Table 1.
Clinical characteristics of (some) monogenic autoinflammatory diseases and PFAPA
| Clinical classification | Fever (length of episodes) | Main organs involved/symptoms | Skin rash | Gene (inheritance) | Protein | Suggested treatment |
|---|---|---|---|---|---|---|
| Periodic fever syndrome | ||||||
| TRAPS | Yes (1–6 weeks) |
Eyes: conjunctivitis, periorbital oedema, pleuritis, pericarditis CNS: headache Abdominal pain Splenomegaly Arthritis/arthralgia, myalgia |
Migrating erysipelas‐like, painful | TNFRSF1A (AD) | TNF receptor 1 (TNFR1) |
IL‐1 blockade Corticosteroids Etanercept NSAID Colchicine |
| FMF | Yes (½–3 days) | Large joints: serositis, peritonitis, pleuritis and/or arthritis | Sometimes erysipelas‐like erythema, most often in the ankle region | MEFV (AR) | Pyrin | Colchicine (IL‐1 blockade in refractory cases or colchicine side‐effects) |
| FCAS (CAPS) |
Yes (12–24 hours) Triggered by cold exposure |
Eyes: conjunctivitis Joints: arthralgia |
Urticaria‐like rash | NLRP3 (AD) | NLRP3 | IL‐1 blockade |
| MWS (CAPS) | Yes (24–48 hours) |
CNS: hearing loss, headache Eyes: conjunctivitis Joints: arthralgia/arthritis |
Urticaria‐like rash | NLRP3 (AD) | NLRP3 | IL‐1 blockade |
| CINCA/NOMID (CAPS) | Continuous with fever during flares |
CNS: meningitis, hearing loss, headache Eyes: conjunctivitis, uveitis and papilloedema Bone: bony overgrowth Joints: arthralgia/arthritis |
Urticaria‐like rash increase with flares | NLRP3 (AD) | NLRP3 | IL‐1 blockade |
| HIDS/MKD |
Yes (3–7 days) Flares triggered by vaccinations |
Abdominal pain, diarrhoea, lymphadenopathy, splenomegaly Headache Oral and/or genital ulcers Arthritis/arthralgia |
Exanthema (Maculopapular or purpuric) | MVK (AR) | Mevalonate kinase (MK) |
IL‐1 blockade NSAID Corticosteroids TNF blockade |
| FCAS2 | Yes, flares triggered by cold |
Arthralgia, headaches, aphthous stomatitis, abdominal pain Hearing loss |
Urticarial rash | NLRP12 (AD) | NLRP12 |
NSAID Corticosteroids |
| PFAPA | Yes (3‐7 days, most commonly 4‐5 days) | Recurrent attacks of fever often regularly associated with sign and symptoms according to the acronym PFAPA in the absence of upper respiratory tract infection | No, in our hands the diagnosis is questioned in patients with skin rash | N/A | N/A |
NSAID Tonsillectomy Colchicine Corticosteroids |
| Diseases with pyogenic lesions | ||||||
| DIRA | No | Multifocal osteomyelitis periarticular soft‐tissue swelling | Pustular | IL‐1RN (AR) | IL1 receptor antagonist | IL‐1 blockade |
| Diseases with granulomatous lesions | ||||||
| BS/PGA | Rarely, not a dominant feature |
Arthritis Uveitis |
Tan coloured rash. Ichthyosis‐like exanthema | NOD2 (AD) | CARD15 |
TNF blockade Corticosteroids Methotrexate |
| Diseases with panniculitis‐induced lipodystrophy | ||||||
| CANDLE/PRAAS | Yes (often continuous) |
Myositis, arthritis/arthralgia Joint contractures, muscle atrophy Hepatomegaly, splenomegaly Basal ganglia calcifications, Anaemia |
Panniculitis, lipodystrophy Nodular exanthema |
PSMB8 (AR), PSMA3, PSMB4, PSMB9, POMP | PSB8, PSMA3, PSMA4, PSMB9 and POMP |
Corticosteroids? JAK inhibition? |
| Diseases with psoriatic lesions | ||||||
| DITRA | Flares with fever | Arthritis, geographic tongue, cholangitis nail dystrophy | Generalised pustular psoriasis (often without psoriasis vulgaris) | IL36RN (AR) | IL‐36Ra |
IL‐1 blockade? TNF blockade? Corticosteroids Methotrexate |
| CAMPS | Not a distinct feature | Psoriatic arthritis |
Generalised pustular psoriasis (often with psoriasis vulgaris) Some cases of familial pityriasis rubra pilaris och psoriasis vulgaris Erythrodermic psoriasis |
CARD14 (AD) | CARD14 |
IL‐12/23 blockade? or IL‐17 blockade? |
| Diseases with neurologic and dermatologic manifestations | ||||||
| AGS | Rarely | Progressive brain disease | Chilblains | Seven different genes (AD or AR) | Several different proteins | No established treatment |
| Diseases with IBD | ||||||
| EO‐IBD (IL‐10 receptor deficiency, IL‐10 deficiency) | Recurrent fever rare | Early‐onset enterocolitis with haematochezia, colonic abscesses, perianal fistulas, oral ulcers and failure to thrive | Recurrent folliculitis | IL‐10, IL‐10RA and IL‐10RB | IL‐10, IL‐10RA and IL‐10RB | Beyond the scope of this review |
TRAPS = Tumour necrosis factor receptor‐associated periodic syndrome; FMF = Familial Mediterranean fever; FCAS = Familial cold autoinflammatory syndrome; MWS = Muckle–Wells syndrome; CINCA = Chronic infantile neurological, cutaneous and articular syndromes; CAPS = Cryopyrin‐associated periodic syndrome; HIDS = Hyperimmunoglobulinaemia D with periodic fever syndrome; MKD = Mevalonate kinase deficiency; FCAS2 = Familial cold autoinflammatory syndrome 2; PFAPA = Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis; DIRA = Deficiency of IL‐I receptor antagonist; BS = Blau syndrome; PGA = Paediatric granulomatous arthritis; CANDLE = Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; PRAAS = Proteasome‐associated autoinflammatory syndrome; DITRA = Deficiency of IL‐36 receptor antagonist; CAMPS = CARD14‐mediated psoriasis; AGS = Aicardi–Goutières syndrome; EO‐IBD = Early‐onset inflammatory bowel disease; AD = Autosomal dominant; AR = autosomal recessive.