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Paediatric Rheumatology Are MEFV Mutations Susceptibility Factors In

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Paediatric Rheumatology Are MEFV Mutations Susceptibility Factors In Paediatric rheumatology Are MEFV mutations susceptibility factors in enthesitis-related arthritis patients in the eastern Mediterranean? B. Gülhan1, A. Akkuş1, L. Özçakar2, N. Beşbaş1, S. Özen1 1Department of Paediatric Nephrology ABSTRACT ILAR, with an aim to also cover the and Rheumatology, and Objective. Enthesitis-related arthritis previously suggested terms of juvenile 2 Department of Physical and Rehabilitation, (ERA), is a complex genetic disease. spondyloarthropathy and seronegative Hacettepe University Faculty of Medicine, Although HLA-B27 is well established, enthesitis arthritis syndrome (1, 2). The Ankara, Turkey. it does not explain all the genetic load etiopathogenesis of ERA is not certain Bora Gülhan, MD in ERA. Familial Mediterranean fe- however, it is a complex genetic disease Abdulkadir Akkuş, MD Levent Özçakar, MD ver (FMF), caused by mutations in the like the other subtypes of JIA. Genetic Nesrin Beşbaş, MD MEFV gene, is a frequent autoinflam- predisposition has a significant impact Seza Özen, MD matory disorder in the eastern Medi- on ERA, where common single nucleo- Please address correspondence to: terranenan. tide polymorphisms in multiple genes Prof. Seza Özen, Methods. We investigated the clini- are contributory as well, with real but Department of Paediatrics, cal and imaging features of 53 ERA variable environmental components. Faculty of Medicine, patients, as well as the frequency of HLA-B27 accounts for the major Hacettepe University, MEFV gene mutations in those who genetic load and is positive in approxi- 06100 Sıhhiye, Ankara, Turkey. were HLA-B27 negative. E-mail: [email protected] mately 90% of the patients with juve- Results. The mean age of the patients nile ankylosing spondylitis (AS) (3). Received on June 17, 2013; accepted in revised form on November 11, 2013. was 13.3±2.2 years and 49 were boys. Familial Mediterranean fever (FMF) is Peripheral arthritis was present in an autosomal recessive autoinflamma- Clin Exp Rheumatol 2014; 32 (Suppl. 84): S160-S164. all and sacroiletis in 26 patients. Ul- tory disorder characterised by recurrent trasonography showed enthesitis in 6 attacks of fever and polyserositis (4). © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2014. patients of the tendons, whereas these Mutations in the gene for FMF (MEFV) were assessed to be normal by physical are very common and the carrier rate Key words: enthesitis-related arthritis, examination. Forty patients (75.5%) is very high in the eastern Mediterra- familial Mediterranean fever were positive for HLA-B27. MEFV nean (5). Several case reports and co- analysis was performed for patients horts suggest an association between who were HLA-B27 negative. One pa- mutations in MEFV gene and certain tient refused MEFV analysis. 9 patients inflammatory disorders, such as rheu- carried MEFV mutations: 2 patients matoid arthritis (6), systemic onset JIA were homozygous for M694V (both (7), seronegative spondyloarthropathy patients were subsequently started col- (8), Henoch-Schönlein purpura (9), chicine along with ERA treatment), 5 polyarteritis nodosa (10, 11), Behçet’s patients were heterozygous for M694V disease (BD) (12, 13), and Crohn dis- mutation, 1 patient was heterozygous ease (14). for E148Q, and 1 patient was heterozy- The aim of this study was to analyse the gous for K695R mutation. None of the characteristics of Turkish children with patients had features suggesting FMF ERA in a single referral centre, and to at diagnosis of ERA; 1 patient subse- determine the frequency of MEFV mu- quently developed typical FMF attacks. tations among those who were HLA- Conclusion. Our findings suggest that B27 negative. MEFV mutations may represent a sus- ceptibility factor for ERA in the popu- Patients and methods lations of the eastern Mediterranean. Patients Patients followed in Hacettepe Univer- Introduction sity Paediatric Nephrology and Rheu- Enthesitis-related arthritis (ERA) is a matology Unit were included in this subtype of juvenile idiopathic arthritis study; the ERA population of our cen- (JIA). The term ERA and its pertinent tre consists of children from all around Competing interests: none declared. classification have been introduced by the country, the minority being from S-160 MEFV mutations in enthesitis-related arthritis patients / B. Gülhan et al. PAEDIATRIC RHEUMATOLOGY the local area. The study group of this I692del, M694V, M694I, K695R, methotrexate was also combined for cross-sectional study consisted of 53 V726A, A744S, R761H in exon 10. the peripheral arthritis in 24 patients Caucasian children (92.5% male; M:F (45.3%). Seventeen patients received ratio was 12.2) who met ERA criteria Radiological findings intraarticular steroids. In 11 patients, introduced by ILAR (1). These criteria Sacroileitis was assessed by magnetic short-term steroids were used in ac- are the presence of arthritis and en- resonance imaging (MRI) and/or x-ray. tive arthritis periods. At the end of the thesitis in the same patient or any two Ultrasonographic imaging was avail- follow-up, all patients improved with a of them that accompany arthritis or able in 34 patients and performed mean BASDAI score of 2.0 (IQR: 0.8- enthesitis; sacroiliac joint tenderness, bilaterally for knee and ankle joints. 4.0). Five patients who continued to HLA-B27 positivity, history of arthritis Quadriceps, patellar and Achilles ten- have active arthritis, with high BAS- after the age of 8, acute anterior uveitis, dons and plantar fasciae were scanned DAI scores and acute phase reactants presence of HLA-B27-related disease longitudinally and axially. The same were switched to etanercept. All of history in first degree relatives. All physician (with musculoskeletal ul- those patients were in remission at 6 patients also met European Spondy- trasound experience of more than 10 months of their follow-up. None of the loarthropathy Study Group (ESSG) cri- years) who was blinded to the clinical patients showed side effects related to teria (15). The study was approved by data performed all the evaluations us- the drugs. the ethics committee at the Hacettepe ing a 8–16 MHz linear probe (Diasus University. Dynamic Imaging). Laboratory parameters Mean ESR at diagnosis was 47 (IQR: Clinical assessment Statistical analysis 18-72) mm/hour. Thirty-three patients During routine outpatient visits, com- The results were analysed by using (62.3%) had elevated acute phase re- plete physical and rheumatological SPSS for windows 13.0 and descrip- actants at diagnosis. Forty patients examinations were performed. Ad- tive statistics are presented as per- (75.5%) were positive for HLA-B27. ditionally, spinal mobility was meas- centages, means and SDs if they were MEFV mutation analysis was carried ured with modified Schober test. The equally distributed, and as median out in 12 children with ERA who were Bath Ankylosing Spondylitis Disease (IQR, interquartile ratio) if they were HLA-B27 negative: the study revealed Activity Index (BASDAI) was used unequally distributed. mutations in 9 patients (11 alleles had to assess disease activity (16). Evalu- MEFV mutations among the 24): 2 pa- ations, treatment plans and follow-up Results tients were homozygous for M694V visits of the patients were performed Patients (both patients were put on colchicine by the same paediatric rheumatologist. In the study cohort, 49 patients (92.5%) treatment along with ERA treatment), 5 Tel-Hashomer Criteria and recently were male and 4 patients (7.5%) were patients were heterozygous for M694V proposed set of FMF criteria for chil- female. Clinical features of the sub- mutation, 1 patient was heterozygous dren were used to evaluate all patients jects are summarized in Table I. The for E148Q, and 1 patient was heterozy- for FMF (17, 18). All patients were mean age of the patients at time of the gous for K695R mutation. None of the treated with non-steroidal anti-inflam- study was 13.3±2.2. The mean age at patients had features suggesting FMF matory drugs (NSAIDs). For resistant diagnosis was 12.7±2.3 years, ranging at diagnosis of ERA; 1 patient started patients, sulfasalazine or methotrexate from 8.0 years to 16.9 years. All 53 pa- to develop typical FMF attacks during was added as disease-modifying drugs tients had peripheral disease; the mean follow-up (after the mutation analysis (DMARDs). Etanercept was used for number of joints involved was 2.1±1.1 was performed). patients unresponsive to DMARDs. (1-4). Nineteen patients (35.8%) had Mean age of the patients with a MEFV 1 joint, 19 patients had ≥3 joints in- mutation was 13.4±1.8 (11.1-15.8) and Laboratory testing volved. The most commonly affected was comparable to the cohort of our High acute phase reactants was de- joint was the knee (56%), followed patients. The pattern of joint and ten- fined as ESR >20 mm/hour and/or C- by the ankle (32%) and the hip (12%). don involvement among the patients reactive >0.5 mg/dl. HLA-B27 was Mean BASDAI score at diagnosis was who had a MEFV mutation, was again checked in all patients and MEFV mu- 5.7 (IQR: 4.4–6.3). Modified Schober similar to the other patients. All of tation analysis was studied in patients test was used for evaluation of thoraco- these nine patients had elevated acute who were HLA-B27 negative. One pa- lomber spinal mobility and mean value phase reactants at presentation. tient who was HLA-B27 negative re- was 5.3±1.1 (3-8). fused MEFV analysis. MEFV analysis Sixteen patients (30.2%) had HLA- Radiological findings was performed in 12 patients by using B27-related disease history in first or Sacroileitis was diagnosed in 26 pa- restriction fragment length polymor- second degree relatives. 40 patients tients (49.1%). Twenty-three patients phism (RFLP). The following MEFV (75.5%) were HLA B27 positive. were evaluated only with x-ray, 18 pa- mutations were investigated: E148Q Only 8 patients (15%) responded to the tients only with MRI and 12 both with in exon 2, P369S in exon 3, F479L in initial NSAID treatment.
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