Familial Mediterranean fever (FMF) is an autoinflammatory disorder, characterized by periodic fever and serosal inflammation, often complicated by systemic amyloidosis. Maintenance treatment of FMF with colchicine can reduce disease activity and prevent amyloidosis. Some patients, however, fail colchicine therapy. Many reports have recently been published concerning the effective use of a recombinant IL‐1 receptor antagonist, anakinra, in several closely related disorders.1,2,3,4 These results prompted us to use anakinra in a 14‐year‐old FMF patient who was unresponsive to colchicine therapy (2 mg/day). A diagnosis of FMF was confirmed by analysis of the MEFV gene (pM694V, M694I).
The patient presented with febrile attacks accompanied by abdominal aches from the age of two years. With increasing age, the attacks became frequent (every 3–10 days), prolonged (12–88 hours) and more severe. The episodes consisted of an abruptly rising fever (>40°C) accompanied by chills, anorexia, abdominal and retrosternal pain, arthralgias and also arthritis. In addition, the patient suffered from frequent bitemporal headaches and depression. Blood tests showed chronic microcytic anaemia and elevated inflammatory markers, which increased even more during attacks.
The patient was admitted to hospital and after confirmation of colchicine‐resistant FMF, the patient and parents gave written informed consent for a trial of daily anakinra 100 mg administered subcutaneously. Colchicine was initially maintained at 2 mg a day.
After the initiation of anakinra treatment the fever did not recur (fig 1), nor did the patient experience abdominal pain or arthralgias even after gradually reducing the daily colchicine dose to 1 mg. The patient was less depressed and much more active. A transient mild urticarial rash on the hands and face was reported, which was well controlled with oral antihistamines. Laboratory results showed a remarkable improvement of the erythrocyte sedimentation rate and complete normalization of C‐reactive protein. Furthermore, there was a reduction in serum IL‐1α, IL‐1β and IL‐8 levels, as measured by multiplex bead analysis5 (table 1). Surprisingly, all other cytokines measured (IL‐2, IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, IL‐18, IFN‐γ and TNF‐α) were either not elevated or did not change upon treatment with anakinra. Contrary to previous reports,2 we did not observe any changes in IL‐6 levels after anakinra treatment.
Figure 1 Disease activity before and during anakinra treatment. The bars indicate days when the patient reported being ill in her diary and/or her temperature exceeded 38°C. The vertical dotted line indicates start of treatment.
Table 1 Inflammatory mediators before and after initiation of anakinra therapy.
| Normal values* | Before | After | |
|---|---|---|---|
| C‐reactive protein | ⩽7.0 | 44.4 ± 9.9 | <7.0 |
| IL‐1α (pg/ml) | ⩽0.1 | 223.9 | 60.6 |
| IL‐β (pg/ml) | ⩽1.3 | 4.1 | 1.2 |
| IL‐8 (pg/ml) | ⩽0.3 | 238.7 | 3.8 |
*Average values for age‐matched healthy children (CRP) or healthy adults (n = 20, cytokines).
Although favourable responses to anti‐TNF‐α agents have been described,6,7,8 this is the first report of a child with colchicine‐resistant FMF successfully treated with anakinra. Similar results were reported in one adult FMF patient.9 Serious side effects of anakinra are rare.10 It therefore seems to be a safe agent for the treatment of auto‐inflammatory disorders. Increased susceptibility to infections may, however, still pose a risk and patients obviously need to be monitored closely when anakinra treatment is initiated. We conclude that anti‐IL‐1 therapy in patients with colchicine‐resistant FMF is potentially beneficial. Although none have been reported, treatment failures might occur in anti‐TNF‐α as well as in anti‐IL‐1 therapy. Therefore, a prospective trial comparing both therapies in FMF is warranted.
Footnotes
Funding: L M K is supported by a grant from the Wilhelmina Children's Hospital Research Fund.
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