Monogenic Autoinflammatory Diseases




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








  • 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.



  • 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.



  • 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.



  • 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.



  • Early diagnosis of these syndromes is essential because effective therapies, particularly for the IL-1-mediated conditions, can change patients’ lives and disease outcomes.



  • 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.



Table 1

Demographic, genetic and clinical features of the monogenic autoinflammatory diseases (AID)






























































































































































































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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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Monogenic Autoinflammatory Diseases

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