Still's disease is a special form of rheumatoid arthritis. A distinction is made between two forms, one occurring in children (systemic juvenile idiopathic arthritis [sJIA]) and the other in adults ("adult-onset Still disease" [AOSD]). The exact cause is not yet clear, but a cytokine storm is postulated, usually preceded by an infectious trigger. In contrast to rheumatoid arthritis, no elevated rheumatoid factors or antinuclear antibodies are detectable. The diagnosis is made according to the clinical criteria (Tab. 2). Based on the cytokine profile, the systemic (IL-1b, IL-18) can be distinguished from the articular (tumor necrosis factor-[TNF-]α, IL-6) phenotype [25]. A severe life-threatening complication of Still's disease is macrophage activation syndrome (MAS), which should be looked for in cytopenia [26]. Other differential diagnoses are Schnitzler syndrome and Sweet syndrome. Schnitzler's syndrome is characterized by a non-pruritic, urticarial exanthema and a monoclonal gammopathy. The diagnosis is made by meeting the Strasbourg criteria [27, 28]. Sweet syndrome is an acute neutrophilic dermatosis. Fever, painful erythematous nodules/plaques, increased neutrophil count, and association with hematologic malignancies, rheumatoid arthritis, and inflammatory bowel disease are key features.
The most important (not complete) differential diagnoses of febrile episodes in adults for us after exclusion of infectious, malignant and autoimmune genesis are summarized in Table 2.
Therapeutic options for (auto)-inflammatory syndromes with periodic fever
Corticosteroids are suitable in the acute episode of PFAPA syndrome. The therapy is a single dose of corticosteroids (0.5-2 mg/kg body weight [bw]/day) during a relapse and a second dose on the following day if there is no response. Administration of corticosteroids may interrupt fever but result in a shortened interval between episodes. Corticosteroids may also be helpful in controlling disease activity in CAPS, HIDS/MKD, TRAPS, AOSD, and Schnitzler syndrome. However, prolonged administration of corticosteroids should be avoided due to its extensive side effect profile [2].
Colchicine, at a dose of 0.5 mg twice daily to a maximum increase to 3 mg/day in adults is the primary therapy for FMF. It is also used in PFAPA. The mechanism of action in FMF is mainly explained by the prevention of activation of the pyrin inflammasome [15, 29]. Side effects include gastrointestinal (diarrhea, nausea, abdominal pain) and leukopenia. It is generally considered to be well tolerated. Is safe in pregnancy. Lifelong, continuous use of colchicine not only serves as seizure prophylaxis but also reduces the risk of amyloidosis [2, 14, 17, 18].
Therapies with TNF-α inhibitors (infliximab, etanercept) find application as third-line therapy in AOSD [26]. The side effect profile of TNF-α inhibitors is an increased risk ofMycobacteria, fungi, and other opportunistic pathogens [2, 18].
In most autoinflammatory diseases, IL-1 pathway inhibitors showed the greatest success. These include anakinra (Kineret®), a recombinant IL-1 receptor antagonist that, due to its short half-life (HWZ) of 4-6 hours, is available as a subcutaneous (s.c.) is administered by injection. An approval exists for CAPS. RheumatoidArthritis (USA). The longer-acting IL-1 inhibitor rilonacept (Arcalyst®) is a recombinant fusion protein with an extracellular domain of IL-1 receptor-. IL-1 "receptor accessory protein" component associated with the Fc portion of human immunoglobulin G1 (IgG1). It is administered at 160 mg s at a time.c. Weekly. Approval exists for CAPS except NOMID (USA).
Canakinumab is a humanized IgG1 monoclonal antibody against IL-1β. It is administered every eight weeks at 150 mg s.c. injected [30]. Approval exists for CAPS, sJIA, AOSD, FMF, HIDS, TRAPS, and also refractory gout (EU, U.S.). Canakinumab is approved in Switzerland according to Swissmedic for the hereditary fever syndromes and sJIA.
As a side effect profile under IL-1 inhibitors, there is an increased risk of viral and bacterial infections (upper respiratory tract infections, urosepsis, meningitis) and local reactions at the injection site. Vaccinations against influenza and pneumococcus before therapy are recommended; live vaccinations are contraindicated during therapy [28].
In FMF with insufficient disease control under colchicine, therapy with IL-1 inhibitors can be attempted. In AOSD, IL-1 inhibitors showed a rapid response when systemically. Allowed a reduction in corticosteroid. Tocilizumab (Actemra®), a humanized antibody against the IL-6 receptor, also showed promising results in refractory systemic and articular AOSD [25, 31]. For PFAPA and Schnitzler syndrome, IL-1 blockade is a good option in case of frequent episodes.
The signaling pathways and mode of action of biologics are summarized in Figure 1.
Figure 1: Signaling pathways and therapeutic targets in autoinflammatory syndromes (Illustration: Rok Humar, Ayla Yalamanoglu).
PAMPs: "pathogen-associated molecular patterns"; DAMPs: "damage-associatedmolecular patterns"; NLRP3: "NOD-like receptor protein 3"; ASC: "apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain"; NF-κB: "nuclear factor kappa-light-chain-enhancer of activated B-cells"; IL: Interleukin; TNFɑ: tumor necrosis factor alpha; TNFR: tumor necrosis factor receptor; HIDS: hyper-immunoglobulinD syndrome; FMF: familial Mediterranean fever; CAPS: cryopyrin-associated periodic syndrome; PFAPA: periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis. – Autoinflammatory syndromes are rare. A diagnosis of exclusion.
– Common features are periodic fever, inflammation, often accompanied by involvement of the inflammasome and excessive cytokine production.
– Presentation at relapse with decrease in inflammatory parameters is helpful. If autoinflammatory disease is suspected to be present, referral to a specialized clinic should be made.
– Current therapy consists primarily of corticosteroids, nonsteroidal anti-inflammatory drugs, and biologics. Interleukin-1 pathway inhibitors have proven promising in reducing disease activity and secondary complications such as AA amyloidosis.