Olga Kukuy

Anakinra for Colchicine‐Resistant Familial Mediterranean Fever: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Familial Mediterranean fever (FMF) is refractory to colchicine prophylaxis in 10–20% of patients. In a number of patient series, treatment with anakinra, an interleukin‐1–blocking agent, prevented FMF attacks in those with colchicine‐resistant FMF. This study was undertaken to evaluate the efficacy and safety of anakinra in the treatment of colchicine‐resistant FMF, using a randomized controlled trial.

Familial Mediterranean fever without MEFV mutations: a case–control study

BackgroundAlthough familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10–20% of FMF patients do not carry any FMF gene (MEFV) mutations. Fine phenotype characterization may facilitate the elucidation of the genetic background of the so called “FMF without MEFV mutations”. In this study we clinically and demographically characterize this subset.MethodsMEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation.ResultsForty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV-mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset.ConclusionsMEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.

Familial Mediterranean Fever (FMF) with Proteinuria: Clinical Features, Histology, Predictors, and Prognosis in a Cohort of 25 Patients

Objective. Reactive (AA) amyloidosis may complicate familial Mediterranean fever (FMF), the prototype of autoinflammatory diseases. Thus, proteinuria in FMF is commonly viewed as resulting from amyloidosis, and kidney biopsy is deemed superfluous. However, nephropathy other than amyloidosis has been described in FMF, but its rate and distinctive characteristics are unknown. Our aim was to determine the rate and underlying pathology of FMF-related nonamyloidotic proteinuria and compare its clinical course, demographic, and genetic features to those of FMF-amyloid nephropathy. Methods. This study is a retrospective analysis of data from patients with FMF undergoing kidney biopsy for proteinuria above 0.5 g/24 h, over 10 years (2001–2011). Clinical, laboratory, genetic, and pathology data were abstracted from patient files. Biopsies were viewed by an experienced pathologist, as necessary. Results. Of the 25 patients referred for kidney biopsy, only 15 (60%) were diagnosed with amyloid kidney disease (AKD), and 10 were diagnosed with another nephropathy. The AKD and nonamyloid kidney disease (NAKD) groups were comparable on most variables, but showed distinct characteristics with regard to the degree of proteinuria (6.45 ± 4.3 g vs 2.14 ± 1.6 g, p = 0.006), rate of severe FMF (14 vs 5 patients, p = 0.022), and rate of development of end stage renal disease (73.3% vs 20%, p = 0.015), respectively. Conclusion. NAKD is common in FMF and, compared to amyloidosis, it is featured with milder course and better prognosis. Contrary to common practice, it is highly recommended to obtain a kidney biopsy from patients with FMF and proteinuria more than 0.5 g/24 h.

Immunoglobulin-free light chain monomer-dimer patterns help to distinguish malignant from premalignant monoclonal gammopathies: A pilot study

Multiple myeloma (MM) and AL amyloidosis (AL) are two malignant forms of monoclonal gammopathies. For the purposes of prognosis and treatment, it is important to distinguish these diseases from the premalignant forms of monoclonal gammopathies, such as monoclonal gammopathy of unknown significance (MGUS) and smoldering myeloma (SMM). Routine serum/urine tests for monoclonal protein are insufficient for differential diagnosis. Thus, invasive procedures, such as tissue aspiration or biopsy, are applied. In this study, we aimed at characterization of serum‐free light chain (FLC) monomer‐dimer patterns to distinguish the malignant from the premalignant forms of monoclonal gammopathies. A quantitative Western blotting was applied to estimate the FLC monomer and dimer levels in AL, MM, MGUS, and SMM patients, and in control subjects (healthy individuals and patients with AA amyloidosis). AL and MM patients displayed an abnormally increased dimerization of monoclonal FLC, accompanied by higher clonality values of FLC dimers, as compared to that of monomers. These abnormalities of FLC patterns were not observed in patients with MGUS, SMM, AA amyloidosis, and healthy individuals. Analysis of FLC patterns helped to differentiate AL and MM from MGUS and SMM, a goal difficult to achieve using routine serum tests. Also, our technique might serve as a complimentary diagnostic tool in the cases with suspected AL amyloidosis, where the diagnosis of MM is excluded, while the results of amyloid typing by routine immunohistochemical techniques are inconclusive. Am. J. Hematol. 89:882–888, 2014.

Clinical Picture in Adulthood and Unusual and Peculiar Clinical Features of FMF

Familial Mediterranean fever (FMF) is classically manifested with painful, irregularly recurrent, short-lasting bouts of serosal inflammation (mainly peritonitis, synovitis or pleuritis), accompanied by fever, and resolving spontaneously [1]. A rise then fall of acute-phase reactants is typical, but some patients might suffer from continuous inflammation and its associated manifestations [2]. The disease onset is usually in childhood or adolescence, but, in some patients, the initial symptoms develop later in life, during the ages of 20–40 years and sometimes even later [3]. In general, late-onset FMF has a mild phenotype and its genotype lacks the homozygous M694V genotype [3]. The clinical manifestations may vary between patients, including members of the same family and even between identical twins [4, 5]. Clinical diversity may also be seen in the same individual, with different site of attacks in different episodes.

P01-029 – Microscopic hematuria in FMF

Hematuria is a recognized feature of familial Mediterranean fever (FMF), but its prevalence and clinical, genetic and demographic correlates are not known.

The use of serum free light chain dimerization patterns assist in the diagnosis of AL amyloidosis

The discrimination between benign and malignant forms of plasma cell dyscrasia (PCD) is often difficult. Free light chain monomer‐dimer pattern analysis (FLC‐MDPA) may assist in solving this dilemma and distinguish between AL amyloidosis and benign PCD. Serum samples of patients with AL amyloidosis and benign PCD were analysed in a blinded manner. Quantitative Western blotting was performed to estimate dimerization and clonality indices, and thereby determine the source of the tested samples, as derived either from benign or malignant PCD. The findings obtained by the FLC‐MDPA were compared with the actual diagnosis. Of 37 samples from patients with active AL amyloidosis, 34 (91·9%) fulfilled dimerization criteria for diagnosis of AL amyloidosis. Of the 45 samples from patients with benign PCD, 10 (21·2%) tested falsely positive or gave an inconclusive result. Thus, the sensitivity of the analysis was 92·5% with a remarkable negative predictive value of 91·9%. In addition, of 20 patients who were in complete or very good partial remission, only one tested positive. By multivariate analysis, FLC‐MDPA was the best independent marker predicting AL amyloidosis (odds ratio of 84). The FLC‐MDPA offers a highly effective tool in the diagnostic assessment of patients with PCD.

Featuring the phenotype of the FMF prototype

Results Compared with the control group, more patients, homozygous for the M694 mutation, suffered from a severe disease (p=0.001), had higher frequency of attacks before and during colchicine treatment (p=0.0001 and 0.0007, respectively), had more related diseases (p=0.0373) and needed higher dose of colchicine to control their disease (p=0.0001). Most other features tested (Table 1) appeared to be more pronounced in M694V homozygous patients (either with or without statistical significance).

Genetic analysis of MEFV mutation negative familial Mediterranean fever for non-MEFV mutations is rarely effective.

Background Systemic autoinflammatory diseases (SAIDs) are a group of diseases characterized by episodes of inflammation, usually manifested with fever and a variety of symptoms, including skin-rash, arthritis and abdominal pain. A clinical overlap between different SAIDs, may cause diagnosis uncertainty. Familial Mediterranean fever (FMF), the prototype of the autoinflammatory syndrome, is manifested with recurrent attacks of fever and serositis. Although most FMF patients present with a typical picture, approximately 10% of them, present with atypical phenotype, and may harbor no mutations in their MEFV gene. In these patients further genetic analysis may be advocated.

Arterial stiffness as a model to dissect chronic inflammation in FMF

Background Familial Mediterranean fever (FMF) is an autoinflammatory disorder, characterized by short attacks of sterile serositis, successfully suppressed by continuous colchicine treatment. Subclinical chronic inflammation however, is a frequent finding in FMF, manifested with elevated levels of inflammatory markers (CRP, SAA). While chronic inflammation is considered an important cardiovascular (CV) risk factor in most inflammatory disorders, findings on the impact of chronic inflammation in FMF are conflicting. Chronic inflammation is an important cause of arterial stiffness, an early sign and independent risk factor of cardiovascular atherosclerosis. Pulse wave velocity (PWV) measurement is a useful marker of arterial stiffness.