ReviewIncomplete response to colchicine in M694V homozygote FMF patients
Introduction
Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent attacks of fever accompanied by sterile peritonitis, arthritis, pleuritis, and a typical inflammatory skin rash termed erysipelas-like erythema (ELE). The development of renal amyloidosis type AA is the most devastating manifestation of the disease and in the past was a major cause of morbidity and mortality in these patients [1]. The disease is caused by mutations in the MEFV gene, which is composed of 10 exons and encodes a 781 amino acid protein [2]. To date more than 50 disease-associated mutations have been identified, most of which are extremely rare (Infevers data base http://fmf.igh.cnrs.fr/infevers). Very high FMF carrier rates have been described among the Mediterranean and Middle Eastern population ranging from 1:5 in North African Jews, Arabs and Turks, to 1:3 among Iraqi Jews and Armenians [3], [4], [5], [6]. Most patients have mutations in exon 10 which is the longest exon in this gene, located in the C-terminal end of the protein encoding the B30.2 domain. The 2 most common exon 10 mutations are M694V which in Israel is found mainly among North African Jews but also in Iraqi Jews and in Arabs, and V726A which is prominent in Ashkenazi Jews but can also be found in Iraqi Jews, Arabs and Druze [7]. M694V in the homozygous state predisposes to a severe disease compared to other mutations [8]. The vast majority of FMF patients are treated with prophylactic colchicine which was introduced in the mid 70s of the last century [9]. Under this treatment 60–65% of the patients were reported to achieve a complete remission, 30–35% a partial remission and 5–10% were defined as non-responders [10]. These studies were performed before patients could be stratified according to their mutations. A recent study from Turkey on pediatric M694V homozygotes has reported complete response and non‐response in 36% and 18% of the patients, respectively, response rates way below the expected [11].
In this study we assessed the response rates to colchicine among adult M694V homozygotes and compared them to two groups of patients, M694V/V726A compound heterozygotes and V726A homozygotes. We show that despite receiving high doses of colchicine, response rates in M694V homozygotes are far less favorable than previously appreciated.
Section snippets
Materials and methods
Patients were recruited at the FMF clinic at the Sheba Medical Center, Israel. The study was approved by the institutional review board and participants gave informed consent.
Overall 112 patients previously tested for MEFV mutations were included; 40 homozygotes for M694V and 2 comparison groups that included 41 M694V/V726A compound heterozygotes and 31 V726A homozygotes. The patients for each genotype were randomly chosen from a list of more than 1000 patients genotyped in the last 10 years for
Results
No significant differences were found in the age or sex distribution between the M694V homozygotes group and both comparison groups (the M694V/V726A compound heterozygote group and the V726A homozygote group). While 67% of the M694V homozygotes were of North African origin, 40% of the V726A homozygotes were of Ashkenazi and/or Iraqi, reflecting the frequency of these two mutations in these populations (p < 0.001). Significant differences between the M694V homozygotes and each of the two
Discussion
Colchicine, an alkaloid used in the treatment of gout since the first century, has constituted the cornerstone of treatment for FMF in the past 40 years, drastically changing the natural history of the disease. Aside from its success at attenuating attack frequency and severity in the majority of FMF patients, colchicine is effective at preventing and arresting the development of renal amyloidosis [12], [13].
Colchicine is given in a daily dose varying between 1 to 2 mg/d, depending on the
Conclusions
We show that FMF patients who are M694V homozygotes, demonstrated a less favorable response to prophylactic colchicine treatment, manifested by the need for higher daily doses and resulting in an increased rate of side effects. This group of poor and non-responder FMF patients shall be the prime candidates for new alternative therapies, such as IL-1 inhibition, in the near future.
Take-home messages
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FMF is caused by mutations in the MEFV gene, which is composed of 10 exons.
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The 2 most common mutations are V726A and M694V which predisposes to a severe disease.
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The vast majority of FMF patients are treated with prophylactic colchicine.
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M694V homozygote patients demonstrate a less favorable response to colchicine.
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New alternative therapies are needed for poor and non-responder FMF patients.
References (26)
- et al.
Familial Mediterranean fever. A survey of 470 cases and review of the literature
Am J Med
(1967) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever
Cell
(1997)- et al.
Familial Mediterranean fever in Turkey. A report of twenty cases
Am J Med
(1971) - et al.
Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization
Semin Arthritis Rheum
(2004) - et al.
Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature
Semin Arthritis Rheum
(2011) - et al.
Genotype/phenotype correlations in Arab patients with familial Mediterranean fever
Semin Arthritis Rheum
(2002) - et al.
Evaluation of disease severity in familial Mediterranean fever
Semin Arthritis Rheum
(2005) - et al.
Colchicine nonresponsiveness in familial Mediterranean fever: clinical, genetic, pharmacokinetic, and socioeconomic characterization
Semin Arthritis Rheum
(2004) - et al.
Colchicine today
Joint Bone Spine
(2006) - et al.
Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state
Am J Med Genet
(2001)
el-Sobki NI, Fenech FF. Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature
Q J Med
Familial Mediterranean fever in Armenians: autosomal recessive inheritance with high gene frequency
Am J Med Genet
Analysis of the three most common MEFV mutations in 412 patients with familial Mediterranean fever
Isr Med Assoc J
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2023, Pediatrics and NeonatologyCitation Excerpt :Another example is the E148Q mutation; while Yilmaz et al.40 reported this mutation as protective against joint involvement, arthritis and arthralgia were most commonly observed with this mutation in our cohort. M694V has been reported to be associated with severe disease,41 poor response to colchicine,42 and increased risk of amyloidosis.43 The only patient who developed amyloidosis in our cohort had a complex allele (M694V homozygous/R202Q homozygous).
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2019, European Journal of Medical GeneticsCitation Excerpt :These findings are in accordance with the findings in our study, which found that M694V homozygosity is significantly associated with a more aggressive disease. Similarly, this study concurs with previous studies regarding clinical features that were shared at the same frequency by patients with other MEFV genotypes, including the rate of abdominal attacks, delay in diagnosis, duration of attacks and low compliance with treatment (Lidar et al., 2005, 2012). Exceptions are the attacks of ELE, a known feature of severe disease, which, although more common in patients homozygous for the M694V mutation, did not reach statistical significance.
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