Immunoglobulin free light chains in saliva: a potential marker for disease activity in multiple sclerosis.

A new procedure was developed and applied to study immunoglobulin free light chains (FLC) in saliva of healthy subjects and patients with multiple sclerosis (MS). The procedure was based on a Western blot analysis for detection and semiquantitative evaluation of monomeric and dimeric FLCs. The FLC indices accounting for the total FLC levels and for the monomer/dimer ratios of κ and λ FLC were calculated, and the cut-off values of the FLC indices were determined to distinguish healthy state from MS disease. The obtained FLC index values were statistically different in the saliva of three groups: active MS patients, MS patients in remission and healthy subjects groups. Our FLC monomer-dimer analysis allowed differentiation between healthy state and active MS with specificity of 100% and a sensitivity of 88·5%. The developed technique may serve as a new non-invasive complementary tool to evaluate the disease state by differentiating active MS from remission with sensitivity of 89% and specificity of 80%.

T helper 17 polarization in familial Mediterranean fever.

Autoinflammatory attacks in familial Mediterranean fever (FMF) are accompanied by elevated levels of interleukin-6 (IL-6), and are controllable by IL-1-targeting drugs. In combination, IL-6 and IL-1 are known to be potent inducers of T helper (Th) 17 cells development. Therefore, we studied the Th17 population size, and activation potential, of FMF patients. Based on the relative mRNA expression of the Th1, Th2, Treg and Th17 transcription factors T-bet, GATA3, FOXP3 and retinoic acid-related orphan receptor γT (RORγT), respectively, the Th17 population in peripheral blood mononuclear cells (PBMCs) of healthy subjects was estimated at 2.5% of the entire Th population and 4.4% in FMF patients in remission (n=6 for each group, P=0.03). IL-17 secretion after universal stimulation of the T-cell receptor in PBMCs culture was twice higher in cultures of patients with frequent attacks (n=18) than in those of patients with infrequent attacks (n=10, 1124±266 vs 615±196 pg ml(-1), P=0.009). IL-17 secretion correlated well with IL17A mRNA level. Part of the increased secretion was related to the deleterious, MEFV p.M694V homozygous genotype (n=19, 1.5-fold, P=0.03). Almost all IL-17 producer cells were CD4-positive (CD4(+)IL-17(+)). In conclusion, frequent attacks and the deleterious FMF genotype appear to drive FMF patients to a heightened Th17 response.

Erysipelas-like erythema as the presenting feature of familial Mediterranean fever.

BACKGROUND: 'Erysipelas-like' erythema (ELE) is a well recognized, although uncommon, manifestation of familial Mediterranean fever (FMF), which is frequently mistaken for infectious erysipelas, especially when forming the initial disease presentation. AIM: To clinically and genetically characterize ELE as the first manifestation of FMF. METHODS: FMF patients with ELE as the first disease presentation (study group), were compared with FMF patients with ELE, appearing during the disease course (control group I), and to those FMF patients who never had ELE (control group II). RESULTS: Patients of the study group were comparable to patients without ELE with respect to all demographic, clinical and genetic features studied, and yet differed from patients with ELE appearing later in the disease course in disease severity score (1.7 ± 0.4 vs. 2.4 ± 0.6, P = 0.01), length of diagnosis delay (7.2 ± 6.4 vs. 2.3 ± 3.3 years, P=0.037), age of FMF onset (24.8 ± 19.9 vs. 5.6 ± 5.7 years of age, P=0.014) and rate of homozygosity to the M694V mutation (14.3% vs. 68.7% respectively). ELE traits in the study and control groups were alike. CONCLUSIONS: FMF with ELE as the first disease manifestation form an uncommon subgroup, clinically and genetically diverging from the rest of the FMF-ELE patients.

Exertional muscle pain in familial Mediterranean fever patients evaluated by MRI and 31P magnetic resonance spectroscopy.

AIM: To evaluate the effect of physical activity on the structural, morphological, and metabolic characteristics of the gastrocnemius muscle in familial Mediterranean fever (FMF) patients, utilizing quantitative (31)P magnetic resonance spectroscopy (MRS), in order to elucidate the mechanism of their exertional leg pain. MATERIALS AND METHODS: Eleven FMF patients suffering from exertional leg pain (eight male, three female; mean age 33 years) and six healthy individuals (three male, three female; mean age 39 years) constituted the control group. All of the participants underwent magnetic resonance imaging (MRI) and non-selective (31)P MRS (3 T) of the leg muscles before and after graded exercise on a treadmill. Phosphocreatine (PCr):inorganic phosphate (Pi), PCr:adenosine triphosphate (ATP) ratios and the intracellular pH of the leg muscles were measured using (31)P MRS. RESULTS: For both groups, normal muscle mass with no signal alterations was observed on the MRI images after exercise. The normal range of pre- and post- exercise MRS muscle parameters was observed in both groups. However, the intracellular pH post-exercise, was significantly higher (less acidic) in the FMF group compared to the control group [pH (FMF) = 7.03 ± 0.02; pH (control) 7.00 ± 0.02; p < 0.0006]. CONCLUSIONS: The finding of a less prominent, post-exercise acidification of the gastrocnemius muscle in this FMF patient group suggests a forme fruste of glycogenosis. This preliminary observation should be further investigated in a future, larger-scale study.

Exertional leg pain as a manifestation of occult spondyloarthropathy in familial Mediterranean fever: an MRI evaluation.

OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever, peritonitis, arthritis, and pleuritis, caused by neutrophil-induced sterile serositis. Another clinical manifestation in patients with FMF is exertional leg and ankle pain that appears after minor exercise, for which the underlying mechanism is obscure. The purpose of the current study was to feature distal leg changes in FMF patients complaining of exertional leg pain, using magnetic resonance imaging (MRI). METHODS: Eleven patients with FMF who suffer from exertional leg pain (eight males, three females; mean age 33 years) and six unaffected controls (three males, three females; mean age 39 years) underwent MRI (3 T) of the ankle, including conventional T1 and T2 with fat saturation sequences, before and after graded exercise on a treadmill. Clinical and genetic data and sacroiliac radiographs were obtained. RESULTS: Ten patients (91%) with FMF but none of the control group had signs compatible with enthesitis of the Achilles tendon, long plantar ligament, or the plantar fascia (including enthesophytes, erosions, and bone marrow oedema). Nine patients (80%) had radiographic signs of sacroiliitis on the pelvic radiograph. CONCLUSIONS: Exertional leg pain in FMF patients, shown to be associated with signs of enthesopathy on imaging, may be included within the spectrum of spondyloarthropathy.

Guidelines for the genetic diagnosis of hereditary recurrent fevers.

Hereditary recurrent fevers (HRFs) are a group of monogenic autoinflammatory diseases characterised by recurrent bouts of fever and serosal inflammation that are caused by pathogenic variants in genes important for the regulation of innate immunity. Discovery of the molecular defects responsible for these diseases has initiated genetic diagnostics in many countries around the world, including the Middle East, Europe, USA, Japan and Australia. However, diverse testing methods and reporting practices are employed and there is a clear need for consensus guidelines for HRF genetic testing. Draft guidelines were prepared based on current practice deduced from previous HRF external quality assurance schemes and data from the literature. The draft document was disseminated through the European Molecular Genetics Quality Network for broader consultation and amendment. A workshop was held in Bruges (Belgium) on 18 and 19 September 2011 to ratify the draft and obtain a final consensus document. An agreed set of best practice guidelines was proposed for genetic diagnostic testing of HRFs, for reporting the genetic results and for defining their clinical significance.

Familial Mediterranean FeVer gene (MEFV) mutations as a modifier of systemic lupus erythematosus.

The objective of this study was to assess the prevalence of the Mediterranean FeVer (MEFV) gene mutations in systemic lupus erythematosus (SLE) patients and their effect on organ involvement, as well as disease activity and severity. The frequencies of three familial Mediterranean fever-related MEFV gene mutations (M694V, V726A and E148Q) were investigated in 70 SLE patients. Organ involvement, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were correlated with mutation carriage. Eleven of 70 patients (15.7%) were found to carry an MEFV mutation. A single patient harbored two mutations, E148Q and V726A, without overt familial Mediterranean fever while the rest were heterozygous carriers. Four of the 11 carried an M694V mutation, four carried V726A and two carried E148Q. The majority of MEFV mutation carriers were Sephardic while non-carriers were mainly of Ashkenazi origin (72.7% vs. 45.7% and 47.4% vs. 9.1%, respectively, p = 0.02). SLE onset was significantly earlier in MEFV carriers (27.6 ± 9.7 vs. 38.2 ± 15.5 years, in carriers vs. non-carriers, p = 0.02). Hematologic and serologic parameters were comparable among mutation carriers and non-carriers. Febrile episodes were more common among MEFV mutation carriers (45.4% vs. 15.2%, p = 0.035) and there was a trend for excess episodes of pleuritis as well (54.5% vs. 23.7%, p = 0.06 in carriers vs. non-carriers, respectively). The frequency of secondary anti-phospholipid antibody syndrome was equivalent among the groups. Conversely, compound urinary abnormalities and renal failure was not observed among MEFV carriers yet was present in 33.4% and 18.6% of non-carriers (p = 0.027 and 0.19, respectively). SLICC damage index and SLEDAI activity index did not differ significantly between the groups. MEFV mutation carriage appears to modify the SLE disease phenotype in that it contributes to an excess of inflammatory manifestations such as fever and pleuritis on the one hand, while thwarting more severe renal involvement on the other.

Neurologic and other systemic manifestations in FMF: published and own experience.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease, presenting with recurrent episodes of fever and polyserositis. Neurologic involvement in FMF is rare and usually considered fortuitous. The aim of this article is to review the spectrum of possible neurologic manifestations, which can be encountered in FMF patients, and to establish their relation to FMF. METHODS: We reviewed the literature based on Pubmed search to find neurologic manifestations, which were reported in FMF patients. To that we added our own experience on the subject, abstracted from our computerised FMF registry of 12000 FMF patients of the National FMF Center and the computerised database of Sheba Medical Center. RESULTS: A wide range of neurologic manifestations involving FMF patients was noted. A large part of these manifestations could be directly related to FMF, its complications, associated diseases and treatment adverse effects. The remaining were incidental, or of uncertain association to FMF. CONCLUSION: A physician, taking care of an FMF patient, can face various neurologic manifestations and should be aware of their origin. The current chapter provides an insight to this association of FMF.

'Silent' carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient.

The presence of two mutations in the familial Mediterranean fever gene, without overt familial Mediterranean fever (FMF), designated as phenotype III, predisposes to developing 'silent' AA amyloidosis, recognized as phenotype II, due to the absence of medical supervision and colchicine prophylaxis. We sought to determine the prevalence of phenotype III in large families with only one subject affected with FMF, in order to assess the population at risk for transformation to phenotype II. A total of seven large families were recruited for the study. Siblings were screened for MEFV mutations and underwent a clinical interview to assess for unrecognized FMF manifestations. Phenotype III, most commonly associated with a V726A/E148Q genotype, was detected in 10% of siblings of index cases from informative families, corresponding to a 10-fold increase in comparison to the expected rate in the general population (p < 0.01). Unnoticed 'FMF-like' manifestations were detected among two siblings in the five families in which the index case was heterozygous, but in none of the siblings of the homozygous index cases. The enrichment for phenotype III and detection of occult FMF in large families, in which only a single member is afflicted with FMF, mandates routine clinical evaluation and genetic screening of siblings.

Pharmacokinetics of colchicine in pediatric and adult patients with familial Mediterranean fever.

This study sought to determine the appropriate starting dose of colchicine in children aged 2 to 4 years with familial Mediterranean fever (FMF) based on steady-state pharmacokinetics in pediatric patients with FMF from 2 to less than 16 years and adult patients with FMF from 16 to 65 years. Outpatients received colchicine for 90 days starting with a fixed dose for 14 days (blood sampling days 14 and 15). After starting doses of colchicine (0.6 mg/day [2 to less than 4 years], 0.9 mg/day [from 4 to less than 6 years], 0.9 mg/day [from 6 to less than 12 years], 1.2 mg/day [from 12 to less than 16 years], and 1.2 mg/day [from 16 to less than 65 years]), the observed steady-state pharmacokinetic parameters were comparable across age groups, despite the higher doses of colchicine on a mg/kg/day basis in the younger age groups. An exception occurred with once-daily colchicine, whereby mean Cmax for colchicine was higher in patients 4 to less than 6 years (9.4 ng/mL) compared with the younger and older age groups (6.1-6.7 ng/mL). Mean AUC0?24h values in children 2 to less than 4, 6 to less than 12, and 12 to less than 16 years were similar to those in adults. However, mean AUC0?24h values in children 4 to less than 6 years were 25 percent higher than those observed in adults. The results show that the recommended starting dose for children 2-4 years and 4-6 years should be 0.6 mg/day (half the US adult dose). Children aged 6 to less than 12 years should receive 0.9 mg/day (i.e. three-quarters of the US adult dose). The safety of colchicine in children 2 to less than 4 years was comparable to that in older children and adults.

Familial Mediterranean fever (FMF) and multiple sclerosis: an association study in one of the world's largest FMF cohorts.

BACKGROUND AND PURPOSE: To describe and characterize the association between familial Mediterranean fever (FMF) and multiple sclerosis (MS). METHODS: The patient registry of The National Center for FMF was screened for the coexistence of FMF and MS. Tel-Hashomer criteria were used for the diagnosis of FMF, and FMF severity was evaluated, using the simplified FMF severity scale. McDonald criteria were used for the diagnosis of MS, and neurologic disability was measured using the expanded disability status scale (EDSS). RESULTS: We identified nine patients, affected with both FMF and MS. The onset of the FMF averaged 15.6 (3-37) years. Most patients suffered from abdominal and joint attacks, and 50% of the patients sustained a moderate to severe FMF. The onset of the MS was at an average age of 31.6 (17-50) years. Neurologic manifestations varied individually, without a dominant deficit, and the course was in a relapsing-remitting pattern in most. The median EDSS was in general of low score (3.0), apart from the patients who were homozygous for the M694V mutation, in whom the MS was more severe. Based on our case series, the frequency of MS in our FMF population is 0.075%, twice higher the expected rate in the general population (P=0.0057). CONCLUSIONS: Multiple sclerosis is more common in FMF than in the general Israeli population. Homozygosity for the M694V MEFV mutation may aggravate the phenotype of MS and predispose FMF patients to develop MS.

Appendectomy in familial Mediterranean fever: clinical, genetic and pathological findings.

BACKGROUND: Abdominal attacks of familial Mediterranean fever (FMF) may simulate acute appendicitis and bring about considerable uncertainty. The similar presentation of the two clinical entities often leads to an unnecessary appendectomy. METHODS: 182 consecutive FMF patients were retrospectively reviewed for this study. Clinical and genetic data was compared between those who had undergone an appendectomy (n=71) and those who had not (n=111). RESULTS: The frequency of appendectomy found in FMF was far above the reported rate in the general population (40% vs. 12-25%). The rate of non-inflamed appendectomies was extremely high (80% vs. 20%) and remained constant over time. Tertiary hospitals and improved therapeutic and diagnostic measures that have evolved over the years did not reduce misdiagnosis of acute appendicitis in FMF. Severe phenotype and homozygosity for M694V were identified as risk factors for appendectomy in FMF. A change from the regular diffuse involvement to right lower quadrant abdominal pain was found to be the best predictor of inflamed appendix in FMF patients undergoing appendectomy for suspected acute appendicitis. CONCLUSION: Reliance on clinical parameters should improve diagnostic accuracy of acute appendicitis in the FMF patient population.

Systemic lupus erythematosus and familial Mediterranean fever: a possible negative association between the two disease entities--report of four cases and review of the literature.

Serositis is a common clinical manifestation of systemic lupus erythematosus (SLE), as well as being the hallmark of familial Mediterranean fever (FMF), the most prevalent monogenic disease in the Jewish population. We have treated four patients who suffered from both SLE and FMF since 2001 in our clinic, which also serves as the national center for FMF. Our cases illustrate both similarities and dissimilarities between the clinical manifestations of these two diseases, an aspect which should be borne in mind, especially in the young female patients. In general, it seems that co-occurrence of FMF moderates the presentation of lupus.

Mutations in the familial Mediterranean fever gene of patients with IgA nephropathy and other forms of glomerulonephritis.

Glomerulonephritis, particularly IgA nephropathy (IgAN), seems to be more common in familial Mediterranean fever (FMF), an inherited disease caused by mutations in the MEditerranean FeVer gene (MEFV). The present study is aimed to determine, in populations not suffering from FMF, whether carriage of MEFV mutations may modify or precipitate IgAN and other forms of primary glomerulonephritis (PGN). Forty patients with biopsy proven IgAN and 40 with PGN were surveyed for the presence of the three most common MEFV mutations (M694V, V726A and E148Q), using polymerase chain reaction amplification and restriction enzyme analysis. The rate of MEFV mutations in the patients was related to the expected carrier rate in the general population of the same ethnic extraction. The effect of mutation carriage on the disease course was determined in the IgAN patient group. The frequency of MEFV mutations in IgAN or PGN was comparable to that found in ethnically adjusted general population (p = 0.1 and 0.5, respectively). Carriage of mutated MEFV was not associated with the course and severity of the disease or findings in kidney biopsy and urine analysis. In a population, mostly of Jewish extraction, MEFV mutations do not seem to predispose to the development of IgAN and other forms of PGN or affect the phenotype.

Familial Mediterranean fever: clinical, molecular and management advancements.

Familial Mediterranean fever (FMF), the most frequent of the periodic fever syndromes, is an autosomal recessive disease, predominantly affecting people of Mediterranean descent. The disease is caused by mutations in the MEFV gene, encoding the pyrin protein thought to be associated with the interleukin-1 related inflammation cascade. The condition manifests as attacks of serositis, commonly involving the abdomen, chest or joints, typically accompanied by fever and elevated acute phase reactants. Attacks subside spontaneously within one to three days, without residue. Continuous treatment with colchicine, at a daily dose of 1 to 2 mg, reduces attack frequency, duration and intensity in the majority of patients, and also prevents the development of secondary amyloidosis, the most dreaded complication of the disease. In this communication we review the current state of the art in the diagnosis and care of FMF patients, starting with the presentation of a typical case.

Unique spectrum of MEFV mutations in Iranian Jewish FMF patients--clinical and demographic significance.

OBJECTIVES: To determine the spectrum of mutations in the Mediterranean fever gene (MEFV) of Iranian Jews with familial Mediterranean fever (FMF) and to analyse their clinical manifestations. METHODS: FMF patients with both parents of Iranian-Jewish (IJ) extraction or with one IJ parent (IJ-other, 10 of each) were characterized for clinical manifestations, and the B30.2 (PRYSPRY) domain of their MEFV was sequenced for mutations. RESULTS: Only one rare mutation, R653H, and one new mutation, G632S were present in the IJ group (in 2/10 patients), whereas the new, and common mutations were present in the IJ-other patients (8/10 patients). The new mutation was traced thrice to an IJ ancestor, and although carried asymptomatically by family members, it was over-represented in the patients (3/28 unrelated IJ alleles) compared non-affected IJ subjects (1/126 alleles, P = 0.03) or with non-Jewish Iranians (0/108 alleles, P = 0.001). The mutation was associated with a distinct phenotype regarding sites involved in the attack (P = 0.001), mild severity, sole expression of febrile episodes (P = 0.01) and a male bias (P = 0.01). In two 3D PRYSPRY models the G632S mutation was localized to a surface loop and close to a putative binding site. CONCLUSIONS: Iranian Jews with FMF have a unique spectrum of mutations including a newly described mutation with a non-typical phenotype.

Common FMF alleles may predispose to development of Behcet's disease with increased risk for venous thrombosis.

BACKGROUND: Behcet's disease (BD) is an inflammatory disorder of unknown cause, associated with vasculitis. Arterial or venous thrombosis occurs in about 25% of BD patients. Familial Mediterranean fever (FMF) is another inflammatory disorder, which stems from mutations in the FMF gene (MEFV) and shares a number of features with BD. OBJECTIVE: MEFV analysis in patients with BD suggests that mutated MEFV may act as a susceptibility gene in BD. We studied the rate and the clinical correlates of MEFV mutations in Israeli BD patients. METHODS: Included were 54 BD patients who satisfied the International Study Group criteria for BD. All BD patients were genotyped using polymerase chain reaction (PCR) and restriction enzyme analysis for the three most common MEFV mutations (M694V, V726A, and E148Q). The association between BD manifestations and MEFV alleles was analysed. RESULTS: Twenty-one BD patients were found to carry a single MEFV mutation and three additional patients were compound heterozygotes, a frequency significantly higher than that expected for ethnically matched healthy individuals. There were no statistically significant differences between carriers and non-carriers with respect to gender, frequency of HLA B5 antigen, cutaneous lesions, joint disease, and severity score. However, carriers did experience thrombosis more often [54% vs. 17%, p<0.005, odds ratio (OR) = 6.9, 95% confidence interval (CI) 1.75-26.9] and uveitis less often (20% vs. 40%, p<0.05, OR = 0.2, 95% CI 0.04-0.92). CONCLUSIONS: MEFV appears to be a susceptibility and modifier gene in BD.