Familial Mediterranean fever in childhood: a single-center experience

The aim of this study is to present demographic and clinical features, MEFV mutation variations, and treatment response of a large number of pediatric familial Mediterranean fever (FMF) patients from a single tertiary centre. Moreover, we aimed to investigate the current outcome of FMF, namely frequency of amyloidosis in children with FMF. We evaluated 708 FMF patients who were followed up in our clinic and who were under colchicine treatment for at least 6 months. The data were recorded from patient records and also verified by negotiations with patients and parents. The male/female proportion of the cohort was 1.05/1 (n = 362/346). Abdominal pain (89.5%, n = 634) was the most common manifestation of FMF episodes, followed by fever (88.8%, n = 629) and arthritis (40.7%, n = 288). However, arthritis in 23 (8%) of the 288 cases was not self-limited; and they subsequently diagnosed with juvenile idiopathic arthritis in addition to FMF. Homozygote or heterozygote M694V mutation was more frequent in patients with arthritis (63.2%) and chronic arthritis (69.6%) than the whole cohort (53.8%). Erythrocyte sedimentation rate and CRP level were in high levels even during attack-free period in 13.9% (n = 97/697) and 11% (n = 78/670) of the patients, respectively. Proteinuria was found in ten patients (1.4%). Amyloidosis was confirmed by renal biopsy in only two of these cases who were homozygous for M694V and compound heterozygous for M694V/M680I. 47 (6.6%) subjects were considered as colchicine resistant. Homozygote M694V mutation was the most frequent mutation in those resistant cases (63.8%, n = 30), followed by compound heterozygote mutation of M694V/M680I (6.3%, n = 3). Homozygous M694V mutation are still the most frequent mutation and associated with the most severe clinical picture and the worst outcome in Turkish children. M694V genotype seems to be more frequently associated with arthritis as well as with chronic arthritis than other genotypes. Recurrence of FMF episodes as well as amyloidosis could only be managed via strict compliance to colchicine treatment. Frequency of amyloidosis significantly decreased compared to the previous studies. A favorable outcome could be obtained with the anti IL-1 in colchicine-resistant FMF patients.


Introduction
Familial Mediterranean fever (FMF) is an autosomal recessively inherited autoinflammatory disease which is clinically manifested with periodic episodes of fever, polyserositis and arthritis. Among the Turkish, Arabic, Armenian and Jewish population the incidence rate ranges between 1 in 500 to 1000. The severity of the disease depends mostly on the MEFV gene mutation variations.

Objective
The objective of this study is to reveal a single center follow-up experience of a wide amount of childhood FMF patients from different regions around Turkey in terms of the demographic and clinical features, the genetic diversity and treatment response.
Material-methods 708 children diagnosed with FMF and under treatment of colchicine for at least 6 months that are seen out patiently in our Pediatric Rheumatology Clinic between November 2014 and March 2015 were reviewed retrospectively with the data based on the patient records and also taken from the parents.

Results
708 patients consisting 362 males and 246 females that are diagnosed with FMF were included in the study. The mean age of the patients by the time of the study was found to be 12,3 ± 4,4 years, while the mean age at the onset of the disease was 4,8 ± 3,4 years and at diagnosis was 7,3 ± 3,8 years. The consanguinity rate was resulted to be %29,2 and positive family history was detected in 370 (52,3%) patients.
The patients were investigated about the MEFV gene mutations and M694V homozygote mutation was found in 154 (21,8%) and M694V heterozygote in 141 (19,8%) children. All the other mutations in exon 10 region (M680I, V726A, M694I) in a compound heterozygous manner with M694V mutation were detected to be in 90 (12,7%) cases and the rate of patients that is a carrier of only one copy of exon 10 region mutations other than M694V was %13. The rest of the mutations (in exon 2,3,5 regions) were revealed in 45 (6,4%) children. In 45 (6,4%) of patients none of the so far known main mutations were shown.
Amyloidosis had been developed only in two cases both of whom were suffering from the disease process for at least 10 years and showing defective compliance to the colchicine treatment. One of them was a 20 years old M694V homozygote mutation carrier and the other was happened to be compound heterozygous with M694V/M680I mutations.
All of the patients were under colchicine treatment, of which 57 (8,1%) were uncompliant. As the side effects of the treatment were evaluated, diarrhea was found out to be in the first rank with the rate of 47(6.6%), then comes Istanbul University, Cerrahpasa Medical Faculty, Pediatric Rheumatology, Istanbul, Turkey the elevation in serum transaminase levels by 10 (1.4%). Only in one case leukopenia and also in another case alopecia developed.
The response to colchicine treatment was investigated and in 559 (79%) patients no episode occurred in the last year. In 149 (21%) cases periodic episodes were reported by the mean rate of 4,9 ± 4,4 per year (median 3/year, ranging between 1-24/year). After the follow up under treatment for at least 6 months the mean episode duration was decreased to 39,7 ± 29,4 hours (median 24 hours ranging between 6-168 hours).
The patients who are taking their colchicine treatment properly but still complaining about at least 6 episodes of any possible manifestations per year were considered resistant and were found to be in the rate of 47 (6,6%) in our cohort. In resistant cases, the most detected mutations were homozygous M694V (71.4%) in the first range and then compound heterozygosity with M694V/ M680I.

Conclusion
The diagnosis of childhood FMF is frequently encountered in our country. The most severe clinical presentation occurs as a result of M694V and other exon 10 region mutations. With the absolute compliance to treatment; the episodes disappear and amyloidosis, the most dreadful complication of the disease, can be prevented.