Familial Mediterranean fever and periodic-fever syndromes

Autoinflammatory disease is innate-immune dysregulation without the high-titre autoantibody or antigen-specific T-cell pattern of classic autoimmunity. The diagnostic unit is an attack: age at onset, interval, duration, fever curve, serosal or skin distribution, lymph nodes, ulcers, hearing and eye features, trigger, objective inflammation and complete versus incomplete recovery. Ask the patient to keep dated temperature, symptom and photograph records before assuming that every reported fever is identical.

FMF typically begins before age 20, but adult diagnosis is common after delayed recognition. Attacks build quickly and resolve within one to three days. Abdominal serositis can mimic a surgical abdomen; unilateral pleurisy, large-joint monoarthritis and sharply demarcated erysipelas-like erythema over lower leg or ankle are characteristic. Orchitis, pericarditis and protracted febrile myalgia occur less often. Ancestry changes pre-test probability but mixed heritage and de novo presentation are common in the UK.

Genetic testing is interpreted with phenotype and ancestry. Biallelic pathogenic MEFV variants, particularly exon 10 variants such as M694V, strongly support FMF and predict amyloid risk, but symptomatic heterozygotes occur and some clinically convincing patients lack two detectable variants. A variant of uncertain significance is not a diagnosis. Use an autoinflammatory service and genetic counsellor when a multigene panel, mosaicism or family testing may change care.

TRAPS often produces attacks longer than five days with severe migratory myalgia, overlying centrifugal erythema, abdominal pain, conjunctivitis or periorbital oedema. Corticosteroid may abort an attack but repeated dependence is harmful. Etanercept has historical benefit, while monoclonal TNF inhibitors can paradoxically exacerbate inflammation. IL-1 inhibition is now preferred for persistent or severe disease.

MKD produces three-to-seven-day attacks beginning in childhood, often after vaccination, infection or stress. Cervical lymphadenopathy, aphthous ulcers, abdominal pain, vomiting, diarrhoea, rash and arthralgia are typical. Serum IgD is neither sensitive nor specific; urinary mevalonic acid rises during attacks and biallelic MVK variants confirm the spectrum. Severe enzyme deficiency causes developmental, neurological and ocular disease beyond periodic fever.

CAPS spans familial cold autoinflammatory syndrome, Muckle–Wells syndrome and severe neonatal-onset multisystem inflammatory disease. The rash resembles urticaria but is often less itchy and histologically neutrophilic. Cold-triggered fever and arthralgia dominate mild disease; hearing loss and amyloid characterise Muckle–Wells; chronic aseptic meningitis, papilloedema, bony overgrowth and developmental effects mark severe disease. Somatic NLRP3 mosaicism can present in adulthood.

PFAPA causes recurrent fever with aphthous stomatitis, pharyngitis and cervical adenitis, with wellness and growth or function between episodes. It usually begins in childhood but can persist or present in adults. A single corticosteroid dose can terminate an episode yet shorten the interval; tonsillectomy is considered mainly in paediatric pathways. Before the label, exclude infection, cyclic neutropenia, monogenic fever and Behçet disease.

During an early untreated attack, obtain FBC with differential, CRP or ESR, serum amyloid A where locally available, ferritin, renal and liver profiles, urinalysis and protein quantification. Culture or image when physiology or localisation warrants it. Repeat inflammatory markers, SAA and urine between attacks: persistent elevation suggests incomplete control, chronic infection or another inflammatory condition and drives amyloid risk even if diary attacks are infrequent.

Colchicine is preventive treatment for FMF, not an on-demand antipyretic. Begin in every convincing patient, including many with few attacks but high-risk genotype or persistent inflammation. Adults usually take 1–1.5 mg daily, divided if gastrointestinal effects occur. If attacks or SAA persist, increase by 0.5 mg steps while monitoring to a maximum of 3 mg daily. Assess response and adherence over three to six months; do not interpret diarrhoea as proof of adequate intracellular exposure.

Colchicine has a narrow therapeutic index. Check FBC, renal and liver function and creatine kinase when muscle symptoms or interacting treatment occurs. Reduce dose in kidney or liver impairment. Clarithromycin, erythromycin, azole antifungals, ciclosporin, verapamil and some antivirals can inhibit CYP3A4 or P-glycoprotein and cause fatal accumulation; the combination may be contraindicated, particularly in organ impairment. Statins add myopathy risk.

Colchicine resistance means ongoing clinical or subclinical inflammation despite the maximum tolerated dose with verified adherence, often operationalised as at least one attack monthly for six months. Recheck whether attacks are inflammatory, whether dose is missed during wellness and whether another syndrome is present. Add IL-1 blockade rather than stopping colchicine because continued colchicine may retain amyloid protection.

Canakinumab is licensed for FMF, TRAPS, MKD and CAPS. Adults and people at least 40 kg commonly receive 150 mg subcutaneously every four weeks, with escalation to 300 mg every four weeks for inadequate response under the product pathway. Daily anakinra 100 mg subcutaneously is an off-label alternative for FMF and licensed for CAPS, with renal adjustment and weight-based paediatric dosing. Screen infection and TB, update non-live vaccines and avoid live vaccines during treatment.

Pregnancy planning protects both disease and treatment continuity. EULAR supports colchicine through conception, pregnancy and breastfeeding because withdrawal can trigger attacks and amyloid. IL-1 inhibitors have increasing but more limited reproductive evidence and require an autoinflammatory and maternal-medicine decision. Renal amyloid, hypertension or reduced eGFR materially increases obstetric risk and needs nephrology co-management.