PREDICT-crFMF score: A novel model for predicting colchicine resistance in children with familial Mediterranean fever.

OBJECTIVES: To develop a novel scoring system to predict colchicine resistance in Familial Mediterranean fever (FMF) based on the initial features of the patients. METHODS: The medical records of patients were analyzed prior to the initiation of colchicine. After generating a predictive score in the initial cohort, it was applied to an independent cohort for external validation of effectiveness and reliability. RESULTS: Among 1418 patients with FMF, 56 (3.9%) were colchicine resistant (cr) and 1312 (96.1%) were colchicine responsive. Recurrent arthritis (4 points), protracted febrile myalgia (8 points), erysipelas-like erythema (2 points), exertional leg pain (2 points), and carrying M694V homozygous mutation (4 points) were determined as the parameters for predicting cr-FMF in the logistic regression model. The cut-off value of 9 was 87% sensitive and 82% specific to foresee the risk of cr-FMF in the receiver operating characteristic. Validation of the scoring system with an independent group (cr-FMF = 107, colchicine responsive = 1935) revealed that the cut-off value was 82% sensitive and 79% specific to identify the risk of cr-FMF. CONCLUSIONS: By constructing this reliable and predictor tool, we enunciate that predicting cr-FMF at the initiation of the disease and interfering timely before the emergence of complications will be possible.

Protracted febrile myalgia as a first and challenging manifestation of familial Mediterranean fever.

OBJECTIVES: Familial Mediterranean fever (FMF) is an auto-inflammatory disease that causes recurrent episodes of fever, abdominal pain, chest pain, and arthritis. Although FMF is well known, protracted febrile myalgia syndrome (PFMS) is a clinical condition that is rare and difficult to diagnose than other symptoms of FMF. PFMS causes fever, myalgia, and acute phase reactant elevation that lasts 2-4 weeks if corticosteroid treatment is not given. In some cases, fever may not be seen. The purpose of this report is to share our experience with PFMS patients in our clinic. METHODS: This is an observational, retrospective, single-centre study. We evaluated patients who had been diagnosed with PFMS at our paediatric rheumatology clinic. RESULTS: Protracted febrile myalgia syndrome was observed in 14 patients. Nine of the patients were female. The median age at the time of diagnosis of PFMS was 10 years. Only three patients had previously been diagnosed with FMF. Most of our patients were patients who had no previous complaint of FMF. PFMS attack was seen as the first clinical manifestation of FMF in 11 patients. Two patients who did not respond to steroid treatment improved with anakinra treatment. CONCLUSIONS: PFMS is a rare condition of FMF disease. It may be the first clinical manifestation of FMF disease. Fever may not be seen in all patients. Clinicians should be aware of this situation.

A Case of Protracted Febrile Myalgia Syndrome with Atypical Course and Severe Asymmetric Loss of Muscle Strength.

Protracted febrile myalgia syndrome (PFMS) is a rare form of familial Mediterranean fever (FMF) characterised by prolonged myalgia. The duration of PFMS is much longer than a typical 2-5-day attack familial Mediterranean fever and lasts for 2-6 weeks until they treated with corticosteroids. Colchicine is not effective for control of PFMS's attacks. The attacks typically resolve with corticosteroid and/or IL-1 receptor blockers. Herein, we present a young adult without typical familial Mediterranean fever clinical features but presenting with atypical course and severe asymmetric muscle strength loss. Thigh magnetic resonance imaging confirmed inflammation and oedema and muscle biopsy showed no pathological findings. Electromyography revealed myopathic findings during attack-period, despite normal results in attack-free study. The patient was treated successfully with anakinra and remarkable rapid recovery in both muscular findings and acute phase reactants were observed. PFMS should be considered even in the absence of apparent FMF attack pattern and in the presence of unexpected severe muscle weakness, especially in areas endemic for FMF and long-lasting myalgia attacks.

The Preferential Use of Anakinra in Various Settings of FMF: A Review Applied to an Updated Treatment-Related Perspective of the Disease.

Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA) amyloidosis, driven by overproduction of interleukin 1 (IL-1) through an activated pyrin inflammasome. Consequently, non-responsiveness to colchicine, the cornerstone of FMF treatment, is nowadays addressed by IL-1- blockers. Each of the two IL-1 blockers currently used in FMF, anakinra and canakinumab, has its own merits for FMF care. Here we focus on anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and explore the literature by using PubMed regarding the utility of anakinra in certain conditions of FMF. Occasionally we enrich published data with our own experience. To facilitate insights to anakinra role, the paper briefs some clinical, genetic, pathogenetic, and management aspects of FMF. The clinical settings of FMF covered in this review include colchicine resistance, AA amyloidosis, renal transplantation, protracted febrile myalgia, on- demand use, leg pain, arthritis, temporary suspension of colchicine, pediatric patients, and pregnancy and lactation. In many of these instances, either because of safety concerns or a necessity for only transient and short-term use, anakinra, due to its short half-life, is the preferred IL-1 blocker.

Magnetic resonance findings may aid in diagnosis of protracted febrile myalgia syndrome: a retrospective, multicenter study.

BACKGROUND: Protracted febrile myalgia syndrome (PFMS) is a rare complication of Familial Mediterranean fever (FMF). The diagnosis is based on clinical symptoms and is often challenging, especially when PFMS is the initial manifestation of FMF. The aim of this report was to describe the magnetic resonance imaging (MRI) findings in pediatric patients with PFMS. RESULTS: There were three girls and two boys ranging in age from 6 months to 16 years, all of Mediterranean ancestry. Three had high-grade fever, and all had elevated inflammatory markers. MRI of the extremities yielded findings suggestive of myositis, which together with the clinical picture, normal CPK levels, and supporting family history of FMF, suggested the diagnosis of PFMS. Out of most common MEFV mutations tested, one patient was homozygous for M694V mutation, three were heterozygous for M694V mutation, and one was compound heterozygous for the M694V and V726A mutations. CONCLUSIONS: MRI may serve as an auxiliary diagnostic tool in PFMS.

Corticosteroid-resistant anakinra-responsive protracted febrile myalgia syndrome as the first manifestation of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common type of monogenic periodic fever syndromes and characterized by recurrent self-limited attacks of fever and polyserositis. Musculoskeletal signs and symptoms are not uncommon and manifested as arthritis and myalgia. Myalgia may be spontaneous or exercise-induced that mostly affects lower limbs and spontaneously resolves in 2-3 days. Protracted febrile myalgia syndrome (PFMS) is another form of rare and severe muscle involvement in FMF. PFMS affects all muscle groups and lasts for several weeks. Herein we present a pediatric case of PFMS that presented as the first manifestation of FMF, not responded to prednisolone at all but showed dramatic improvement with anakinra. Our case has a few distinctive points. She did not have a diagnosis of FMF and also she did not have any previous complaints compatible with FMF. Thus, PFMS was the first sign of FMF in this patient. Most of the cases of PFMS show dramatic response to corticosteroids, but our case did not respond at all to high-dose corticosteroids and anakinra resulted in rapid resolution of the symptoms. Protracted febrile myalgia syndrome may be the first manifestation of FMF. It should be suspected in cases with prolonged and unexplained fever, severe myalgia, and high acute phase reactants.

Protracted febrile myalgia as a challenging manifestation of familial Mediterranean fever: case-based review.

Protracted febrile myalgia syndrome (PFMS) in familial Mediterranean fever (FMF) patients is a vasculitic condition characterized by severe myalgia, fever, abdominal pain, diarrhea, and arthralgia/arthritis episodes lasting 4-6 weeks. Symptoms typically resolve with corticosteroid treatment. However, in recent years, corticosteroid-resistant PFMS patients have been reported. We herein report five pediatric FMF patients complicated with PFMS. In addition, demographic findings, Mediterranean fever (MEFV) gene analysis, symptoms at disease onset, time interval between the diagnoses of FMF and PFMS, co-existent diseases, and treatment responses were evaluated. Resolution of all PFMS symptoms was accepted as complete response, while decreased symptoms without full recovery as partial response. We searched PubMed using the keywords 'protracted febrile myalgia' and 'anakinra', and reviewed the literature. There were three male and two female patients. Median age at the diagnosis of FMF was 6 (3-10) years. The time from diagnosis of FMF to the development of PFMS was changed from 0 to 8 (median: 2) years. All of the patients, except one, had homozygous M694V mutation. All patients were treated with corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) first. Two out of five patients were exhibited partial response, while others exhibited complete response. Patients with partial response to the conventional therapies were treated with anakinra, and achieved a great response after the first dose. Anti-interleukin-1 (IL-1) therapy may be a beneficial and a reasonable treatment option, when there is insufficient response to NSAID and corticosteroid therapies in pediatric PFMS patients.

Polyarteritis nodosa in case of familial Mediterranean fever.

Gökçe I, Altuntas Ü, Filinte D, Alpay H. Polyarteritis nodosa in case of familial Mediterranean fever. Turk J Pediatr 2018; 60: 326-330. Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limited attacks of fever accompanied by peritonitis, pleuritis, and arthritis. Protracted febrile myalgia syndrome (PFMS) is a rare form of vasculitic disease which is an uncommon dramatic manifestation of FMF, characterized by severe crippling myalgia and high fever. Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis affecting medium or small arteries. It is rarely observed in children, but its incidence increases in the presence of FMF. In this article we described a 14-year-old child diagnosed with FMF associated with PAN. Physicians should be aware of this possible association.

Protracted febrile myalgia syndrome treated with pulse of corticosteroids.

OBJECTIVE: This study describes our 5-year experience treating protracted febrile myalgia syndrome (PFMS) with pulsed doses of corticosteroids. METHODS: Eight patients with PFMS who received pulse corticosteroid therapy were identified from the electronic database of a tertiary pediatric medical center (2011-2016). Their clinical and laboratory data were collected. Differences in continuous variables between hospital admission and discharge were analyzed using Wilcoxon's matched pairs test. RESULTS: There were 6 female and 2 male patients of median age 10.45 years (range 6.2-17.1) Six patients were found to be homozygous for the M694V mutation. In 4 patients, PFMS was the first-ever manifestation of familial Mediterranean fever. Pulse corticosteroid therapy was administered at a dose of 10mg/kg for 3 days. Pain was alleviated (visual analog scale score, 0) within hours of initiation of therapy, although pain flare-ups lasting for minutes to hours were still observed during hospitalization. At discharge, all patients were prescribed continuous oral corticosteroids (1-2mg/kg) with gradual tapering down over 6 weeks. CONCLUSION: Pulse corticosteroid therapy is effective in alleviating PFMS pain; however, it does not completely abort a PFMS episode.

Protracted febrile myalgia in a patient with Familial Mediterranean Fever and Ankylosing Spondylitis.

BACKGROUND: Protracted Febrile Myalgia is a rare form of vasculitis that is diagnosed in patients with Familial Mediterranean Fever. OBJECTIVE: To present a case with Familial Mediterranean and Anklosing Spondylitis on anti-TNF therapy for three years, who developed protracted febrile myalgia syndrome. METHODS: Case report. RESULTS: A 35-year-old woman with known Familial Mediterranean Fever and Anklosing Spondylitis for 3 years presented with fever, diarrhea, intermittent abdominal pain and severe diffuse muscular pain lasting for two weeks. The patient was investigated for any infection focus. The patient was diagnosed as having Protracted Febrile Myalgia four weeks after the onset of the symptoms. Prednisolone 1 mg/kg per day was applied. Her fever and muscle pain resolved within 48 hours. CONCLUSION: The coexisting Ankylosing Spondylitis disease and the use of anti-TNF treatment in patients with Familial Mediterranean Fever could be a confounding factor for the investigation of fever. Steroid therapy has a dramatic response.

Rapid resolution of protracted febrile myalgia syndrome with anakinra: Report of two cases.

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.