Background Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease, characterized by self-limiting periodic fever attacks with typical clinical features and oversecretion of proinflammatory cytokines as interleukin-1 (IL1).
Objectives The standard of care since the early 1970s is oral colchicine, which can help to prevent attacks. Unfortunately, 5–10% of the patients are unresponsive. In these cases there is no further approved treatment. MEFV, the underlying gene mutated in FMF, encodes pyrin, which takes part in the process of IL1 secretion. In this report we analyzed the benefit of anakinra, an IL1 receptor antagonist, in patients who were unresponsive to colchicine.
Methods This is a single center retrospective case series of 13 patients. Anakinra was applied subcutaneously at a standard dose of 100mg per day. There are no defined criteria for responders as well as non-responders to a certain treatment in FMF. We therefore defined colchicine resistance in analogy to other studies (1) as increasing frequency of attacks (>1/month and/or >1.5-fold of the time of best response) or as increasing inflammatory proteins i.e. CRP and SAA (>1.5-fold from upper limit). Disease activity was evaluated by laboratory parameters and clinical symptoms based on patient's and physician's assessment. Complete response (CR) was defined as no attacks and acute phase reactants below the upper limit. Partial response (PR) was defined as FMF-50 response, meaning reducing the attack rate by 50% and/or decreasing acute phase reactants, i.e. CRP or SAA, by 50%.
This retrospective case series was approved by the ethics committee of Eberhard-Karls-university, Tübingen.
Results All results presented in mean±SD.
13 patients were included, median age at starting anakinra was 30.5±8.5 years, six patients were female. Nine patients had homozygous exon ten mutation, three patients had heterozygous exon 10 mutations of the MEFV-gene, one patient showed no detectable mutation. All patients were taking therapeutic oral doses of colchicine before starting treatment with anakinra. During treatment the attack rate declined from 15.8±13.1 per year to 4.1±6.6 (p=0.047). This was also the case for laboratory parameters: SAA decreased from 287.1 ± 428.4 mg/l to 10.9±12.0 mg/l (p=0.006) after three months and to 53.8±73.4 mg/l (p=0.125) after six months of treatment. CRP decreased from 6.8±7.7 mg/dl to 0.8±0.8 (p=0.005) after three months, respectively 0.7±0.9 (p=0.029) after six months. We didn't observe any major complications.
Conclusions This report, to our knowledge, analyses the largest group of adults with FMF, treated with anakinra after failure of colchicine. All 13 patients of our case series responded to anakinra, four of them with CR. Interestingly, all of them showed a homozygous MEFV exon 10 mutation, which goes along with higher IL1 rates and more often are not responsive to colchicine (2). Here we could show, that anakinra is an effective treatment option for patients with FMF. Still, further prospective studies should be performed to evaluate the dosage and long-term efficacy as well as safety of anakinra.
Ben-Chetrit et al. (2008). Non-response to colchicine in FMF-definition, causes and suggested solutions. Clin Exp Rheumatol;26(4 Suppl 5)
Soylemezoglu O et al. (2010) Unresponsiveness to colchicine therapy in patients with FMF homozygous for the M694V mutation. J Rheumatol. 37(1)
Disclosure of Interest None declared