Modern Rheumatology
ISSN: 1439-7595 (Print) 1439-7609 (Online) Journal homepage: http://www.tandfonline.com/loi/imor20
Rapid resolution of protracted febrile myalgia syndrome with anakinra: Report of two cases Rıdvan Mercan, Aynur Turan, Berivan Bitik, Abdurrahman Tufan, Seminur Haznedaroglu & Berna Goker To cite this article: Rıdvan Mercan, Aynur Turan, Berivan Bitik, Abdurrahman Tufan, Seminur Haznedaroglu & Berna Goker (2014): Rapid resolution of protracted febrile myalgia syndrome with anakinra: Report of two cases, Modern Rheumatology, DOI: 10.3109/14397595.2014.882221 To link to this article: http://dx.doi.org/10.3109/14397595.2014.882221
Published online: 18 Feb 2014.
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Date: 31 March 2016, At: 07:44
http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; Early Online: 1–2 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2014.882221
CASE REPORT
Rapid resolution of protracted febrile myalgia syndrome with anakinra: Report of two cases Rıdvan Mercan1, Aynur Turan2, Berivan Bitik1, Abdurrahman Tufan1, Seminur Haznedaroglu1, and Berna Goker1 1Department of Internal Medicine, Division of Rheumatology, Gazi University Hospital, Ankara, Turkey and 2Department of Radiology, Yildirim Beyazit
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Training and Research Hospital, Etlik, Ankara, Turkey Abstract
Keywords
Protracted febrile myalgia syndrome (PFMS) is a very rare but severe manifestation of familial Mediterranean fever (FMF) which is characterized by severe debilitating pain in large muscle groups that may last for several weeks. Colchicine is ineffective and treatment is largely supportive. Demonstration of crucial role of interleukin-1 (IL-1) in the pathogenesis of FMF has increased the use of IL-1 blockers in colchicine resistant or intolerant patients. Herein, we reported successful use of an IL-1 inhibitor, anakinra, in treatment of two patients with PFMS.
Familial Mediterranean fever, Protracted febrile myalgia, Anakinra, Interleukin-1, Treatment History
Introduction Familial Mediterranean fever (FMF) is characterized by recurrent febrile inflammatory attacks of serosal and synovial membranes. FMF attacks most commonly involve peritoneum and pleura; however, many patients also suffer from musculoskeletal complaints including arthritis, arthralgia and myalgia. Protracted febrile myalgia syndrome (PFMS) is a very rare but severe manifestation of FMF. The condition is characterized by debilitating severe pain in large muscle groups of upper and lower extremities and fever lasting up to 6 weeks without treatment. Despite severe muscle pain, muscle enzymes remain within normal limits as is the electromyography. High-grade acute-phase response is a rule and most of the patients harbour M694V mutation in the MEFV gene [1–3]. Magnetic resonance imaging (MRI) is highly sensitive for the diagnosis that shows remarkable oedema in involved muscles [4]. Severe crippling pain usually results in bed confinement and significant disability. Colchicine, the cornerstone of FMF treatment, is ineffective for PFMS. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are mainstay of treatment with variable success [1,5]. Even with high-dose steroids, resolution of symptoms take 5–7 days in most cases [1]. Moreover, in some cases corticosteroids may not be helpful for treating PFMS [6]. Interleukin-1 (IL-1) antagonists, anakinra, canakinumab and rilonacept are reported to be effective in colchicine unresponsive FMF patients [7–9]. Herein, we reported successful use and prompt response of PFMS to anakinra in two patients.
Case 1 A 41-year-old female patient presented with severe calf and thigh pain, fever and malaise from which she had been suffering for 4 weeks. She was diagnosed with FMF 2 years before with a history of peritonitis, pleuritis and arthritis beginning from her childhood, and her genetic test showed heterozygous M694V mutation. She also had attacks of severe myalgia involving large muscle groups Correspondence to: Abdurrahman Tufan, MD, Gazi Universitesi Hastanesi, Ic Hastalıkları ABD, Romatoloji BD, 06500, Besevler, Ankara, Turkey. Tel: ⫹ 90-312-2025825. E-mail:
[email protected]
Received 25 October 2013 Accepted 8 January 2014 Published online 10 February 2014
of lower and upper extremity, which lasted for 4–6 weeks once to thrice a year, for about 10 years. Her attacks responded to 1 mg/kg prednisone treatment in every occasion. She was taking colchicine, 2 mg/day for 2 years and that controlled her serositis attacks while it had no effect on her muscle and arthritic complaints. Her muscle attacks recurred while she was on methotrexate, leflunomide or azathioprine. On admission, she was febrile and unable to move because of severe leg pain. Her temperature was 38.8°C, blood pressure was 175/100 mmHg and affected muscles were tender and oedematous. Rest of the physical examination was unremarkable. Her erythrocyte sedimentation rate (ESR) was 84 mm/h and C reactive protein (CRP) was 172 mg/L (normal ⬍ 6). There was a mild leukocytosis. Other pertinent laboratory examinations were within normal limits, including muscle enzymes. Her MRI revealed remarkable muscle oedema in her calf muscles which was consistent with PFMS (Figure 1). Due to concerns on uncontrolled hypertension she refused prednisone treatment. She was started on anakinra, 100 mg/day subcutaneously. Her complaints completely resolved after two doses of anakinra. Her ESR and CRP returned to normal levels within a week. No recurrence was observed in her 3-month follow-up.
Case 2 A 44-year-old female patient presented with severe right thigh pain for 3 weeks. She also complained of diarrhoea and ankle pain. She had a diagnosis of FMF since she was 17 years old. She had attacks of peritonitis, pleuritis and arthritis, and was homozygous for M694V mutation. She had serositis attacks, every 2–4 weeks despite regular use of colchicine 2 mg/day. On presentation, she was febrile with a temperature of 38.5°C and unable to ambulate because of the continuous thigh pain for 3 weeks. Her quadriceps were very tender and surrounding skin was tight on palpation. She had swelling and warmth over her right ankle. The rest of her physical examination was unremarkable. ESR and CRP levels were 78 mm/h and 66 mg/L, respectively. Her muscle enzymes and pertinent laboratory tests were within normal limits. She was taking a maximum dose of
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PFMS may last for several weeks causing significant disability [5]. Treatment is mainly symptomatic, including high-dose corticosteroids and NSAIDs. Successful use of corticosteroids has been reported, however, efficacy of NSAIDs is controversial [1,5]. In both of our patients, NSAIDs were not effective and in one, prednisone worked well previously, however uncontrolled hypertension restricted its use. There is only one use of anakinra in a patient with inflammatory myositis and spondyloarthritis, reporting good response [14]. In both of the presented cases, anakinra was very effective in bringing a rapid and complete resolution of PFMS symptoms, as well as in normalizing inflammatory markers within a few days. We suggest that anakinra might be a good treatment option in PFMS. Moreover, very rapid action of anakinra suggests that IL-1 may have a major role in the pathogenesis of PFMS, similar to other manifestations of FMF. Figure 1. Coronal T2-weighted fat saturation MRI of the right calf muscles at presentation. There is remarkably increased intensity and swelling within the muscles representing severe oedema.
Conflict of interest None.
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References naproxen with no satisfactory response since the beginning of her muscle pain. On the basis of these symptoms and findings she was diagnosed with PFMS. Her attacks were also considered as colchicine resistant and prescribed anakinra 100 mg/day, subcutaneously. She showed more than 50% improvement even after the first dose of anakinra and complete recovery after the second dose.
Discussion FMF is an autosomal recessive inherited disorder caused by mutations of the MEFV gene which encodes pyrin, a key molecule in the regulation of inflammatory pathways. Although the exact mechanism of FMF remains to be elucidated, it is wellknown that pyrin has a critical role in the regulation of IL-1 pathway and mutations result in increased IL-1 production, which is believed to be responsible for the clinical characteristics of FMF [10]. Colchicine is the mainstay of treatment of FMF which reduces frequency and duration of attacks and prevents development of amyloidosis. To date, immunomodulatory agents like interferon, azathioprine and tumor necrosis factor inhibitors have been employed in refractory cases and severe manifestations of disease with variable success [11]. In the last decade, with the observation of impaired IL-1 pathway in FMF, the use of IL-1 antagonists for refractory cases has significantly increased. Recently, IL-1 antagonists are shown to be effective in the prevention of serositis attacks [8,12]. These agents induced a rapid and lasting clinical response in all reported cases [13]. However, their long-term efficacy is yet to be determined. FMF manifests itself as recurrent, self-limiting episodes of sterile peritonitis, pleuritis and arthritis, hence named also as “polyserositis”. However, less often, FMF can manifest with different but prolonged and severe clinical pictures. Amongst these, PFMS is first described by Langevitz et al. in 1994 [2]. Since then, our knowledge on its pathogenesis or treatment has improved only a little. PFMS is thought to be a vasculitic process although the supporting pathologic evidence is lacking [5]. PFMS is mainly diagnosed with clinical features [1]; however MRI is a helpful imaging tool for the confirmation of diagnosis. MRI features that suggest PFMS are diffuse oedema of subcutaneous fat tissue, increased intensity and contrast enhancement of the muscles and increased signal intensity of vascular beds [4].
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