and on-demand anakinra in TRAPS, surveillance schedules and organisation in reference centres — and diverge from international recommendations and labels on maximum doses, reduction time frames, canakinumab regimens in TRAPS, reproductive counselling and pregnancy on IL-1 inhibitors.

NLRP1-associated diseases extend the concept of inflammasomopathy to epithelial barriers: gain-of-function variants of the predominant sensor in keratinocytes cause MSPC, with palmoplantar and conjunctival keratoacanthomas and a risk of squamous cell carcinoma, AIADK, with dyskeratosis, arthritis and autoinflammation, and syndromic JRRP, with dominant or recessive transmission depending on the variant. Diagnosis depends on recognition of the epithelial phenotype and inclusion of NLRP1 in genetic testing, and treatment relies on retinoids, surgery, IL-1 blockade and JAK inhibitors, with evidence limited to case reports.

The Behçet-like autoinflammatory diseases of the canonical NF-κB pathway join this article through a common mechanism: loss of a brake on NF-κB signalling downstream of the TNF receptor. In haploinsufficiency of A20, heterozygous loss-of-function variants of TNFAIP3 remove half of the enzyme that edits ubiquitin chains and terminates NF-κB activation, and the result is an immune dysregulation disease that combines orogenital ulceration in more than 70% of patients, recurrent fever, Crohn-like intestinal inflammation, non-erosive arthritis, autoantibodies in more than 70%, thyroiditis, autoimmune hepatitis, cytopenias, central nervous system vasculitis and, in a significant minority, humoral deficiency; onset is generally before 10 years of age, penetrance approaches 96%, there is no established genotype–phenotype correlation, and autoinflammatory manifestations predominate in childhood and autoimmune ones in adolescence and adulthood. Diagnosis is molecular and requires, when sequencing is negative, a search for 6q23 deletions; rare missense variants remain largely of uncertain significance and require functional assays not available in clinical practice, and common variants of the gene are risk alleles for autoimmune diseases and not a Mendelian diagnosis. Treatment is entirely off-label and guided by phenotype and biomarkers: colchicine and phosphodiesterase 4 inhibitors in mild and mucosal disease, IL-1 blockade in autoinflammation, TNF inhibition in intestinal and joint disease, Janus kinase inhibitors with a raised interferon signature and in lupus-like disease, and allogeneic transplantation in refractory disease; secondary failure of biologics and the risk of rebound on abrupt discontinuation are the dominant practical problems. RELA-associated inflammatory disease results from the loss of half of the transactivating subunit of NF-κB or from a dominant-negative effect of truncated proteins from the 3' segment of the gene, and manifests as chronic TNF-dependent orogenital mucocutaneous ulceration, with rash, arthritis and fever, few infections and autoimmunity mainly in the dominant-negative subgroup, which has a type I interferon signature and more severe disease. Both are transmitted in an autosomal dominant manner with incomplete penetrance and highly variable expressivity within the same family, both mimic Behçet disease and are therefore systematically diagnosed with a delay of several years, and for neither is there a guideline, confirmatory biomarker, registered clinical trial or validated population prevalence estimate; the sources consulted include no data from Portugal or Brazil. The immediate clinical implication concerns the indication for testing: in recurrent orogenital ulceration with onset in childhood, early intestinal inflammation, immune cytopenias or an accumulation of immunological diagnoses, genetic testing that includes TNFAIP3 and RELA changes follow-up, family counselling and the choice of treatment.

CARD8-associated inflammatory bowel disease shows the other side of inflammasomes: instead of an activated sensor, a regulator is lost. The p.(Val44Ile) variant, restricted to the T60 isoform, prevents CARD8 from restraining NLRP3 and from braking the normal isoforms, and caused, in a family of three affected individuals, Crohn disease with raised IL-1β, refractory to TNF inhibitors in the proband and responsive to IL-1 blockade. The association remains provisional, with a variant of uncertain significance in ClinVar, and identification of a CARD8 variant requires the MANE transcript in the analysis, separation from the common variants associated with PFAPA and other inflammatory diseases, and a segregation study before any causal conclusion or reproductive decision.

13. References

1. Deuitch N, Chavez De Paz Solis D, Stone D, Ombrello A, Aksentijevich I. Familial Mediterranean Fever. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. 2000 Aug 8 [updated 2026 Jul 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1227/
2. Clinical Genome Resource (ClinGen). Gene-disease validity curations: MEFV (HGNC:6998) — Familial Mediterranean Fever (AR) and Familial Mediterranean Fever (AD), Definitive classification. Available from: https://search.clinicalgenome.org/kb/genes/HGNC:6998
3. Deuitch N, Cudrici C, Ombrello A, Aksentijevich I. TNF Receptor-Associated Periodic Fever Syndrome. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. 2022 Nov 10. Available from: https://www.ncbi.nlm.nih.gov/books/NBK586171/
4. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 464–467.
5. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 61–64.
6. Waterham HR, Clayton PT. Disorders of Isoprenoid/Cholesterol Synthesis. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 37, section 37.1 Mevalonate Kinase Deficiency. doi:10.1007/978-3-662-63123-2_37
7. Orphanet. Orphadata: Epidemiology of rare diseases (en_product9_prev) — ORPHA:342, ORPHA:208650, ORPHA:575, ORPHA:32960, ORPHA:309025, ORPHA:343, ORPHA:29. Paris: INSERM; 2026. Available from: https://www.orphadata.com/epidemiology/ and https://www.orpha.net/en/disease/detail/342
8. Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, Kone-Paut I, Goldbach-Mansky R, Lachmann H, et al. Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis. 2017;76(6):942-947. doi:10.1136/annrheumdis-2016-209686
9. Romano M, Arici ZS, Piskin D, Alehashemi S, Aletaha D, Barron KS, et al. The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist. Ann Rheum Dis. 2022;81(7):907-921. doi:10.1136/annrheumdis-2021-221801
10. Ozen S, Sağ E, Oton T, Gül A, Sieiro Santos C, Bayraktar D, et al. EULAR/PReS endorsed recommendations for the management of familial Mediterranean fever (FMF): 2024 update. Ann Rheum Dis. 2025;84(6):899-909. doi:10.1016/j.ard.2025.01.028
11. Lengvári L, Takács K, Lengyel A, Pálinkás A, Wouters CH, Koné-Paut I, et al. Mevalonate kinase deficiency: an updated clinical overview and revision of the SHARE recommendations. Front Immunol. 2024;15:1466844. doi:10.3389/fimmu.2024.1466844
12. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Fièvre méditerranéenne familiale (FMF). Centre de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CeReMAIA) and Filière de santé des maladies auto-immunes et auto-inflammatoires rares (FAI²R); coordinated by S. Georgin-Lavialle e V. Hentgen; text of November 2022. Saint-Denis La Plaine: HAS; 2022 dez 12. Available from: https://www.has-sante.fr/jcms/p_3390301
13. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Déficit en mévalonate kinase (MKD). Centre de référence des maladies auto-inflammatoires rares de l'enfant (CEREMAI). Saint-Denis La Plaine: HAS; July 2015 (published on 10 Jul 2015). Available from: https://www.has-sante.fr/jcms/c_2044016
14. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Fièvres récurrentes héréditaires — Syndromes périodiques associés à la cryopyrine (CAPS). Centre de référence des maladies auto-inflammatoires rares de l'enfant (CeRéMAI); coordinated by S. Guillaume-Czitrom; text of January 2013. Saint-Denis La Plaine: HAS; 2013 mai 27. Available from: https://www.has-sante.fr/jcms/c_1545879
15. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): TRAPS — Tumor necrosis factor-Receptor-Associated Periodic Syndrome ou syndrome de fièvre récurrente lié au récepteur du facteur de nécrose tumorale. CeRéMAIA and Filière FAI²R; coordinated by V. Hentgen. Saint-Denis La Plaine: HAS; 2018 jul 5. Available from: https://www.has-sante.fr/jcms/c_2860686
16. Zhong FL, Mamaï O, Sborgi L, Boussofara L, Hopkins R, Robinson K, et al. Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell. 2016;167(1):187-202.e17. doi:10.1016/j.cell.2016.09.001. PMID: 27662089
17. Grandemange S, Sanchez E, Louis-Plence P, Tran Mau-Them F, Bessis D, Coubes C, et al. A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis. 2017;76(7):1191-1198. doi:10.1136/annrheumdis-2016-210021. PMID: 27965258
18. Drutman SB, Haerynck F, Zhong FL, Hum D, Hernandez NJ, Belkaya S, et al. Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis. Proc Natl Acad Sci U S A. 2019;116(38):19055-19063. doi:10.1073/pnas.1906184116. PMID: 31484767
19. Dobre A, Nedelcu RI, Turcu G, Brinzea A, Struna I, Tudorache G, et al. Multiple Keratoacanthomas Associated with Genetic Syndromes: Narrative Review and Proposal of a Diagnostic Algorithm. Am J Clin Dermatol. 2025;26(1):45-59. doi:10.1007/s40257-024-00900-0. PMID: 39572470
20. Orphanet. Corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome (ORPHA:352662). Accessed on 1 November 2026. Available from: https://www.orpha.net/en/disease/detail/352662
21. Online Mendelian Inheritance in Man (OMIM). NLRP1 (606636); Palmoplantar carcinoma, multiple self-healing (615225); Autoinflammation with arthritis and dyskeratosis (617388); Respiratory papillomatosis, juvenile recurrent, congenital (618803). Baltimore: Johns Hopkins University. Available from: https://omim.org/entry/606636
22. Schwartz DM, Deuitch N, Aksentijevich I. Haploinsufficiency of A20. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 19 December 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK610430/
23. Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48(1):67-73. doi:10.1038/ng.3459. PMID: 26642243
24. He T, Wang J, Carpio Tumba M, Wang S, Luo Y, Chen J, et al. Multicenter international cohort study of haploinsufficiency of A20 reveals novel genetic architecture and phenotypic evolution. J Allergy Clin Immunol. 2026;157(6):1395-1410. doi:10.1016/j.jaci.2026.02.002. PMID: 41692116
25. Shiraki M, Kadowaki S, Miwa Y, Nishimura K, Maruyama Y, Kishida D, et al. Clinical characteristics and treatment strategies for A20 haploinsufficiency in Japan: a nationwide survey. Front Immunol. 2025;16:1548042. doi:10.3389/fimmu.2025.1548042. PMID: 40574834
26. Li J, Zhou JY, Carpio Tumba M, He T, Cetin Gedik K, Schwartz DM. How I Treat: Haploinsufficiency of A20. J Hum Immun. 2026;2(4):e20250138. doi:10.70962/jhi.20250138. PMID: 42169681
27. Badran YR, Dedeoglu F, Leyva Castillo JM, Bainter W, Ohsumi TK, Bousvaros A, et al. Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration. J Exp Med. 2017;214(7):1937-1947. doi:10.1084/jem.20160724. PMID: 28600438
28. An JW, Pimpale-Chavan P, Stone DL, Bandeira M, Dedeoglu F, Lo J, et al. Case report: Novel variants in RELA associated with familial Behcet's-like disease. Front Immunol. 2023;14:1127085. doi:10.3389/fimmu.2023.1127085. PMID: 36926348
29. Karaçayır N, Yazol M, Sunar Yayla EN, Esmeray Şenol P, Yıldız Ç, Belder N, et al. A Case-Based Literature Review of RELA Associated Inflammatory Diseases. J Clin Immunol. 2026;46(1):17. doi:10.1007/s10875-025-01968-x. PMID: 41591550
30. Alsabbagh M, Hubrack SZ, Gamgoum L, Osman MJA, Ford KE, Al Shakaki A, et al. Autosomal recessive A20 zinc finger 7 mutation is associated with early-onset lupus-like disease. Inflamm Res. 2026;75(1):180. doi:10.1007/s00011-026-02326-2. PMID: 42470447
31. Online Mendelian Inheritance in Man (OMIM). Autoinflammatory syndrome, familial, Behcet-like 1 (616744); Autoinflammatory disease, familial, Behcet-like 3 (618287); TNFAIP3 (191163); RELA (164014). Baltimore: Johns Hopkins University. Accessed on 1 November 2026. Available from: https://omim.org/entry/616744
32. Orphanet. Early-onset autoinflammatory syndrome due to A20 haploinsufficiency (ORPHA:674762); RELA haploinsufficiency-associated inflammatory disease (ORPHA:596759). Accessed on 1 November 2026. Available from: https://www.orpha.net/en/disease/detail/674762
33. Mao L, Kitani A, Similuk M, Oler AJ, Albenberg L, Kelsen J, et al. Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn's disease. J Clin Invest. 2018;128(5):1793-1806. doi:10.1172/JCI98642. PMID: 29408806; PMCID: PMC5919822
34. Online Mendelian Inheritance in Man (OMIM). CARD8 (609051); ?Inflammatory bowel disease (Crohn disease) 30, IBD30 (619079). Baltimore: Johns Hopkins University. Accessed on 1 November 2026. Available from: https://omim.org/entry/619079
35. Orphanet. CARD8-related inflammatory bowel disease (ORPHA:714410). Accessed on 1 November 2026. Available from: https://www.orpha.net/en/disease/detail/714410
36. Karakaya T, Slaufova M, Di Filippo M, Hennig P, Kündig T, Beer HD. CARD8: A Novel Inflammasome Sensor with Well-Known Anti-Inflammatory and Anti-Apoptotic Activity. Cells. 2024;13(12):1032. doi:10.3390/cells13121032. PMID: 38920661; PMCID: PMC11202080
37. Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019;78(8):1025-1032. doi:10.1136/annrheumdis-2019-215048
38. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644-651. doi:10.1136/annrheumdis-2015-208690
39. Siegal S. Benign paroxysmal peritonitis. Ann Intern Med. 1945;23(1):1-21. doi:10.7326/0003-4819-23-1-1
40. Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med. 1972;287(25):1302. doi:10.1056/NEJM197212212872514
41. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986;314(16):1001-1005. doi:10.1056/NEJM198604173141601
42. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879-1885. doi:10.1002/art.1780401023
43. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25-31. doi:10.1038/ng0997-25
44. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90(4):797-807. doi:10.1016/s0092-8674(00)80539-5
45. Muckle TJ, Wells M. Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Q J Med. 1962;31:235-248. doi:10.1093/oxfordjournals.qjmed.a066967
46. Prieur AM, Griscelli C. Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation. J Pediatr. 1981;99(1):79-83. doi:10.1016/s0022-3476(81)80961-4
47. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301-305. doi:10.1038/ng756
48. Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46(12):3340-3348. doi:10.1002/art.10688
49. Williamson LM, Hull D, Mehta R, Reeves WG, Robinson BH, Toghill PJ. Familial Hibernian fever. Q J Med. 1982;51(204):469-480. doi:10.1093/oxfordjournals.qjmed.a067736
50. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133-144. doi:10.1016/s0092-8674(00)80721-7
51. van der Meer JW, Vossen JM, Radl J, van Nieuwkoop JA, Meyer CJ, Lobatto S, et al. Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet. 1984;1(8386):1087-1090. doi:10.1016/s0140-6736(84)92505-4
52. Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999;22(2):175-177. doi:10.1038/9691
53. Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet. 1999;22(2):178-181. doi:10.1038/9696
54. Soler VJ, Tran-Viet KN, Galiacy SD, Limviphuvadh V, Klemm TP, St Germain E, et al. Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis. J Med Genet. 2013;50(4):246-254. doi:10.1136/jmedgenet-2012-101325. PMID: 23349227
55. Mamaï O, Boussofara L, Denguezli M, Escande-Beillard N, Kraeim W, Merriman B, et al. Multiple self-healing palmoplantar carcinoma: a familial predisposition to skin cancer with primary palmoplantar and conjunctival lesions. J Invest Dermatol. 2015;135(1):304-308. doi:10.1038/jid.2014.311. PMID: 25050600
56. Lemus-Arteaga K, Ballona-Chambergo R, Córdova-Calderón W, Ventura-León A, Torrelo A, Velásquez-Valderrama F. NLRP1-associated autoinflammatory disease with epithelial dyskeratosis. Pediatr Dermatol. 2024;41(2):279-283. doi:10.1111/pde.15464. PMID: 38044752
57. Karri U, Harasimowicz M, Carpio Tumba M, Schwartz DM. The Complexity of Being A20: From Biological Functions to Genetic Associations. J Clin Immunol. 2024;44(3):76. doi:10.1007/s10875-024-01681-1. PMID: 38451381
58. Moriya K, Nakano T, Honda Y, Tsumura M, Ogishi M, Sonoda M, et al. Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity. J Exp Med. 2023;220(9):e20212276. doi:10.1084/jem.20212276. PMID: 37273177
59. Cheung MS, Theodoropoulou K, Lugrin J, Martinon F, Busso N, Hofer M. Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome Is Associated with a CARD8 Variant Unable To Bind the NLRP3 Inflammasome. J Immunol. 2017;198(5):2063-2069. doi:10.4049/jimmunol.1600760. PMID: 28137891
60. Xiao T, Brewer JR, Carlino M, Han A, Takabe YJ, Lee CY, et al. Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency. J Clin Invest. 2026;136(18):e207530. doi:10.1172/JCI207530. PMID: 42741941; PMCID: PMC13574144
61. Online Mendelian Inheritance in Man (OMIM). #249100 Familial Mediterranean fever, AR; #134610 Familial Mediterranean fever, AD. Baltimore: Johns Hopkins University. Available from: https://omim.org/entry/249100 and https://omim.org/entry/134610
62. Romano M, Piskin D, Kul Cinar O, Sag E. Familial Mediterranean Fever; Recent Advances, Future Prospectives. Diagnostics (Basel). 2025;15(7):813. doi:10.3390/diagnostics15070813
63. Jesenak M, Jurkova EM, Bobcakova A, Hrubiskova K, Petrovicova O, Kapustova L, et al. Unexpectedly high prevalence of familial Mediterranean fever in Slovakia. Clin Exp Med. 2025;25(1):101. doi:10.1007/s10238-025-01634-x
64. Shinar Y, Ceccherini I, Rowczenio D, Aksentijevich I, Arostegui J, Ben-Chétrit E, et al. ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era. Clin Chem. 2020;66(4):525-536. doi:10.1093/clinchem/hvaa024
65. Mertz P, Boursier G, Hentgen V, Georgin-Lavialle S. New Diseases Linked to MEFV Variants or Pyrinopathies. J Allergy Clin Immunol Pract. 2025;13(3):522-532. doi:10.1016/j.jaip.2024.12.022
66. Rowczenio DM, Gomes SM, Aróstegui JI, Mensa-Vilaro A, Omoyinmi E, Trojer H, et al. Late-Onset Cryopyrin-Associated Periodic Syndromes Caused by Somatic NLRP3 Mosaicism-UK Single Center Experience. Front Immunol. 2017;8:1410. doi:10.3389/fimmu.2017.01410
67. Cudrici C, Deuitch N, Aksentijevich I. Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives. Int J Mol Sci. 2020;21(9):3263. doi:10.3390/ijms21093263
68. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208(3):519-533. doi:10.1084/jem.20102049
69. Bauernfried S, Hornung V. Human NLRP1: From the shadows to center stage. J Exp Med. 2022;219(1):e20211405. doi:10.1084/jem.20211405. PMID: 34910085
70. Zhong FL, Robinson K, Teo DET, Tan KY, Lim C, Harapas CR, et al. Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding. J Biol Chem. 2018;293(49):18864-18878. doi:10.1074/jbc.RA118.004350. PMID: 30291141
71. Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, et al. DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature. 2021;592(7856):778-783. doi:10.1038/s41586-021-03350-4. PMID: 33731932
72. Robinson KS, Teo DET, Tan KS, Toh GA, Ong HH, Lim CK, et al. Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia. Science. 2020;370(6521):eaay2002. doi:10.1126/science.aay2002. PMID: 33093214
73. Robinson KS, Toh GA, Rozario P, Chua R, Bauernfried S, Sun Z, et al. ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science. 2022;377(6603):328-335. doi:10.1126/science.abl6324. PMID: 35857590
74. Barry K, Murphy C, Mansell A. NLRP1- A CINDERELLA STORY: a perspective of recent advances in NLRP1 and the questions they raise. Commun Biol. 2023;6(1):1274. doi:10.1038/s42003-023-05684-3. PMID: 38104185
75. Herlin T, Jørgensen SE, Høst C, Mitchell PS, Christensen MH, Laustsen M, et al. Autoinflammatory disease with corneal and mucosal dyskeratosis caused by a novel NLRP1 variant. Rheumatology (Oxford). 2020;59(9):2334-2339. doi:10.1093/rheumatology/kez612. PMID: 31873740
76. Burlakov V, Kozlova A, Pershin D, Rodina Y, Khamin I, Novichkova G, et al. Combined therapy with IL-1 and JAK inhibitors in a patient with the NLRP1 gene mutation and a complex inflammatory phenotype. J Allergy Clin Immunol Glob. 2024;3(3):100251. doi:10.1016/j.jacig.2024.100251. PMID: 38706460
77. National Center for Biotechnology Information. ClinVar: NM_033004.4(NLRP1) — VCV000375413, VCV000375414, VCV000050316, VCV000393319, VCV000827581, VCV000393320. Accessed on 1 November 2026. Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=NLRP1%5Bgene%5D
78. Chen J, Zhou S, Xu T, Wu M. Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases. Front Immunol. 2026;17:1910164. doi:10.3389/fimmu.2026.1910164. PMID: 42812552
79. Harapas CR, Robinson KS, Lay K, Wong J, Moreno Traspas R, Nabavizadeh N, et al. DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling. Sci Immunol. 2022;7(75):eabi4611. doi:10.1126/sciimmunol.abi4611. PMID: 36112693
80. VariantValidator. HGVS validation on GRCh38 with the MANE Select transcript for the TNFAIP3 (NM_001270508.2 and NM_001270507.2) and RELA (NM_021975.4) variants cited in this article; identification of MANE Select transcripts by the gene2transcripts_v2 service. Accessed on 1 November 2026. Available from: https://variantvalidator.org/
81. Elhani I, Riller Q, Boursier G, Hentgen V, Rieux-Laucat F, Georgin-Lavialle S. A20 Haploinsufficiency: A Systematic Review of 177 Cases. J Invest Dermatol. 2024;144(6):1282-1294.e8. doi:10.1016/j.jid.2023.12.007. PMID: 38128752
82. National Center for Biotechnology Information. ClinVar: NM_001270508.2(TNFAIP3) — VCV000219109, VCV000219111, VCV000219113. Accessed on 1 November 2026. Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=TNFAIP3%5Bgene%5D
83. Kadowaki T, Ohnishi H, Kawamoto N, Hori T, Nishimura K, Kobayashi C, et al. Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders. J Allergy Clin Immunol. 2018;141(4):1485-1488.e11. doi:10.1016/j.jaci.2017.10.039. PMID: 29241730
84. National Center for Biotechnology Information. ClinVar: NM_021975.4(RELA) — VCV000617486, VCV000617487, VCV001075392, VCV001452423, VCV001453182, VCV002446403. Accessed on 1 November 2026. Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=RELA%5Bgene%5D
85. Adeeb F, Dorris ER, Morgan NE, Lawless D, Maqsood A, Ng WL, et al. A Novel RELA Truncating Mutation in a Familial Behçet's Disease-like Mucocutaneous Ulcerative Condition. Arthritis Rheumatol. 2021;73(3):490-497. doi:10.1002/art.41531. PMID: 32969189
86. Ito S, Hara Y, Kubota T. CARD8 is a negative regulator for NLRP3 inflammasome, but mutant NLRP3 in cryopyrin-associated periodic syndromes escapes the restriction. Arthritis Res Ther. 2014;16(1):R52. doi:10.1186/ar4483. PMID: 24517500; PMCID: PMC4060228
87. National Center for Biotechnology Information. ClinVar: VCV000252559 (NM_001184900.3(CARD8):c.130G>A, p.Val44Ile) and VCV001170357 (NM_001184900.3(CARD8):c.440_441dup, p.Val148fs). Accessed on 1 November 2026. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/252559/
88. National Center for Biotechnology Information. dbSNP: rs140826611 and rs2043211 (CARD8), gnomAD (genomes) and TOPMed frequencies. Accessed on 1 November 2026. Available from: https://www.ncbi.nlm.nih.gov/snp/rs140826611
89. Nakamura H, Kikuchi A, Sakai H, Kamimura M, Watanabe Y, Onuma R, et al. Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease. Front Pediatr. 2024;12:1340263. doi:10.3389/fped.2024.1340263. PMID: 38510083; PMCID: PMC10952825
90. Wolf C, Fischer H, Kühl JS, Koss S, Jamra RA, Starke S, et al. Hemophagocytic lymphohistiocytosis-like hyperinflammation due to a de novo mutation in DPP9. J Allergy Clin Immunol. 2023;152(5):1336-1344.e5. doi:10.1016/j.jaci.2023.07.013. PMID: 37544411; PMCID: PMC7615848
91. Endo Y, Koga T, Ishida M, Fujita Y, Tsuji S, Takatani A, et al. Musculoskeletal manifestations occur predominantly in patients with later-onset familial Mediterranean fever: Data from a multicenter, prospective national cohort study in Japan. Arthritis Res Ther. 2018;20(1):257. doi:10.1186/s13075-018-1738-1
92. Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356(23):2361-2371. doi:10.1056/NEJMoa070265
93. Kisla Ekinci RM, Kilic Konte E, Akay N, Gul U. Familial Mediterranean Fever in Childhood. Turk Arch Pediatr. 2024;59(6):527-534. doi:10.5152/TurkArchPediatr.2024.24188
94. Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014;73(12):2160-2167. doi:10.1136/annrheumdis-2013-204184
95. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, Clinical Approach to Inborn Errors of Metabolism in Paediatrics, sections 1.3.8, 1.4.7 and 1.6.7.
96. Vatansever G, Karali Z, Karali Y, Artac H, Kilic SS. Successful Treatment of Skin Dyskeratosis Due To NLRP1 Mutation Using Baricitinib. J Clin Immunol. 2025;45(1):110. doi:10.1007/s10875-025-01909-8. PMID: 40616725
97. Hernández Sánchez J, García Olivas DJ, Machín García S. Autoinflammatory syndrome associated with a variant of the NLRP1 gene (NAIAD): description of a pediatric case treated with canakinumab. Med Clin (Barc). 2026;166(2):107325. doi:10.1016/j.medcli.2025.107325. PMID: 41539075
98. Alicea-Negrón AJ, Pagan-Gonzalez AD, Torres-Rosario LM, González-Chávez JR, Sánchez-Colón N. PAPASH-like disease associated with a heterozygous NLRP1 variant complicated by papulopustular folliculitis. JAAD Case Rep. 2026;75:321-326. doi:10.1016/j.jdcr.2026.06.053. PMID: 42668523
99. Deniz R, Tansu Yavuz C, Aydın Gümüş A, Yılmaz L, Ercoşkun P, Gül A, Bes C. Beyond NLRP3: expanding the spectrum of NLR-associated autoinflammatory diseases. Rheumatology (Oxford). 2026;65(9):keag518. doi:10.1093/rheumatology/keag518. PMID: 42755046
100. Anselmi F, Frémond ML, Remaux H, Laurent A, Fieschi C, Schvartz A, et al. Tackling the diagnosis of HA20 in children: challenges of a highly variable clinical and genetic presentation. RMD Open. 2026;12(1):e006379. doi:10.1136/rmdopen-2025-006379. PMID: 41741169
101. De Nardi L, Federici S, De Martino E, Celani C, Girardelli M, Matteo V, et al. Clinical phenotype and laboratory markers in patients affected by haploinsufficiency of A20 (HA20). RMD Open. 2026;12(2):e006763. doi:10.1136/rmdopen-2026-006763. PMID: 42128528
102. Gennaro VL, Maclin J, Weiser P, Stoll ML, Smitherman EA. Juvenile Idiopathic Arthritis With Associated Inflammatory Bowel Disease and CARD8 Mutation. Pediatrics. 2023;152(4):e2022058964. doi:10.1542/peds.2022-058964. PMID: 37724393
103. Iuhas A, Marinău C, Niulaș L, Futaki Z, Balmoș A, Kozma K, et al. Familial Mediterranean fever in Romania: a case report and literature review. Front Pediatr. 2024;12:1546387. doi:10.3389/fped.2024.1546387
104. Gordon H, Minozzi S, Kopylov U, Verstockt B, Chaparro M, Buskens C, et al. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis. 2024;18(10):1531-1555. doi:10.1093/ecco-jcc/jjae091. PMID: 38877997
105. Yalçinkaya F, Ozen S, Ozçakar ZB, Aktay N, Cakar N, Düzova A, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48(4):395-398. doi:10.1093/rheumatology/ken509
106. Morales J, Pujar S, Loveland JE, Astashyn A, Bennett R, Berry A, et al. A joint NCBI and EMBL-EBI transcript set for clinical genomics and research. Nature. 2022;604(7905):310-315. doi:10.1038/s41586-022-04558-8 (MANE Select v1.5 consulted)
107. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30
108. National Center for Biotechnology Information. ClinVar: records VCV000004374 (NLRP3 c.778C>T), VCV001701129 (NLRP3 c.778_780delinsTGG) and VCV000011929 (MVK c.1129G>A, p.Val377Ile). Accessed on 6 October 2026. Available from: https://www.ncbi.nlm.nih.gov/clinvar/
109. Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990-1007.e3. doi:10.1053/j.gastro.2014.07.023. PMID: 25058236; PMCID: PMC5376484
110. National Center for Biotechnology Information. ClinVar: VCV000097909 (NM_001243133.2(NLRP3):c.1043C>T, p.Thr348Met), VCV000004371 (c.592G>A, p.Val198Met), VCV000004370 (c.1316C>T, p.Ala439Val) and VCV000004377 (c.907G>A, p.Asp303Asn). Accessed on 6 November 2026. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/97909/
111. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426-2437. doi:10.1056/NEJMoa0807865
112. Salehzadeh F, Babazadeh Khoei F. Infantile Onset Haploinsufficiency of A20 Treated by Infliximab, a Case Report and Brief Review. Int Med Case Rep J. 2026;19:1-6. doi:10.2147/IMCRJ.S587900. PMID: 42572791
113. Takeda Pharmaceuticals America. COLCRYS (colchicine, USP) tablets — Prescribing Information. NDA022352. Revision of October 2022. DailyMed. Available from: https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=COLCRYS
114. European Medicines Agency. Medicines data (medicines output report): Ilaris, Kineret, Rilonacept Regeneron (previously Arcalyst), Rilonacept FGK Representative Service GmbH. Amsterdam: EMA; 2026. Available from: https://www.ema.europa.eu/en/medicines/download-medicine-data
115. Ben-Zvi I, Kukuy O, Giat E, Pras E, Feld O, Kivity S, et al. Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2017;69(4):854-862. doi:10.1002/art.39995
116. Özen S, Sag E, Ben-Chetrit E, Gattorno M, Gül A, Hashkes PJ, et al. Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach. Rheumatology (Oxford). 2021;60(8):3799-3808. doi:10.1093/rheumatology/keaa863
117. Swedish Orphan Biovitrum. KINERET (anakinra) injection — Prescribing Information. BLA103950. Revision effective 3 April 2026. DailyMed. Available from: https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=KINERET
118. European Medicines Agency. Ilaris (canakinumab): EPAR — Product Information (Summary of Product Characteristics). Amsterdam: EMA; 2026. Available from: https://www.ema.europa.eu/en/documents/product-information/ilaris-epar-product-information_en.pdf
119. Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58(8):2443-2452. doi:10.1002/art.23687
120. Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533-541. doi:10.7326/0003-4819-157-8-201210160-00003
121. Novartis Pharmaceuticals. ILARIS (canakinumab) injection — Prescribing Information. BLA125319. Revision effective 8 June 2026. DailyMed. Available from: https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=ILARIS
122. U.S. Food and Drug Administration. Drugs@FDA: submission history of ILARIS (BLA125319), KINERET (BLA103950), ARCALYST (BLA125249) and COLCRYS (NDA022352). Drugs@FDA; 2026. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/
123. De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, et al. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med. 2018;378(20):1908-1919. doi:10.1056/NEJMoa1706314
124. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360(23):2416-2425. doi:10.1056/NEJMoa0810787
125. European Medicines Agency. Kineret (anakinra): EPAR — Product Information (Summary of Product Characteristics). Amsterdam: EMA; 2026. Available from: https://www.ema.europa.eu/en/documents/product-information/kineret-epar-product-information_en.pdf
126. Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581-592. doi:10.1056/NEJMoa055137
127. Kiniksa Pharmaceuticals. ARCALYST (rilonacept) for injection — Prescribing Information. BLA125249. Revision effective 16 December 2025. DailyMed. Available from: https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=ARCALYST
128. ter Haar NM, Oswald M, Jeyaratnam J, Anton J, Barron KS, Brogan PA, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636-1644. doi:10.1136/annrheumdis-2015-207546
129. Soriano A, Soriano M, Espinosa G, Manna R, Emmi G, Cantarini L, et al. Current Therapeutic Options for the Main Monogenic Autoinflammatory Diseases and PFAPA Syndrome: Evidence-Based Approach and Proposal of a Practical Guide. Front Immunol. 2020;11:865. doi:10.3389/fimmu.2020.00865
130. ClinicalTrials.gov. Records NCT05812781 (VTX2735 in CAPS) and NCT04868968 (DFV890 in FCAS); search by condition (FMF, CAPS, TRAPS, MKD) with start since 2022. Accessed on 6 October 2026. Available from: https://clinicaltrials.gov/
131. Ventyx Biosciences. Ventyx Biosciences reports first quarter 2024 financial results and highlights recent corporate progress (press release; exhibit 99.1 to Form 8-K, SEC EDGAR, May 2024). Available from: https://www.sec.gov/Archives/edgar/data/1851194/000095017024056914/vtyx-ex99_1.htm
132. Youngstein T, Hoffmann P, Gül A, Lane T, Williams R, Rowczenio DM, et al. International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors. Rheumatology (Oxford). 2017;56(12):2102-2108. doi:10.1093/rheumatology/kex305
133. U.S. Food and Drug Administration / National Library of Medicine. Acitretin capsules — prescribing information (DailyMed, setid a6546625-acb8-460e-b34e-f795bfb3680a). Updated August 2026. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a6546625-acb8-460e-b34e-f795bfb3680a
134. Incyte Corporation. JAKAFI (ruxolitinib) tablets — prescribing information (DailyMed, setid f1c82580-87ae-11e0-bc84-0002a5d5c51b). Updated August 2026. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f1c82580-87ae-11e0-bc84-0002a5d5c51b
135. Eli Lilly and Company. OLUMIANT (baricitinib) tablets — prescribing information (DailyMed, setid 866e9f35-9035-4581-a4b1-75a621ab55cf). Updated October 2026. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=866e9f35-9035-4581-a4b1-75a621ab55cf
136. Xue F, An C, Lei Z, Dong S, Guo Y, Hou J, et al. Clinical features and genetic analysis of A20 haploinsufficiency. Orphanet J Rare Dis. 2025;20(1):457. doi:10.1186/s13023-025-04004-8. PMID: 40859316
137. Amgen Inc. OTEZLA / OTEZLA XR (apremilast) tablets — prescribing information (DailyMed, setid f6b1f516-4972-4d82-bced-113e47b41cc5). Revision effective 2 September 2026. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6b1f516-4972-4d82-bced-113e47b41cc5
138. AbbVie Inc. HUMIRA (adalimumab) injection — prescribing information (DailyMed, setid 4977567e-3525-44ac-9ff5-f1e74b053950). Revision effective 23 December 2025. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4977567e-3525-44ac-9ff5-f1e74b053950
139. Janssen Biotech Inc. REMICADE (infliximab) for injection — prescribing information (DailyMed, setid a0a046c1-056d-45a9-bfd9-13b47c24f257). Revision effective 3 June 2025. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0a046c1-056d-45a9-bfd9-13b47c24f257
140. ClinicalTrials.gov. Search by condition “A20 haploinsufficiency”, “TNFAIP3” and “Behcet-like autoinflammatory”, with no interventional trial registered in these diseases. Accessed on 1 November 2026. Available from: https://clinicaltrials.gov/
141. Takeda Pharmaceuticals America. ENTYVIO (vedolizumab) — prescribing information (DailyMed, setid 6e94621c-1a95-4af9-98d1-52b9e6f1949c). Revision effective 29 April 2026. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6e94621c-1a95-4af9-98d1-52b9e6f1949c
142. European Medicines Agency. Ketek (telithromycin): EPAR — withdrawal of the marketing authorisation in the European Union (7 June 2019); not marketed in the EU since 1 July 2018 [Internet]. Amsterdam: EMA. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ketek. Accessed on 7 Nov 2026.
143. Haute Autorité de Santé. Révision de la stratégie de vaccination contre les infections invasives à pneumocoques: place des vaccins à haute valence Prevenar 20 chez les nourrissons, les enfants et les adultes et Capvaxive chez les adultes. Vaccination recommendation validated on 23 July 2026 (decision no. 2026.0154/DC/SESPEV). [https://has-sante.fr/jcms/p_3601959/fr/](https://has-sante.fr/jcms/p_3601959/fr/). Accessed on 7 Nov 2026.
144. Centers for Disease Control and Prevention. Pneumococcal vaccine recommendations [Internet]. Atlanta (GA): CDC; 2026 Feb 25 [accessed 2026 Nov 7]. Available from: https://www.cdc.gov/pneumococcal/hcp/vaccine-recommendations/index.html
145. Centers for Disease Control and Prevention. Summary of risk-based pneumococcal vaccination recommendations [Internet]. Atlanta (GA): CDC; 2026 May 8 [accessed 2026 Nov 7]. Available from: https://www.cdc.gov/pneumococcal/hcp/vaccine-recommendations/risk-indications.html
146. Agence nationale de sécurité du médicament et des produits de santé. Advilmed enfants et nourrissons 20 mg/1 ml, suspension buvable (ibuprofen): summary of product characteristics, section 4.2 [Internet]. Base de données publique des médicaments, CIS 61902232. [https://base-donnees-publique.medicaments.gouv.fr/medicament/61902232/extrait](https://base-donnees-publique.medicaments.gouv.fr/medicament/61902232/extrait). Accessed on 7 Nov 2026.
147. Unichem Pharmaceuticals (USA). Tramadol hydrochloride tablets — prescribing information (DailyMed, setid 007bf37f-0e46-426a-ac8c-be63d4b7414c). Revision effective 10 April 2026. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=007bf37f-0e46-426a-ac8c-be63d4b7414c
148. Agence nationale de sécurité du médicament et des produits de santé (ANSM). CONTRAMAL 100 mg/ml, solution buvable en gouttes (chlorhydrate de tramadol): résumé des caractéristiques du produit. Base de données publique des médicaments, CIS 60477650; mise à jour le 30/10/2025 [accessed 2026 Nov 7]. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/60477650/extrait
149. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 811–814 (Appendix, Table A8: Top ten most common carrier frequencies by population, adapted from Lazarin GA et al., Genet Med).
150. Zegarska J, Wiesik-Szewczyk E, Hryniewiecka E, Wolska-Kusnierz B, Soldacki D, Kacprzak M, et al. Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) with a New Pathogenic Variant in TNFRSF1A Gene in a Family of the Adult Male with Renal AA Amyloidosis-Diagnostic and Therapeutic Challenge for Clinicians. J Clin Med. 2021;10(3):465. doi:10.3390/jcm10030465
151. European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory, Autoimmune and Paediatric Rheumatic Diseases (ERN RITA). Accessed on 6 October 2026. Available from: https://ern-rita.org/
152. European Federation of Crohn's & Ulcerative Colitis Associations (EFCCA). Accessed on 1 November 2026. Available from: https://www.efcca.org/
153. Herrera CN. A 9-Year-Old Patient with Recurrent Fever, Urticarial Rash and Demyelinating Brain Lesions: NLRP3-Autoinflammatory Disease in Ecuador. Open Access Rheumatol. 2022;14:1-5. doi:10.2147/OARRR.S333562