The pathogenesis of monogenic autoinflammatory diseases converges on the presence of exaggerated immune responses that are triggered through activation of altered pattern recognition receptor (PRR) pathways and result in cytokine/chemokine amplification loops and the inflammatory clinical phenotype seen in autoinflammatory patients. The PRR response can be triggered by accumulation of metabolites, by mutations in sensors leading to their constitutive overactivation, or by mutations in mediator cytokine pathways that lead to amplification and/or inability to downregulate an inflammatory response in hematopoietic and/or nonhematopoietic cells. The study of the pathogenesis of sterile inflammation in patients with autoinflammatory syndromes continues to uncover novel inflammatory pathways.
Key points
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Monogenic autoinflammatory diseases are caused by single-gene defects in innate immune regulatory pathways. They present in childhood with sterile inflammation and can mimic infections.
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Gain-of-function mutations in NLRP3/CIAS1 , encoding the first intracellular danger sensor identified in humans, cause the clinical spectrum of the cryopyrinopathies and link danger recognition to the activation of the proinflammatory alarm cytokine interleukin (IL)-1.
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The pivotal role of IL-1 in the cryopyrinopathies was confirmed in clinical studies using IL-1 blocking therapies and encouraged their use in the classic periodic fever syndromes, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome.
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Novel autoinflammatory conditions with poor responses to IL-1 blocking therapies include the proteasome-associated autoinflammatory syndromes (PRAAS), deficiency of IL-36 receptor antagonist, CARD14-mediated psoriasis and early-onset inflammatory bowel disease, and suggest a role of cytokine dysregulation beyond IL-1.
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Early diagnosis of these syndromes is essential because effective therapies, particularly for the IL-1-mediated conditions, can change patients’ lives and disease outcomes.
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An emerging theme in our understanding of the pathogenesis of exaggerated sterile inflammatory responses in autoinflammatory syndromes converges on dysregulation in intracellular innate immune sensing, and on the amplification of proinflammatory cytokine circuits that cannot be downregulated.
Old and emerging new concepts
Monogenic autoinflammatory diseases can be defined as a group of immune dysregulatory conditions marked by excessive inflammation that is predominantly mediated by increased responses to known and unknown triggers by cells and molecules of the innate immune system ( Table 1 ). These illnesses typically present in childhood and can mimic infections or hematologic malignancies, but the inflammatory lesions are aseptic and nonmalignant. The discovery of single-gene defects in the interleukin (IL)-1 pathway that cause the spectrum of the cryopyrinopathies or cryopyrin-associated periodic syndromes (CAPS) and the rare condition, deficiency of the IL-1 receptor antagonist (DIRA), pointed to the pivotal role of IL-1 and provided deeper insights into the molecular bases that drive the inflammatory phenotypes. These findings translated into therapeutic approaches using IL-1 blocking agents, which have become standard of care for the cryopyrinopathies and DIRA, and their use has been expanded to other monogenic disorders, the periodic fever syndromes, and to disorders with unidentified genetic causes, including aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome, systemic-onset juvenile idiopathic arthritis (SJIA), adult-onset Still disease (AOSD), and Behçet disease, that share clinical similarities with monogenic autoinflammatory diseases.
| Inheritance/Ethic Distribution | Gene/Protein | Clinical Manifestations | Treatment | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Skin | CNS | Eye | Inner Ear | MSK | Systemic Inflammation | ||||||
| IL-1-Mediated Diseases | Cryopyrinopathies | FCAS | AD/Primarily European | NLRP3 (1q44)/Cryopyrin (NLRP3) | Cold-induced neutrophilic urticaria | Headache | Conjunctivitis | None | Myalgia, arthralgia | Fever,↑ acute phase reactants Complications: Amyloidosis is uncommon ( ˜ 2%) | Anti-IL1 agents: anakinra, canakinumab, rilonacept |
| MWS | AD/Northern European | NLRP3 (1q44)/Cryopyrin (NLRP3) | Neutrophilic urticaria | Headache | Conjunctivitis episcleritis, optic disk edema Complications: corneal opacification | Cochlear edema Complications: SNHL hearing loss | Myalgia, arthralgia, oligo-arthritis | Fever, ↑ acute phase reactants, occasional lymphadenopathy Pericarditis, pleuritis and peritonitis are rare Complications: Amyloidosis is observed in ˜ 25% of cases. Peritoneal adhesions | |||
| NOMID | AD, sporadic/Any ethnicity | NLRP3 (1q44)/Cryopyrin (NLRP3) | Neutrophilic urticaria | Headache, chronic aseptic meningitis Complications: Developmental delay | Conjunctivitis Uveitis Complications: Papilledema, progressive vision loss, corneal opacification | Cochlear edema Complications: SNHL hearing loss | Arthralgia and chronic arthritis Complications: Epiphyseal overgrowth, joint contractures | Fever, ↑ acute phase reactants, occasional lymphadenopathy hepatosplenomegaly Pericarditis, pleuritis and peritonitis are rare. Complications: Amyloidosis in untreated patients who achieve adulthood | |||
| Classic Periodic Fever Syndromes | FMF | AR or AD/Jewish, Arab, Armenian, Turkish, Italian | MEFV (16p13.3)/Pyrin | Erysipelas-like erythema (ELE) | Aseptic meningitis (rare) | Uncommon | None | Exercise-induced myalgia, protracted febrile myalgia, arthritis Complications: sacroiliitis, joint arthrosis, hip arthritis & erosions | Fever and ↑ acute phase reactants Serositis: peritonitis, pleuritis, pericarditis, epididymitis Complications: Peritoneal adhesions Amyloidosis risk varies according with genotype and environment. | Daily oral colchicine, anti-IL1 agents (anakinra, rilonacept and canakinumab | |
| TRAPS | AD/Broad ethnic distribution Originally Irish/Scottish | TNFRSF1A (12p13)/55kDaTNF receptor | Migratory erythema often associated myalgia; ELE | Headache; aseptic meningitis (rare) | Periorbital edema, conjunctivitis Uveitis | None | Migratory myalgia, arthralgia, non-erosive arthritis | Fever, ↑ acute phase reactants and occasional lymphadenopathy Serositis: peritonitis, pleuritis, pericarditis, scrotal pain Complications: Amyloidosis is observed in ˜ 14% of cases. Peritoneal adhesions | Etanercept, anti-IL1 agents (anakinra) | ||
| HIDS | AR/Dutch, Northern European | MVK (12q24)/Mevalonate kinase | Maculo-papular purpuric exanthema, apthous oral ulcers | Uncommon | Uncommon | None | Arthralgia, non-erosive acute polyarthritis; myalgia (rare) | Fever, ↑ acute phase reactants, cervical lymphadenopathy hepatosplenomegaly Peritonitis is uncommon. Pericarditis is rare. | NSAIDs, CS, simvastatin, anti-IL1 (anakinra, canakinumab) | ||
| Autoinflammatory Bone Diseases | DIRA | AR/Newfoundland, Puerto Rican, Brazilian, Dutch, Palestinian | IL1RN (2q14.2)/IL1RA | Pustular dermatitis | Rare CNS vasculitis Complications: Rare encephalomalacia | Conjunctivitis is rare | None | Recurrent multifocal aseptic osteomyelitis Periosteitis Complications: Vertebral and odontoid destruction | Occasional fever in few patients and increased acute phase reactants Complications: Amyloidosis risk is unknown. | Anti-IL1 agents (anakinra, rilonacept in clinical trial) | |
| Majeed | AR/Originally Jordanian | LPIN2 (18p11.31)/Lipin2 | Pustular dermatoses | Uncommon | Uncommon | Uncommon | Recurrent multifocal aseptic osteomyelitis Complications: Contractures joint deformities | Hematologic manifestations: dyserythropoietic anemia | CS, anti-TNF agents, anti-IL-1 agents-anakinra and canakinumab | ||
| IFN-Mediated Diseases | PRAAS | CANDLE | AR/Originally Japan Any race or ethnicity | PSMB8 ( 6p21.3)/ | Nodular exanthema, panniculitis, lipodystrophy, periorbital erythema | Aseptic meningitis Complications: Basal ganglia calcification | Conjunctivitis | None | Arthralgias, arthritis, myalgias, myositis Complications: Joint contractures | Fever, dyslipidemia, growth delay, intra-abdominal fat deposition, pancreatic abnormalities, microcytic anemia, cytopenias Complications: Lipodystrophy, failure to thrive | CS, JAK inhibition in clinical trial (baricitinib) |
| NF−κB Mediated Diseases | CAMPS | AD | CARD14/ CARD14 | Plaque or pustular psoriasis | Uncommon | Uncommon | None | Arthritis in 30% of patients | Fever can present with super-infections of the skin | MTX, CsA, anti-TNF agents, psoriasis medications | |
| DITRA | AR/Originally Tunisia-England | IL36RN (2q14)/IL36RA | Generalized pustular psoriasis Oral mucosa involvement | Uncommon | Uncommon | None | Uncommon | Fever, asthenia, elevated acute phase reactants and leucocytosis | CS, CsA, retinoids, anti-TNF agents | ||
| Other Pathogenesis Pathways | PAPA | AD/Originally Caucasian; any ethnicity | PSTPIP1 (12q24-q25.1)/PSTPIP1 | Pyoderma gangrenosum pathergy, skin abscesses, cystic acne, hidradenitis | Uncommon | Uncommon | None | Deforming aseptic pyogenic arthritis Complications: Joint destruction Impaired QOL related to physical disability | Occasional lymphadenopathy, splenomegaly, thrombocytopenia. | CS, anti-TNF agents, anti-IL1 agents | |
| PGA | AD, sporadic/Originally Caucasian but other ethnicities also seen | NOD2 / CARD15 (16q12.1-13) | Icthyosis-like exanthema non-caseating granulomata | Rare, central neuropathy, stroke, and hearing loss | Chronic uveitis, cataract, glaucoma, blindness. Complications: Blindness | None | Polyarthritis, hypertrophic tenosynovitis | Fever is rare. Elevated acute phase reactants | CS, methotrexate, azathioprine, cyclosporine, anti-TNF agents | ||
| EO-IBD | AR/Originally Lebanese and Turkish | IL10 (1q31-q32); IL10RA (11q23); IL10RB (21q22.11)/IL-10; IL-10RA/IL-10RB | Folliculitis | Uncommon | Uncommon | None | Arthritis | Fever, severe colitis: bloody diarrhea, abscesses, perianal fistula, oral aphtous lesions | CS, CsA, AZA, mesalamine, mercaptopurine, MTX, TAC, anti-TNF agents, allogenic HSCT | ||
| PLCγ2-associated diseases | AD/Ashkenazi Jewish and European | PLCG2 (16q23.3) | PLAID: cold-induced urticaria and granulomatous skin rash. APLAID: blistering skin lesions and cellulitis | None | PLAID: none APLAID: corneal blisters evolving to corneal erosions, ulcerations, intraocular hypertension and cataracts. | None | PLAID: seronegative inflammatory arthritis (rare) APLAID: arthralgia | PLAID: Positive autoantibodies and autoimmune manifestations, recurrent and/or severe infections APLAID: interstitial lung disease, mild immunodeficiency, ulcerative colitis | PLAID: IVIG for immunodeficiency APLAID: high dose corticosteroids and anti-IL-1 agent (partial response). | ||
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