Table 1.
‘Monogenic’ autoinflammatory syndromes
| Inflammatory cause | Disease (MIM #) | Gene | Protein | Inheritance pattern/year of discovery/Refs | Disease onset | Flare/fever pattern | Specific organ inflammation | Treatment |
|---|---|---|---|---|---|---|---|---|
| IL-1β | CAPS | |||||||
| FCAS #120100 | CIAS1 (1q44) | Cryopyrin | AD/(2001)/[4] | First 6 months of life, cold-induced | <24 h | Skin, eyes, joints, systemic | IL-1 blockade | |
| MWS #191900 | CIAS1 (1q44) | Cryopyrin | AD/(2001)/[4] | Infancy to adolescence | 24–48 h | Skin, eyes, joints, inner ears, meninges (mild), systemic | IL-1 blockade | |
| NOMID #607115 | CIAS1 (1q44) | Cryopyrin | AD/de novo/(2002)/[5,6] | Neonatal or early infancy | Continuous with flares | Skin, eyes, joints, inner ears, meninges, bony epiphyseal hyperplasia, systemic | IL-1 blockade | |
| IL-1β and IL-1α | DIRA #612852 | IL1RN (2q14) | IL-1 receptor antagonist | AR/(2009)/[11] | Neonatal or early infancy | Continuous with flares | Skin, bones, lungs (rare), vasculitis (rare) | Anakinra |
| IL-1+ 0ellip; | FCAS2 #611762 | NLRP12 (19q13) | NLRP12 | AD/(2008)/[13] | Neonatal or early infancy | Continuous with flares | Skin, eyes, joints, systemic | IL-1 blockade |
| IL-1+ 0ellip; | FMF #249100 | MEFV (16p13) | pyrin | AR/(1997)/[1,2] | 80% of the cases occur before the age of 20 | 1–3 days | Skin, joints, peritoneum, pleura | Colchicine, rarely |
| IL-1 and TNF blockade or thalidomide if colchicine-resistant | ||||||||
| IL-1+ 0ellip; | HIDS #260920 | MVK (12q24) | Mevalonate kinase | AR/(1999)/[14,15] | Median age at onset 6 months | 3–7 days | Skin, eyes, joints, prominent lymph nodes | NSAIDS, corticosteroids, TNF and IL-1 blockade |
| IL-1+ 0ellip; | Majeed's Syndrome #609628 | LPIN2 (18p11) | Lipin2 | AR/(2005)/[16] | Early infancy (1–19 months) | Weeks–months | Bones, periosteum, anaemia | NSAIDS, corticosteroids, interferon-α, possibly IL-1 blockade |
| IL-1+TNF 0ellip; | TRAPS #191190 | TNFRSF1A (12p13) | TNF receptor 1 | AD/(1999)/[3] | Median age at onset 3 years | 1–4 weeks | Skin, eyes, joints, peritoneum, pleura | TNF blockade, steroids, IL-1 blockade, colchicine is ineffective |
| IL-1+TNF 0ellip; | PAPA #604416 | CD2BP1 (15q24) | PSTPIP1 | AD/(2002)/[17] | Early childhood | Common | Skin, joints | Local and systemic corticosteroids, TNF or IL-1 blockade |
| Other pathways | ||||||||
| TNF, IL-1+ 0ellip; | PGA* #186580 | NOD2 (16q12) | Nod2 | AD/de novo (2001,2005)/[18,19] | Early childhood | Uncommon | Skin, eyes, joints | NSAIDS, corticosteroids, methotrexate, cyclosporin, TNF or IL-1 blockade |
| TNF+ 0ellip; | Cherubism #118400 | SH3BP2 (4p16) | SH3BP2 | AD/(2001)/[20] | Childhood, spontaneous remission by 3rd decade | Uncommon | Jaws, eyes (rare) | NSAIDS, TNF inhibition, interferon-α, azithromycin, bisphosphonates |
| Lack of IL-10 signalling | Early-onset inflammatory bowel disease #613148 | IL10RA (11q23) | IL-10 receptor, IL10RB also forms IL-22, -26, -28-29 receptors | AR/(2010)/[21] | Neonatal or early infancy | Continuous with flares | Colitis with fistula formation, folliculitis in patients with IL10RB mutations | Bone marrow transplantation |
| IL10RB (21q22) | ||||||||
| IL-36α, IL-36β, IL-36γ (role of IL-1 unknown but unlikely complete) | DITRA # 614204 | IL36RN/IL1F5 (2q13-14) | IL-36 | AR/ 2011)/[22,23] | Carriable to adulthood, early onset at 2 weeks was reported in some cases | Flares of generalized and palmoplantar pustulosis | Skin | Acitretin |
| Topical steroids | ||||||||
| Limited use of biologics, i.e. adalimumab | ||||||||
| Increase in IFN signalling? | JMP, NNS, JASL, CANDLE #613732 | PSMB8 (6p21) | Inducible β5 subunit of the immunoproteasome | AR/(2011)/[24]–[27] | Neonatal or early infancy | Continuous with flares | Skin, joints, lipodystrophy and muscle atrophy | Partial response to steroids, TNF inhibition, IL-6R inhibition |
CAPS: cryopyrin-associated periodic syndromes; FCAS: familial cold autoinflammatory syndrome; MWS: Muckle–Wells syndrome; NOMID: neonatal-onset multi-system inflammatory disease; DIRA: deficiency of the interleukin (IL)-1 receptor antagonist; DITRA: deficiency of the IL-thirty-three receptor antagonist; FMF: familial Mediterranean fever; HIDS: hyperimmunoglobulin D syndrome; PAPA: pyogenic arthritis, pyoderma gangrenosum and acne syndrome; TRAPS: tumour necrosis factor receptor-associated periodic syndrome; PGA: paediatric granulomatous arthritis, *including Blau syndrome (MIM 186580) and early-onset sarcoidosis (MIM 609464); JMP: joint contractures, muscle atrophy, panniculitis-induced lipodystrophy; NNS: Nakajo–Nishimura syndrome; JASL: Japanese autoinflammatory syndrome with lipodystrophy; CANDLE: chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperatures; AR: autosomal recessive; AD: autosomal dominant; NSAID: non-steroidal inflammatory drug; TNF: tumour necrosis factor.