The data in the literature on periods of colchicine-free remission in FMF is scarce, therefore this disease trait is under-recognized [11–13]. To the best of our knowledge our study is the first to characterize this phenomenon. Compared to a regular FMF population, patients with long-term remission, occurring sometimes during the course of their disease, emerge as a unique group, with distinct clinical, demographic and molecular features. Clinically, this subset of patients has a mild disease, presenting mostly with abdominal attacks, and excellent response to low dose colchicine prevention. Demographically and genetically, this subset is distinct by the low rate of patients of North-African origin (a trend), and by absence of patients homozygous to the M694V mutation, both are markers of a severe phenotype [14–16]. The prevalence of disease remission in FMF population, which until currently was unknown, is estimated based on the present study as 3.3%. We believe that the findings of this study will help avoid the misinterpretation of long-term cessation of febrile episodes as an argument against the possibility of FMF.
Large proportion of patients (24%) related induction of remission to abdominal surgery. There is no data in the literature on this association, and this seemingly cause-and-effect relationship is still questionable. However, unawareness of such a relationship may lead to the erroneous misdiagnosis of FMF, as chronic recurrent appendicitis. In other words, recovery from a disease with recurrent episodes of abdominal pain, particularly after abdominal operations, should not be held as an argument against a diagnosis of FMF. Another association noted is between the flare of FMF that terminated the remission period and psychological stress, caused by major life events, such as becoming pregnant. Previous reports have also shown that stress (mental or physical), as well as pregnancy and menstrual cycle might trigger FMF attacks [12, 13, 17].
The delay in the diagnosis of FMF in patients with long-term remission led to a significant delay in the initiation of colchicine treatment. Nevertheless, only one of the patients in the remission group had clinical signs of chronic inflammation, such as amyloidosis, proteinuria or anemia. The laboratory finding that none of the patients in the remission group had elevated acute phase reactants commensurate with the absence of chronic sequelae. Thus, in patients with long term remission, the clinical and subclinical manifestations merge to reflect a subset of FMF with mild phenotype.
The unexpected insignificant difference in the proportion of patients of Northern-African origin between the remission and the control groups, is most likely due to the low rate of North-African patients in the control group (36%), reflecting a major demographic change in the FMF population, used to be dominated by subjects of North-African origin (53-61%) [13, 18]. These demographic changes are marked by an increased proportion of FMF patients of European extraction and of mixed origin.
Long term remission is strongly determined by genetic factors, as reflected by the finding that none of the patients in the remission group was homozygous to the M694V mutation versus 32% in the control group. The absence of M694V homozygosity is consistent with the milder form of the disease and with the absence of amyloidosis in this group, as was shown previously [19]. On the other hand, the long term remission phenotype seems to also be affected by environmental factors, as implied from the finding that only one of 33 patients had siblings with long-term remission, despite multiplicity of additional family members with FMF in the study group.
The phenotype in the subset of patients with long-term remission is comparable to patients with late-onset FMF, published previously [20]. Both patient groups share low rates of extra-abdominal attacks and chronic manifestations, low disease severity, good response to colchicine and absence of homozygosity to the M694V mutation. These findings suggest that late-onset and long-term remission constitutes 2 faces of the same genetic-environmental make-up in FMF. Further subtyping of FMF into certain phenotypic classes may lead to increase understanding of the disease.
The main limitations of this cross sectional survey, stems from its dependence to some extent on patients’ recall of events. However, using computerized patient files, conducting a very thorough interview and carefully completing a detailed questionnaire should bridge this gap. Another limitation is the small sample size. However, this limitation is inevitable because remission in FMF is rare, and subjects of the study group were derived from a very large cohort of FMF patients, one of the largest worldwide. Thus, our findings seem to truly reflect the features of remission in FMF.
Third, an interventional study, looking for remission rate upon deliberate cessation of colchicine treatment in an unselected large cohort of FMF patients may yield higher than the 3.3% remission rate found by this observational study. However, obviously, such a study is unethical. Finally, the study neither tries to define patient candidature or appropriate time for colchicine termination, nor it explores long term outcomes of colchicine abstinence in FMF. These questions are beyond its scope. However, this proof of concept study establish and introduce the idea of colchicine free remission in FMF and features patients with such an experience, thus serving to incite future research in these directions.