rheum.reviews

Overview of Autoinflammatory Diseases

Contents

    BOTTOM LINE

    • Autoinflammatory disease generally refers to a broad spectrum of disorders related to inappropriate, antigen-independent activation of the innate immune system.
    • Periodic fever is common but not universal. Other inflammatory lesions may include arthritis, osteomyelitis, rash, enterocolitis or mucositis, serositis, vasculitis, lymphadenopathy, conjunctivitis, meningitis and basal ganglia calcification.
    • Many patients present at a young age or have consanguinity or affected family members. Diagnosis requires recognition of innate immune activation, disease-pattern recognition, concordant ESR/CRP elevation and careful interpretation of genetic testing.
    • Treatment is guided by the primary aberrant pathway and may include colchicine, IL-1, IL-6, IL-18 or TNF inhibition, or JAK inhibition.
    • Diagnostic delay is common: the average diagnostic delay in adults is approximately 14 years (compared with 3 years in children), and misdiagnosis as psychosomatic illness is frequent. A UK national referral centre reported a median delay of 4.5 years for new adult diagnoses and 6 years for late-onset SAID.
    • Undifferentiated or unclassified SAID (uSAID) is among the most common autoinflammatory diagnoses in adult practice. An estimated 40–60% of patients with phenotypes typical of SAID cannot be assigned a defined monogenic diagnosis even after comprehensive genetic testing.
      [🕑 20 minute read ]

    CONTINUUM OF AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES

    Innate immunityAdaptive immunity
    Specificityhard-wired recognition of molecular patterns shared by pathogens and damaged host cellslearned recognition of microbial and non-microbial antigens
    Responserapid initial response over minutes to hoursslower initial response over days to weeks
    Memorynone or limited; subsequent responses are similarsubsequent responses are more rapid and intense
    Blood proteinscomplement, lectins and agglutininsantibodies
    Cellular effectorsphagocytes (macrophages and neutrophils), dendritic cells, NK cells, mast cells and innate lymphoid cellsB- and T-cell lymphocytes
    DiseaseAutoinflammatory disease: antigen-independent inappropriate activation. Lack of MHC association, autoantibodies and sex predominance is a useful heuristic, but type I interferonopathies such as AGS and monogenic SLE may feature autoantibodies.Autoimmune disease: inappropriate failure of self/non-self discrimination; may show MHC association, autoantibodies and female predominance

    In practice, innate and adaptive immunity and autoinflammatory and autoimmune disease exist on a continuum with complex interplay.

    PATHOGENTIC CATEGORIES

    1. Inflammasomopathies: inappropriate inflammasome activation; may respond to IL-1, TNF or IL-18 inhibition
    2. Interferonopathies: inappropriate type I interferon activation; may respond to JAK inhibition
    3. NF-kB-opathies, aberrant TNF activity or relopathies: NF-kB dysregulation; may respond to IL-1, IL-6 or TNF inhibition
    4. Other: diverse and evolving mechanisms that do not fit neatly into the categories above

    Classification criteria

    • Evidence-based Eurofever/PRINTO classification criteria have been validated for FMF, TRAPS, MKD, CAPS and PFAPA with high sensitivity (0.94–1.0) and specificity (0.93–1.0). Both genetic-plus-clinical and clinical-only formats are available.
    • Caveat: sensitivity may be lower in populations with high carrier rates of common variants (e.g., MEFV E148Q in Mediterranean populations).

    1. INFLAMMASOMOPATHIES

    The normal inflammasome

    • Inflammasomes are protein complexes that assemble in response to pathogenic or physiological stimuli.
    • Damage-associated molecular patterns arise from cell or tissue damage; pathogen-associated molecular patterns include lipopolysaccharide from microorganisms.
    • Pattern-recognition receptors, including pyrin and nucleotide-binding domain-like receptors, detect these signals and assemble with proteins including ASC and pro-caspase-1.
    • Inflammasomes activate caspase-1, IL-1β and IL-18 and cause pyroptosis, an inflammatory form of cell death.

    Mechanism overview

    • Most inflammasomopathies result from gain-of-function mutations in inflammasome sensors themselves (including NLRP3, MEFV, NLRC4 and NLRP1); a smaller group results from loss-of-function defects in negative regulators or antagonists (including IL1RN and IL36RN).

    —Pyrin activation

    FMF: Familial Mediterranean Fever
    • Gene/inheritance:
      • MEFV (Autosomal recessive; a substantial proportion of clinically affected patients carry only one demonstrable MEFV mutation)
    • Patient:
      • Age at onset <20 years; Eastern Mediterranean (Jewish, Turkish, Armenian, Arab)
    • Features:
      • Attacks: fever, polyserositis (peritonitis, pericarditis, pleuritis), inflammatory arthritis; AA amyloidosis risk
    • Therapy:
      • Colchicine is first-line and the mainstay of maintenance therapy (adult maintenance 1.2–1.8 mg/day); it prevents attacks and AA amyloidosis
      • IL-1 inhibition is reserved for colchicine-resistant or colchicine-intolerant disease
      • NSAIDs for flares
    • Pregnancy/fertility:
      • Continue colchicine during conception, pregnancy and breastfeeding unless a patient-specific contraindication exists
    MKD (HIDS); Mevalonate kinase deficiency (hyperimmunoglobulin D syndrome)
    • Gene/inheritance:
      • MVK (AR)
    • Patient:
      • Usually begins before age 1 year; diagnosis may be delayed to adolescence or adulthood
      • Attacks typically last 4–6 days
      • Also known as HIDS
    • Features:
      • Fever, lymphadenopathy, abdominal/joint pain, diarrhea, rash, headache, aphthous ulcers and splenomegaly
      • Infection, vaccination and stress are triggers rather than manifestations
      • Serum IgD and IgA may be elevated; IgD is normal in approximately 22%, so a normal IgD does not exclude MKD
      • Urinary mevalonic acid is elevated during attacks
    • Therapy:
      • Canakinumab has randomized-trial support and is approved for HIDS/MKD
      • Anakinra, corticosteroids at attack onset, etanercept and tocilizumab have weaker evidence
    • Vaccination:
      • vaccination may trigger a disease flare in MKD, but this is not a contraindication to vaccination
    PAAND: Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis
    • Gene/inheritance: MEFV (AD)
    • Features: Childhood fever, neutrophilic dermatosis, pyoderma gangrenosum, arthralgias/myalgias
    • Therapy: IL-1i, colchicine
    PAPA (Pyogenic Arthritis, Pyoderma Gangrenosum, Acne)
    • Gene/inheritance: PSTPIP1 (AD)
    • Features: Juvenile-onset inflammatory arthritis; adolescent/adult pyoderma gangrenosum, ulcers, acne
    • Therapy: IL-1i, TNFi
    PFIT: periodic fever, immunodeficiency, and thrombocytopenia
    • Gene/inheritance: WDR1 (AR)
    • Features: Fevers, immunodeficiency, oral inflammation, perianal ulcers, thrombocytopenia
    • Therapy: IL-18i

    —Cryopyrin activation

    FCAS: Familial Cold Autoinflammatory Syndrome
    • Gene/inheritance: NLRP3 (AD)
    • Patient: Typically presents in infancy or early childhood
    • Features: Mildest fever, cold-induced neutrophilic urticaria, arthralgia, extremity pain, conjunctivitis, fever
    • Therapy: IL-1 inhibition: canakinumab (approved for FCAS/MWS in patients ≥4 years), rilonacept or anakinra
    MWS: Muckle-Wells syndrome
    • Gene/inheritance: NLRP3 (AD)
    • Patient: Typically presents in infancy or early childhood
    • Features: Mild fever, neutrophilic urticaria, inflammatory arthritis, deafness, conjunctivitis, episcleritis; AA amyloidosis risk
    • Therapy: IL-1 inhibition: canakinumab, rilonacept or anakinra
    NOMID: Neonatal-Onset Multisystem Inflammatory Disease
    • Gene/inheritance: NLRP3 (AD)
    • Features: Neonatal severe fever, rash, uveitis, various CNS manifestations (e.g., meningitis, hydrocephalus); high mortality
    • Therapy: IL-1 inhibition; anakinra is approved for NOMID
    Majeed Syndrome
    • Gene/inheritance: LPIN2 (AR)
    • Features: Chronic recurrent multifocal osteomyelitis, fevers, rash, anemia
    • Therapy: IL-1i

    —NLRC4 activation

    NLRC4 gain-of-function produces massive IL-18 elevation together with IL-1β, causing infantile enterocolitis and a strong propensity to recurrent macrophage activation syndrome (MAS).

    AIFEC(Autoinflammation with Infantile Enterocolitis)
    • Gene/inheritance: NLRC4 (AD)
    • Features: Infantile enterocolitis, rash, fever, macrophage activating syndrome, arthritis
    • Therapy: IL-1i, IL-18i
    FCAS/NOMID
    • Gene/inheritance: NLRC4 (AD)
    • Features: Cold urticaria, extremity pain, fever, CNS disease
    • Therapy: IL-1i

    —NLRP12 activation

    FCAS
    • Gene/inheritance: NLRP12 (AD)
    • Features: Cold urticaria, extremity pain, fever, aphthous ulcer
    • Therapy: TNFi, IL-1i

    —NLRP1 activation

    NAIAD: NLRP1-associated autoinflammation with arthritis and dyskeratosis
    • Gene/inheritance: NLRP1 (AD)
    • Features: Ocular, laryngeal, skin dyskeratosis, fever, arthritis
    • Therapy: IL-1i, TNFi

    —Receptor antagonist deficiency

    DIRA: deficiency of the interleukin 1 (IL-1) receptor antagonist
    • Gene/inheritance: IL1RN (AR)
    • Features: Pustular rash, inflammatory arthritis, hepatosplenomegaly, osteomyelitis, periostitis, fever
    • Therapy: IL-1i
    DITRA: deficiency of the IL-36 receptor [IL-36R] antagonist
    • Gene/inheritance: IL36RN (AR)
    • Features: Pustular psoriasis, fever, malaise
    • Therapy:
      • Anti-IL-36 receptor therapy (spesolimab) is approved for generalized pustular psoriasis and is pathway-directed
      • Intravenous spesolimab can clear acute flares within 1 week; high-dose subcutaneous spesolimab can prevent flares
      • Other reported options include TNF, IL-1, IL-17, IL-12/23 and IL-23 inhibition

    Notes

    • AR = Autosomal recessive. AD = Autosomal dominant.
    • Some name inflammasomopathies by genetic mutation, e.g., NLRP3-AID (autoinflammatory disease), NLRP12-AID
    • AA amyloidosis surveillance is relevant to FMF, MWS, TRAPS and MKD.
      • Monitor urine protein/urinalysis and serum amyloid A regularly
      • Sustained serum amyloid A >10 mg/L predicts amyloidosis.
      • Individualize the surveillance interval according to disease control and risk.
    • A response to colchicine is not specific to an inflammasomopathy; colchicine is also effective in idiopathic recurrent pericarditis, Behçet mucocutaneous disease and gout.
    • If infection cannot be excluded, do not characterize IL-1 blockade as safe during active infection.
      • Anakinra’s short half-life makes it the preferred IL-1 agent when infection remains a concern.

    2. INTERFERONOPATHIES

    Normal interferon function

    • Interferons are cytokines released in response to sensing of viral nucleic acid or mislocalized self nucleic acid.
    • Type I interferons include IFN-α and IFN-β, participate in antiviral defence and signal through the type I interferon receptor, JAK1 and TYK2.
    • Type II interferon (IFN-γ) participates in innate and adaptive immunity and signals through the type II interferon receptor, JAK1 and JAK2.
    • Type III interferons (IFN-λ) signal through a receptor that shares kinases with the type I interferon receptor.

    Mechanism and assessment

    • Type I interferon may be induced by cytosolic sensing of viral nucleic acid or mislocalized self nucleic acid.
    • Type I interferonopathies, including AGS and monogenic SLE, may feature autoantibodies despite their classification as autoinflammatory disorders.
    • For AGS, SAVI and CANDLE/PRAAS, assess the interferon signature where available; JAK inhibition, particularly baricitinib, is a pathway-directed treatment.

    —Nucleic acid processing and degradation disorders

    Aicardi-Goutières Syndrome (AGS)
    • Gene/inheritance:
      • TREX1, ADAR1, RNASEH2A/B/C, SAMHD1, IFIH1 (AR; AD: IFIH1)
    • Features:
      • Neonatal to later-onset fever, neurologic decline, encephalopathy, cerebral calcification, chilblains, hepatosplenomegaly, autoantibodies
    • Therapy:
      • JAK inhibition, particularly baricitinib
      • Consider interferon-signature testing
      • Reverse transcriptase inhibitor or IFN-receptor antagonist: investigational/uncertain
    Monogenic SLE
    • Gene/inheritance: DNASE1/2/1L3, complements (AR; AD: DNASE1)
    • Features: Neonatal inflammatory arthritis, cytopenias, glomerulonephritis, rash, mucositis, liver fibrosis
    • Therapy: ?JAKi, ?IFN-RA

    —Nucleic acid sensing enhanced

    SMS: Singleton-Merten Syndrome
    • Gene/inheritance: IFIH1, DDX58 (RIGI) (AD)
    • Features: Early onset calcification of aorta/cardiac valves, osteopenia, acro-osteolysis, dental anomalies
    • Therapy: JAK inhibition; IFN-receptor antagonist remains uncertain/investigational
    SAVI: STING-associated vasculopathy with onset in infancy
    • Gene/inheritance: STING1 (formerly TMEM173) (AD)
    • Features: Infant-onset vasculopathy (chilblains, small vessel vasculitis), skin ulcers/necrosis, arthritis, ILD
    • Therapy: JAK inhibition, particularly baricitinib
    • Consider interferon-signature testing
    • IFN-receptor antagonist remains uncertain/investigational

    —Proteasome dysfunction

    CANDLE / PRAAS / PRAID
    • Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature
      Proteasome-Associated Autoinflammatory Syndromes
      POMP-Related Autoinflammatory Disease
    • Gene/inheritance: PSMB3, PSMB4, PSMB8, PSMB9, POMP (AR; AD: POMP)
    • Features: Infant-onset fever, annular plaques and eyelid swelling, joint contractures, hepatosplenomegaly, lipodystrophy, failure to thrive, developmental delay, anemia
    • Therapy:
      • JAK inhibition, particularly baricitinib
      • Consider interferon-signature testing
      • IFN-receptor antagonist remains uncertain/investigational

    3. NF-kB DISORDERS AND/OR ABERRANT TNF ACTIVITY

    Normal NF-kB and TNF function

    • NF-kB integrates cell-surface and intracellular danger signals and triggers production of proinflammatory cytokines including TNF and IL-6.
    • NF-kB regulation involves multiple sensor and inhibitor proteins and ubiquitin-dependent functional modifications.
    • NF-kB-opathies, or relopathies, arise from disorders of this complex regulatory system. Hallmarks include fever, systemic inflammation and sometimes granuloma formation.

    —Dysregulated NF-kB signaling

    HA20
    • Gene/inheritance: TNFAIP3 (AD)
    • Patient: Childhood onset but adolescence/adulthood reported; most common European and Japanese
    • Features: Fever (44%), mouth/genital/GI ulcers (63%), erythema nodosum, psoriasis, folliculitis, diarrhea, arthralgia/arthritis. Resembles Behçet disease and may resemble IBD, RA, SLE or sJIA; A20 is a prototype of Behçet-like monogenic disease
    • Therapy: Colchicine, TNFi, IL-1i, IL-6i, ?JAK
    RELA haploinsufficiency
    • Gene/inheritance: RELA (AD)
    • Features: Oral and gastrointestinal ulcerations, cytopenias, lymphoproliferative disease
    • Therapy: TNFi
    ORAS
    • Gene/inheritance: OTULIN (AR)
    • Features: Neonatal fever, panniculitis, diarrhea, inflammatory arthritis, failure to thrive
    • Therapy: TNFi
    LUBAC deficient
    • Gene/inheritance: HOIL1, HOIP (AR)
    • Features: Neonatal fever, recurrent infection, failure to thrive, amylopectin-like deposits in muscles
    • Therapy: Hematopoietic stem cell transplant, ?TNF

    —Dysregulated TNF

    TRAPS
    • Gene/inheritance: TNFRSF1A (AD)
    • Patient: Age at onset varies from infancy to adulthood (22%), tends to be childhood
    • Features: Fever flares ×1–4 weeks, abdominal pain, myalgias, centrifugal rash, conjunctivitis, periorbital edema
    • Therapy:
      • IL-1 inhibition is the treatment of choice; canakinumab is approved for TRAPS
      • Etanercept may provide partial benefit, but responses often wane
      • Infliximab and adalimumab can cause paradoxical inflammatory flares and should be avoided
      • Short-term glucocorticoids may help during flares
    • Complication:
      • TRAPS carries a risk of AA amyloidosis; monitor urine protein/urinalysis and serum amyloid A as described in the amyloidosis surveillance note
    DADA2
    • Gene/inheritance: ADA2 (AR)
    • Patient: Childhood onset, but later and adult onset reported (sometimes due to delayed recognition)
    • Features: Fever, PAN-like vasculitis, young-onset ischemic/hemorrhagic stroke, livedo, cytopenias, hypogammaglobulinemia
    • Therapy:
      • TNF inhibition is the treatment of choice and is generally lifelong; consider TNF inhibition even in presymptomatic biallelic carriers
      • Hematopoietic stem cell transplant for marrow failure or refractory cytopenias
      • Avoid: Antiplatelet agents, anticoagulants and antithrombotics should generally be avoided because of the risk of hemorrhagic conversion
    Blau
    • Gene/inheritance: NOD2 (AD)
    • Features: Early-onset familial sarcoid: granulomatous dermatitis, uveitis, polyarticular arthritis
    • Therapy: TNFi
    CRIA
    • Gene/inheritance: RIPK1 (AD)
    • Features: Fever, lymphadenopathy, hepatosplenomegaly
    • Therapy: ?IL-6i

    Notes

    • HA20: haploinsufficiency of A20, TRAPS: TNF receptor-associated periodic fever syndrome, DADA2: deficiency of adenosine deaminase 2

    4. OTHER AUTOINFLAMMATORY DISORDERS

    Disorders that are more prevalent in adult than paediatric patients

    Schnitzler syndrome
    • Patient:
      • Median age 55 years, slight male predominance
    • Diagnostic criteria:
      • The Strasbourg criteria require an urticarial rash plus monoclonal IgM (or IgG) as obligate criteria
    • Features:
      • Recurrent fever (72%), urticaria, bone/joint pain (40%), lymphadenopathy (25%), paraprotein (IgM > IgG)
      • Urticaria may precede other symptoms by years
    • Treatment:
      • Anakinra is first-line and produces a complete response in approximately 95%
      • IL-6 inhibition is an alternative
    • Follow-up:
      • CBC and CRP every 3 months with MGUS surveillance because of the risks of AA amyloidosis and lymphoproliferative transformation
    CNO/CRMO, SAPHO
    • CNO (Chronic nonbacterial osteomyelitis), aka CRMO (Chronic Recurrent Multifocal Osteomyelitis)
      • May be within the same disease spectrum as SAPHO (Synovitis acne pustulosis hyperostosis osteitis) in adults
      • Preferred terminology is CNO. Adult CNO overlaps with spondyloarthritis, including psoriatic and axial spondyloarthritis, although most adults present with isolated osteomyelitis.
    • Mechanism:
      • Sporadic CNO is not monogenic and remains a diagnosis of exclusion. Current model: failure of monocytes to produce IL-10/IL-19 leads to NLRP3 inflammasome activation with IL-1β and TNF excess; rare P2RX7 variants have been reported. Monogenic mimics include LPIN2 (Majeed) and IL1RN (DIRA); PSTPIP2 is a murine model.
    • Patient:
      • May affect adults or children; adults commonly present at 29–46 years, with a female predominance of approximately 60–73%
    • Features:
      • Bone: swelling and bone pain due to uni- or multifocal aseptic osteitis commonly at metaphyses/epiphyses of long bones, shoulder girdle (clavicle and sternum), vertebral bodies, mandible (rare)
      • Musculocutaneous (20%): palmoplantar pustulosis, cystic acne, inflammatory arthritis (more in SAPHO)
      • Spondyloarthropathy features: IBD (10%), psoriasis, hidradenitis suppurativa; association of CNO with seronegative spondyloarthropathy may be stronger in adults than in children
    • Imaging:
      • Whole-body STIR MRI is the most sensitive modality for detecting clinically silent lesions and defining multifocality
      • MRI whole-body or regional with STIR: bone marrow edema signifies osteitis
      • X-ray: may show osteolytic or hyperostotic features but is often normal early
      • Can evaluate for fracture, sarcoma, metastases, infarction; bone biopsy and culture may be required
    • Differential diagnosis:
      • Infectious osteomyelitis
      • Primary bone tumour or metastases
      • Axial or psoriatic spondyloarthritis
      • Rheumatoid arthritis
      • Osteoarthritis
      • Sternoclavicular subluxation or trauma
      • Paget disease
      • Osteomalacia or hypophosphatasia;
      • Tietze syndrome
      • Fibrous dysplasia
    • Treatment of osteitis
      • First line: NSAIDs
      • Refractory:
        • Methotrexate, sulfasalazine (±NSAIDs, steroids), or
        • TNF inhibitors: adalimumab, etanercept, other TNFi (±methotrexate), or
        • Bisphosphonates: pamidronate (first choice), zoledronate (±NSAIDs, steroids)
        • Refer refractory disease to an expert centre
    PFAPA — Periodic fever with aphthous stomatitis, pharyngitis and adenitis
    • Patient:
      • Usually pediatric disease, adult cases reported
    • Features:
      • Every 4–6 weeks: fever with aphthous stomatitis, pharyngitis, cervical adenitis lasting 3–6 days
      • 41% of adults have all 4/4 features, 60% of adults have 2/4 features
      • Adults may develop exudative pharyngitis
    • Treatment:
      • Single dose of prednisone 0.5 mg/kg/d
      • Colchicine, IL-1i if frequent flares
      • Tonsillectomy: moderate-certainty evidence supports symptom resolution and a marked reduction in episode frequency; response is more likely with steroid-responsive episodes and exudative pharyngitis, and less likely with rash or arthralgia/myalgia
      • H2 blockers (cimetidine or famotidine) may be considered, including in post-tonsillectomy refractory cases
    IRP — Idiopathic recurrent pericarditis
    • Definitions:
      • Recurrent pericarditis: pericarditis with relapse after at least 4 weeks
      • Chronic pericarditis: symptoms persisting >3 months without symptom-free interval for 4 weeks
    • Features:
      • Chest pain (100%), pleurisy (36%), fever (30%), ALT elevation (8%), peritonitis (5%)
      • Recurrence rate: 20–30% after first episode, 20–50% after first relapse
    • Investigations:
      • ESR/CRP elevation, compatible ECG, echocardiographic evidence of effusion
    • Treatment:
      • First line: dual therapy with an NSAID or aspirin plus colchicine, together with exercise restriction; continue colchicine for 3 months after a first episode and at least 6 months after a first recurrence
      • For the inflammatory phenotype (CRP >10 mg/L), anti-IL-1 therapy is preferred over corticosteroids: rilonacept is approved for recurrent pericarditis; anakinra and goflikicept are additional options
      • Avoid anti-IL-1 therapy in tuberculosis-endemic settings unless tuberculosis risk has been appropriately assessed and managed
      • Corticosteroids, methotrexate or azathioprine may be used in selected refractory cases; pericardiectomy is a last resort
    AOSD — Adult-onset Still’s disease
    • Contributions from auto-immunity and auto-inflammation
    • IL-1/IL-18-driven disease with risk of macrophage activation syndrome
    • Canakinumab is approved for Still disease.
    • See dedicated chapter.
    Undifferentiated systemic autoinflammatory disease (uSAID)
    • ~40–60% of patients with clinical phenotypes typical of SAID cannot be assigned a defined monogenic diagnosis even after comprehensive genetic testing.
      • In a UK national referral centre, undifferentiated SAID accounted for 11% of all SAID diagnoses and was the third most common category after FMF and recurrent pericarditis.
    • Presentation:
      • Recurrent fever and systemic inflammation fitting the clinical pattern of autoinflammatory disease but not meeting classification criteria for a defined entity after thorough genetic and laboratory workup.
    • Diagnostic and therapeutic trial:
      • Anakinra can serve as both a diagnostic and therapeutic trial; in one series, 9 of 11 uSAID patients responded to anakinra.
    • Management:
      • Treat according to the dominant clinical phenotype and suspected pathway; escalate empirically as outlined in Step 5 of the general approach.
    VEXAS — Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome
    • Genetics:
      • Somatic, myeloid-restricted UBA1 variants, most often missense or splice-site variants at exon 3 (p.Met41); not heritable; detectable in blood or marrow DNA
      • Active treatment can lower variant allele frequency and cause false-negative results; Sanger sequencing or ddPCR may miss low-variant-allele-frequency or non-exon-3 variants
    • Patient:
      • Usually men aged 55–65 years (reported range approximately 40–85 years); a small number of female cases have been identified
    • Systemic features:
      • Recurrent fever
    • Cutaneous features:
      • Neutrophilic dermatoses, livedo, panniculitis, urticaria and ulcers
    • Chondritis:
      • Airway or costochondral chondritis and vestibular symptoms
    • Pulmonary features:
      • Dyspnea, dry cough, pleural effusion, lymphadenopathy and ground-glass pulmonary change
    • Vascular features:
      • DVT/PE, superficial thrombophlebitis and variable-vessel vasculitis; may resemble polyarteritis nodosa clinically without classic arteriographic findings
    • Articular features:
      • Oligoarticular or polyarticular inflammatory arthritis
    • Ocular features:
      • Episcleritis, uveitis, iritis, scleritis, blepharitis, and orbital or periorbital inflammation that can mimic cellulitis
    • Other features:
      • Reported associations include pericarditis, myocarditis, hearing loss, interstitial nephritis, mononeuritis, diarrhea, relapsing polychondritis, myelodysplastic syndrome and myelofibrosis
    • Laboratory features:
      • Macrocytic anemia, thrombocytopenia or neutropenia; elevated ESR and CRP
    • Treatment:
      • Prednisone often controls inflammation initially, but steroid dependence is common
      • IL-6 inhibitors are the most widely used anticytokine therapy
      • IL-1 inhibitors may be considered. If IL-1 blockade is pursued, canakinumab is preferred because anakinra causes severe injection-site reactions, including skin ulceration, at unusually high rates in VEXAS; few data support anakinra in this setting
      • TNF inhibitors do not appear effective in VEXAS
      • Ruxolitinib is the preferred JAK inhibitor (10–20 mg twice daily); monitor for cytopenias, thromboembolism and viral reactivation, and consider herpesvirus prophylaxis
      • B-cell-depleting therapy is contraindicated
      • Azacitidine 75 mg/m² for 7 days every 4 weeks can reduce clonal burden and control inflammation, particularly with myelodysplastic syndrome
      • Allogeneic hematopoietic stem cell transplantation is the only curative option
      • Provide thromboprophylaxis and opportunistic-infection prophylaxis in all patients, individualized to contraindications and clinical context

    SUMMARY TABLE

    ➞ Swipe/scroll left to view the complete table ➞

    CategoryDiseaseGene (Inheritance)Key FeaturesFirst-Line TherapyPearls
    Inflammasomopathy (Pyrin)FMFMEFV (AR)Onset <20y; Mediterranean ancestry; episodic fever, serositis, erysipelas-like rash; AA amyloid riskColchicine; IL-1i if colchicine-resistantShort attacks (6–72h) with complete resolution between flares; erysipelas-like rash on lower legs is nearly pathognomonic; colchicine non-response should prompt re-evaluation of diagnosis; M694V homozygosity = highest amyloid risk
    MKD (HIDS)MVK (AR)Onset <1y; 4–6d fever attacks, lymphadenopathy, abdominal pain, diarrhea, aphthous ulcers, rash; ↑IgD, ↑urinary mevalonic acidCanakinumab; anakinra/steroids for attacksVaccination and minor illness trigger flares; IgD is normal in ~22%; urinary mevalonic acid during attacks is more reliable; prominent cervical lymphadenopathy distinguishes from FMF
    PAANDMEFV (AD)Childhood fever, neutrophilic dermatosis, pyoderma gangrenosum, arthralgias/myalgiasIL-1i, colchicineAD inheritance of MEFV (distinct mutations from classic FMF); neutrophilic dermatosis/PG pattern differentiates from FMF
    PAPAPSTPIP1 (AD)Juvenile inflammatory arthritis → adolescent/adult pyoderma gangrenosum, acne, ulcersIL-1i, TNFiAge-dependent phenotype shift: destructive arthritis in childhood transitions to skin-dominant disease in adolescence; part of the PSTPIP1-associated spectrum (PAPA/PAMI)
    PFITWDR1 (AR)Fevers, immunodeficiency, oral inflammation, perianal ulcers, thrombocytopeniaIL-18iOne of few inflammasomopathies with significant immunodeficiency; thrombocytopenia is a distinguishing lab finding
    Inflammasomopathy (Cryopyrin)FCASNLRP3 (AD)Mildest CAPS; cold-induced neutrophilic urticaria, arthralgia, conjunctivitis, feverIL-1i (canakinumab, rilonacept, anakinra)Cold exposure triggers attacks within hours; urticaria is neutrophilic (non-pruritic, non-migratory). Biopsy distinguishes from allergic urticaria; typically presents in infancy
    MWSNLRP3 (AD)Neutrophilic urticaria, sensorineural deafness, inflammatory arthritis, episcleritis; AA amyloid riskIL-1i (canakinumab, rilonacept, anakinra)Progressive sensorineural hearing loss is the hallmark differentiating MWS from FCAS; IL-1i can halt/reverse hearing loss if started early; monitor SAA and urinalysis for amyloidosis
    NOMID/
    CINCA    		NLRP3 (AD)Neonatal onset; severe fever, rash, uveitis, chronic aseptic meningitis, hydrocephalus; high mortalityAnakinra; canakinumabMost severe CAPS; continuous (not episodic) inflammation; characteristic overgrowth of epiphyses/patellae; ~40% are somatic mosaics (standard Sanger may miss)
    MajeedLPIN2 (AR)Chronic recurrent multifocal osteomyelitis, fevers, dyserythropoietic anemia, rashIL-1iCongenital dyserythropoietic anemia distinguishes from sporadic CNO/CRMO; onset typically <2 years
    Inflammasomopathy (NLRC4)AIFECNLRC4 (AD)Infantile enterocolitis, rash, fever, recurrent MAS, extreme ↑IL-18IL-1i, IL-18iMassively elevated free IL-18 (often >10,000 pg/mL) is the biochemical signature; MAS is recurrent and life-threatening; gut-predominant due to NLRC4 expression pattern
    FCAS4/
    NOMID-like    		NLRC4 (AD)Cold urticaria, extremity pain, fever, CNS diseaseIL-1iPhenotypic overlap with NLRP3-CAPS but check IL-18 levels (markedly elevated in NLRC4)
    Inflammasomopathy (NLRP12)FCAS2NLRP12 (AD)Cold urticaria, extremity pain, fever, aphthous ulcersTNFi, IL-1iAphthous ulcers distinguish from NLRP3-FCAS; loss-of-function mechanism (unlike GOF in NLRP3)
    Inflammasomopathy (NLRP1)NAIADNLRP1 (AD)Ocular, laryngeal, and skin dyskeratosis, fever, arthritisIL-1i, TNFiSkin-predominant due to NLRP1 expression in keratinocytes; dyskeratosis pattern is distinctive
    Receptor antagonist deficiencyDIRAIL1RN (AR)Neonatal pustular rash, osteomyelitis, periostitis, inflammatory arthritis, hepatosplenomegalyIL-1i (anakinra)Neonatal onset with sterile pustulosis + periostitis/osteomyelitis is classic; fatal without IL-1 blockade; absence of endogenous IL-1Ra confirmed by serum level
    DITRAIL36RN (AR)Generalized pustular psoriasis flares, fever, malaiseSpesolimab (anti–IL-36R, FDA-approved); TNFi, IL-1iLakes of pustules on erythematous skin + systemic inflammation; spesolimab clears flares within 1 week; distinct from plaque psoriasis (IL-17/23 agents less reliable)
    InterferonopathyAGSTREX1, ADAR1, RNASEH2A/B/C, SAMHD1, IFIH1 (AR; AD: IFIH1)Neonatal–later onset; encephalopathy, cerebral calcification, chilblains, hepatosplenomegaly, autoantibodiesJAKi (baricitinib)Mimics congenital TORCH infection; basal ganglia calcification + CSF lymphocytosis + elevated CSF IFN-α; interferon gene signature in blood supports diagnosis; autoantibodies can be present (blurs auto-immune/inflammatory line)
    Monogenic SLEDNASE1/2/1L3, complements (AR; AD: DNASE1)Neonatal inflammatory arthritis, cytopenias, glomerulonephritis, rash, mucositis?JAKiEarly-onset lupus phenotype without typical autoimmune demographics; complement deficiency (especially C1q, C2, C4) is the most common monogenic cause of SLE-like disease
    SAVISTING1/TMEM173 (AD)Infant-onset vasculopathy (chilblains, small-vessel vasculitis), skin ulcers/necrosis, ILD, arthritisJAKi (baricitinib)Acral vasculopathy with tissue loss (nasal septum, digits) is characteristic; ILD can be progressive and life-limiting; STING GOF confirmed by genetic testing
    SMSIFIH1, DDX58 (AD)Early-onset aortic/cardiac valve calcification, osteopenia, acro-osteolysis, dental anomalies?JAKiAortic/valve calcification in infancy is a striking and unusual feature; shared genes with AGS but distinct phenotype
    CANDLE/
    PRAAS    		PSMB3/4/8/9, POMP (AR; AD: POMP)Infant-onset fever, annular plaques, eyelid swelling, lipodystrophy, joint contractures, FTTJAKi (baricitinib)Violaceous periorbital/eyelid swelling is a visual hallmark; progressive lipodystrophy; proteasome dysfunction leads to accumulation of ubiquitinated proteins and IFN signature
    NF-κB / Aberrant TNFHA20TNFAIP3 (AD)Childhood onset; Behçet-like oral/genital/GI ulcers, erythema nodosum, arthritisColchicine, TNFi, IL-1i, IL-6iThe “monogenic Behçet mimic”: consider in early-onset Behçet or Behçet with family history; can also mimic IBD, SLE, or sJIA; A20 protein levels may be reduced on functional testing
    TRAPSTNFRSF1A (AD)Fever flares ×1–4 weeks, abdominal pain, myalgias, centrifugal rash, periorbital edema, conjunctivitis; AA amyloid riskCanakinumab; etanercept (not infliximab/adalimumab — may worsen)Longest fever episodes of the hereditary fevers (1–4 weeks); centrifugal migratory rash over myalgia is characteristic; periorbital edema is a classic clue; anti-TNF monoclonal antibodies are paradoxically harmful
    DADA2ADA2 (AR)Childhood onset; PAN-like vasculitis, young-onset stroke, livedo, cytopenias, hypogammaglobulinemiaTNFi (lifelong); HSCT for marrow failureYoung-onset stroke (especially lacunar) + livedo racemosa should prompt testing; avoid anticoagulants/antiplatelets (hemorrhagic risk); low ADA2 enzyme activity confirms diagnosis; pure red cell aplasia or pancytopenia can be presenting feature
    Blau syndromeNOD2 (AD)Early-onset granulomatous triad: dermatitis, uveitis, polyarticular arthritisTNFi“Pediatric sarcoid” triad before age 5; non-caseating granulomas on biopsy; same gene as Crohn-associated NOD2 but different mutations (GOF vs LOF)
    ORASOTULIN (AR)Neonatal fever, panniculitis, diarrhea, inflammatory arthritis, FTTTNFiSevere neonatal-onset panniculitis with nodular skin lesions is the hallmark; OTULIN deficiency causes linear ubiquitin accumulation
    RELA haploinsufficiencyRELA (AD)Oral/GI ulcerations, cytopenias, lymphoproliferative diseaseTNFiMucosal ulceration + lymphoproliferation overlaps with ALPS; haploinsufficiency (not GOF) mechanism
    CRIARIPK1 (AD)Fever, lymphadenopathy, hepatosplenomegaly?IL-6iRecently described; cleavage-resistant RIPK1 mutations; prominent lymphoproliferation
    Other Adult-predominantSchnitzler
    syndrome    		Acquired (not monogenic)Median age ~55y; chronic urticaria, fever, bone/joint pain, lymphadenopathy; monoclonal IgM (or IgG); AA amyloid and lymphoproliferative riskAnakinra (~95% response); IL-6iUrticaria may precede systemic symptoms by years; Strasbourg diagnostic criteria require urticaria + monoclonal Ig; ~15–20% risk of lymphoproliferative transformation. Requires MGUS-type surveillance; dramatic anakinra response is nearly diagnostic
    CNO/
    CRMO/
    SAPHO    		Polygenic (not monogenic)Multifocal aseptic osteitis (metaphyses, clavicle/sternum, vertebrae); palmoplantar pustulosis, acne; IBD/psoriasis overlapNSAIDs → MTX/SSZ or TNFi or bisphosphonatesWhole-body STIR MRI is the most sensitive modality for multifocal disease (often clinically silent lesions); sternoclavicular involvement is a classic clue; bone biopsy to exclude infection/malignancy when unifocal; diagnosis of exclusion
    VEXASUBA1 (somatic, X-linked)Men >40y; fever, chondritis, neutrophilic dermatoses, DVT/PE, macrocytic anemia, thrombocytopenia; ↑ESR/CRPGlucocorticoids + azacitidine or ruxolitinib; IL-6i; allogeneic HSCT (curative). Avoid IL-1i, B-cell depletionSomatic (not inherited): standard germline panels miss it; bone marrow shows cytoplasmic vacuoles in myeloid/erythroid precursors; macrocytic anemia + thrombocytopenia in a man with “polychondritis” or “unclassified vasculitis” should trigger UBA1 testing; prevalence ~1/4,000 men >50y
    PFAPAUnknownUsually pediatric; q4–6 week fever with aphthous stomatitis, pharyngitis, cervical adenitis ×3–6 daysSingle-dose prednisone; tonsillectomy; colchicine/IL-1i for frequent flaresClockwork periodicity is the hallmark; single-dose steroid aborts the flare (nearly diagnostic); completely well between episodes with normal growth; tonsillectomy resolves symptoms in majority; must exclude cyclic neutropenia (serial CBCs)
    Idiopathic
    recurrent pericarditis    		UnknownChest pain, pleurisy, fever; 20–50% recurrence after first relapse; ↑ESR/CRP, effusion on echoNSAID/aspirin + colchicine; rilonacept (FDA-approved) or anakinra for refractory/CRP-high phenotypeCRP >10 mg/L identifies the “autoinflammatory phenotype” most responsive to IL-1 blockade; avoid corticosteroids early (increase recurrence risk); exercise restriction during active inflammation; rilonacept is the only FDA-approved anti–IL-1 agent for this indication
    AOSDPolygenicQuotidian fever, salmon-colored rash, arthritis, serositis, ↑↑ferritin (often >1,000), ↑IL-18; MAS riskIL-1i (anakinra, canakinumab), IL-6i (tocilizumab); glucocorticoidsQuotidian (spiking daily) fever with evanescent salmon-pink rash is classic; ferritin >10,000 + glycosylated fraction <20% is highly suggestive; watch for MAS (falling ferritin paradox, rising LDH/AST, falling ESR with rising CRP); IL-18 elevation mirrors disease activity

    GENERAL APPROACH TO AUTOINFLAMMATORY DISEASES

    Step 1 — Recognize features suggesting an autoinflammatory disorder

    • Periodic fever is common but not always present.
    • Onset may be at a young age, particularly in monogenic disease. Diagnostic delay in adults averages 14 years; maintain a high index of suspicion.
    • Consanguinity or a family history of autoinflammatory disease may be present.
    • Multiorgan inflammation may involve joints, skin, gastrointestinal mucosa, serosa, blood vessels, lymph nodes, eyes or brain.
    • Flares often begin quickly and are stereotyped from episode to episode.
    • ESR and CRP should rise objectively and concordantly with flares. Autoantibodies are usually absent, except that type I interferonopathies may produce multiple autoantibodies.

    Step 2 —Recognize a specific disease-pattern

    DiseaseFeatures
    FMFFever with 6–72 hours of serositis or erysipelas-like rash in a patient of Mediterranean or Middle Eastern heritage
    MKD/HIDSFever lasting 3–6 days with rash, vomiting or diarrhea and lymphadenopathy; infection, vaccination and stress may trigger attacks
    FCAS/MWSFever and urticaria, sometimes cold-induced, with deafness, conjunctivitis or inflammatory arthritis
    TRAPSFever lasting 1–4 weeks with abdominal pain, myalgias, centrifugal rash, conjunctivitis or periorbital edema
    DADA2Fever, PAN-like vasculitis, young-onset stroke, livedo, cytopenias or hypogammaglobulinemia
    Schnitzler syndromeFever, urticaria and bone or joint pain with a monoclonal paraprotein, often beginning around age 50
    CNO/SAPHOBone pain or swelling in the axial skeleton, sternoclavicular joint or long bones, with possible IBD, pustular rash or psoriasis
    VEXASFever, chondritis, neutrophilic dermatoses, arthritis, macrocytic anemia and thrombocytopenia in a man over age 40
    uSAIDrecurrent fever and systemic inflammation fitting an autoinflammatory pattern but not meeting criteria for a defined entity after thorough workup

    Step 3 — Investigate the hypothesis

    • Baseline testing:
      • CBC, creatinine, urinalysis and urine albumin-to-creatinine ratio, SPEP, immunoglobulins, ESR/CRP and ferritin.
    • Additional markers when accessible:
      • IL-6, IL-18, IgD, IgA, CXCL markers, urinary mevalonic acid or MVK activity, ADA2 activity and interferon signature.
    • Genetic testing strategy — practical hierarchy:
      • First line: targeted NGS panel (e.g., 20–30 SAID genes) for suspected classical recurrent-fever syndromes
      • UBA1 somatic testing (requires specific methodology not covered by standard germline panels) when VEXAS is suspected
      • Trio exome or genome sequencing reserved for atypical phenotypes, negative panels with high clinical suspicion, or research settings — always with expert genetic interpretation
      • Explicitly assess for somatic mosaicism in late-onset CAPS/Schnitzler-like disease and VEXAS. Conventional germline sequencing pipelines and variant-allele-frequency filters may miss these variants.

    Interpreting low-penetrance variants

    • Common low-penetrance variants include TNFRSF1A R92Q (p.Arg92Gln) and P46L (p.Pro46Leu), MEFV E148Q, and NLRP3 Q703K.
    • These variants are enriched in patients with autoinflammatory features relative to the general population but do not behave like pathogenic mutations functionally. Individuals with low-penetrance TNFRSF1A variants typically have milder symptoms (if any), and such variants are often inherited from an asymptomatic parent.
    • Do not treat low-penetrance variants as confirmatory of a specific monogenic disease. Distinguish from clearly pathogenic variants (e.g., cysteine-disrupting TNFRSF1A mutations, high-penetrance MEFV mutations such as M694V).
    • The Infevers database (fmf.igh.cnrs.fr/ISSAID/infevers) catalogues all reported variants in SAID-associated genes with genotype–phenotype associations and is a freely available tool for variant interpretation. The Eurofever registry is an additional resource.

    Step 4 — Establish the diagnosis and differential diagnosis

    • The probability of autoinflammatory disease rises when inflammation and end-organ dysfunction are plausibly explained by innate immune activation in a recognized pattern and are supported by genetic testing or disease-specific biomarkers.
    • Consider the underlying mechanism: inflammasomopathy, interferonopathy, NF-kB-opathy or aberrant TNF activity, or another pathway.
    • If no defined monogenic disease is identified despite thorough workup, consider a diagnosis of undifferentiated SAID (uSAID).
    • Important alternatives include infection, malignancy and systemic autoimmune rheumatic disease.

    Step 5 — Treat empirically when clinical suspicion is sufficiently high

    • NSAID and corticosteroid responses are nonspecific, although a PFAPA flare may resolve after a single corticosteroid dose.
    • A colchicine response is not specific to inflammasomopathy; colchicine also treats recurrent pericarditis, Behçet mucocutaneous disease and gout.
    • Do not initiate IL-1 blockade during active infection. When infection cannot be excluded but IL-1 blockade is being considered, anakinra is preferred because of its short half-life. However, do not discontinue established IL-1 therapy during viral infection (including COVID-19) because stopping may trigger rebound inflammation.
    • A response to JAK inhibition may support a role for interferon or IL-6 signaling, but empirical use requires caution because of broad immunologic effects.
    • TNF inhibition may be useful in selected settings, with appropriate screening and monitoring for immunosuppression and infection.
    • In uSAID, anakinra can serve as both a diagnostic and therapeutic trial.

    DISEASE ACTIVITY MONITORING

    • CRP, ESR and serum amyloid A (SAA) are used to assess systemic inflammation during flares and between flares.
    • CRP is preferred over SAA for routine monitoring because SAA is influenced by BMI; both discriminate flares from quiescent disease at a threshold of approximately 9 mg/L.
    • S100 proteins (S100A8/A9/A12) are emerging as sensitive research-grade markers and are increasingly available clinically.
    • Sustained SAA >10 mg/L predicts AA amyloidosis and should prompt intensification of anti-inflammatory therapy.

    OTHER CONSIDERATIONS

    VACCINATION

    • Patients on IL-1 blocking therapy should be vaccinated in accordance with regional recommendations, including pneumococcal vaccination; benefits generally outweigh the risks of local and systemic reactions.
    • In MKD, vaccination may trigger a disease flare, but this is not a contraindication to vaccination.
    • Live vaccines should be avoided during biologic therapy, consistent with general immunosuppression guidance.

    PREGNANCY AND BIOLOGIC THERAPY

    • FMF: Continue colchicine during conception, pregnancy and breastfeeding unless a patient-specific contraindication exists.
    • IL-1 inhibitors: Data on IL-1 treatment in pregnancy remain limited; decisions should be individualized based on disease severity and the risks of uncontrolled inflammation.
    • TNF inhibitors: Generally considered compatible through at least the second trimester per existing ACR reproductive health guidelines. Third-trimester use requires case-by-case risk-benefit assessment regarding neonatal immunosuppression and live-vaccine timing.

    TRANSITION OF CARE

    • Up to half of adolescent patients with monogenic SAID are not appropriately transferred to adult specialist care, placing them at risk of AA amyloidosis, sensorineural hearing loss and vision loss from uncontrolled disease.
    • Adult rheumatologists receiving patients in transition should ensure a structured handover that includes the specific genetic diagnosis, current therapy, surveillance schedule (including amyloidosis monitoring and audiometry where relevant) and any outstanding genetic counselling needs.

    REFERENCES

    An, J., Marwaha, A., & Laxer, R. M. (2024). Autoinflammatory Diseases: A Review. The Journal of rheumatology, 51(9), 848–861. https://doi.org/10.3899/jrheum.2023-1209

    Nigrovic PA, Lee PY, Hoffman HM. Monogenic Autoinflammatory Disorders: Conceptual Overview, Phenotype, and Clinical Approach. J Allergy Clin Immunol. 2020;146(5):925–937.

    Cetin Gedik K, et al. 2021 EULAR/ACR Points to Consider for Diagnosis and Management of Autoinflammatory Type I Interferonopathies. Arthritis Rheumatol. 2022;74(5):735–751.

    Romano M, et al. 2021 EULAR/ACR Points to Consider for Diagnosis, Management and Monitoring of IL-1-Mediated Autoinflammatory Diseases. Arthritis Rheumatol. 2022;74(7):1102–1121.

    Lee PY, et al. Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement. JAMA Netw Open. 2023;6(5):e2315894.

    Wang TKM, et al. 2025 ACC Expert Consensus Statement on Diagnosis and Management of Pericarditis. J Am Coll Cardiol. 2025;86(25):2691–2719.

    Mekinian AM, et al. American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS. Arthritis Rheumatol. 2025.

    Groarke EM, et al. VEXAS Syndrome: A Comprehensive Review. Lancet. 2026;407:637–648.

    Eviatar T, et al. Comparative Efficacy and Safety of Anakinra and Canakinumab in VEXAS Syndrome. Arthritis Rheumatol. 2026;78(2):475–482.

    Roberts E, et al. An Improved Understanding of Pediatric CNO Pathophysiology. J Bone Miner Res. 2024;39(11):1523–1538.

    Gattorno M, et al. Classification Criteria for Autoinflammatory Recurrent Fevers. Ann Rheum Dis. 2019;78(8):1025–1032.

    Caterson HC, et al. Systemic Autoinflammatory Disease Diagnoses in a Single Year From a UK National Referral Centre. Rheumatology. 2025;64(7):4218–4226.

    Krainer J, et al. Systemic Autoinflammatory Diseases. J Autoimmun. 2020;109:102421.

    Harrison SR, et al. Anakinra as a Diagnostic Challenge and Treatment Option for Systemic Autoinflammatory Disorders of Undefined Etiology. JCI Insight. 2016;1(6):e86336.

    Deuitch N, et al. TNF Receptor-Associated Periodic Fever Syndrome. GeneReviews. Updated 2022.

    Delplanque M, et al. Diagnostic and Therapeutic Algorithms for Monogenic Autoinflammatory Diseases Among Adults. Rheumatology. 2023;62(8):2665–2672.

    Papa R, et al. A Web-Based Collection of Genotype-Phenotype Associations in Hereditary Recurrent Fevers From the Eurofever Registry. Orphanet J Rare Dis. 2017;12(1):167.

    Parentelli AS, et al. C-Reactive Protein Is More Suitable Than Serum Amyloid A to Monitor Crises and Attack-Free Periods in Systemic Auto-Inflammatory Diseases. Eur J Intern Med. 2024;127:91–96.

    Rech J, et al. Patient Experiences and Challenges in the Management of Autoinflammatory Diseases. J Clin Med. 2024;13(5):1199.

    Updated on August 27, 2026
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