Inflammatory comorbidities in the largest pediatric Familial Mediterranean fever cohort: a multicenter retrospective study of Pediatric Rheumatology Academy (PeRA)-Research Group (RG).

AIM: The aim of this study was to investigate the frequency and type of FMF-associated inflammatory diseases in a large FMF pediatric patients and to compare them to those FMF patients without concomitant inflammatory diseases. MATERIALS AND METHODS: Familial Mediterranean fever patients enrolled in the Pediatric Rheumatology Academy (PeRA)-Research Group (RG) were included. The patients were divided into two groups according to concomitant inflammatory disease as FMF patients who had a concomitant inflammatory disease (group 1) and FMF patients who did not have a concomitant inflammatory disease (group 1). The clinical findings and treatments were compared between the two groups. RESULTS: The study group comprised 3475 patients with FMF. There were 294 patients (8.5%) in group 1 and 3181 patients (91.5%) in group 2. Juvenile idiopathic arthritis (n = 136) was the most common accompanying inflammatory disease. Arthritis, M694V homozygosity, and the need for biological therapy were more frequently observed in Group 1 (p < 0.05). Fever and abdominal pain were more frequently detected in Group 2 (p < 0.05). FMF patients with concomitant inflammatory diseas more frequently demonstrated colchicine resistance. There were no significant differences in the median attack frequency, chest pain, amyloidosis, erysipelas-like erythema, or family history of FMF between the two patient groups. CONCLUSION: To the best of our knowledge, this is the largest pediatric cohort reviewed to date. FMF patients may have different clinical profiles and colchicine responses if they have with concomitant inflammatory diseases. Key points • FMF is associated with some inflammatory comorbidities diseases. • To the best of our knowledge, this is the largest cohort evlauated pediatric FMF associated inflammatory comorbidities diseases reviewed to date.

Anxiety and depression among patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is a systemic autoinflammatory disease that requires lifelong treatment and is associated with several comorbidities, including mental health disorders such as anxiety and depression. FMF and mental health necessitate further research; hence, this study aims to observe anxiety and depression and their relationship with several variables in patients with FMF. METHODS: As the study population, 360 FMF patients were surveyed between June and October 2022. Surveys included inventories assessing anxiety and depression, i.e., the Beck's Depression Inventory (BDI), the Beck's Anxiety Inventory (BAI), and the State-Trait Anxiety Inventory (STAI). RESULTS: Mean scores for STAI-Y1 (state), STAI-Y2 (trait), BAI, and BDI were 42.2 ± 12.0, 45.9 ± 10.6, 24.0 ± 13.9, and 13.1 ± 8.99, respectively. Medication-adherent patients had significantly lower scores on STAI-Y1 (41.5 ± 11.4 vs. 45.2 ± 14.0; p-value: 0.04). M694V homozygous patients exhibited significantly lower scores in the BDI (12.4 ± 9.37 vs. 13.2 ± 8.93; p-value: < 0.001) and BAI (17.0 ± 12.1 vs. 25.1 ± 13.9; p-value: 0.001). The patients with an exon-10 mutation demonstrated significantly lower scores compared to patients with an exon­2 mutation (17.9 ± 12.3, 29.6 ± 13.3; p-value: < 0.001). CONCLUSION: The patients with FMF had mild depression and moderate anxiety scores. A higher level of education and medication adherence were associated with lower levels of anxiety. Likewise, the patients with genotypes associated with severe disease courses had lower levels of anxiety. We suggest that physicians should be more attentive to patients with a milder disease course and ensure that these patients are provided with sufficient treatment and knowledge about their disease.

The Influence of Coexisting Familial Mediterranean Fever on Crohn's Disease: Data From an FMF Endemic Area.

GOAL: The goal of this study was to evaluate the impact of coexisting familial Mediterranean fever (FMF) on Crohn's disease (CD) patients' phenotype and disease course in an endemic region for FMF. BACKGROUND: CD and FMF are inflammatory diseases characterized by recurrent abdominal pain and fever attacks. The impact of coexisting FMF on CD patients' phenotype and disease course is currently unknown. MATERIALS AND METHODS: We reviewed the medical records of 210 adult CD patients who were regularly followed up at a tertiary gastroenterology clinic between November 2006 and April 2018. The patients were divided into FMF positive (CD-FMF) and FMF negative (CD-control) groups. The severity of CD was assessed by the rate of hospitalization because of CD, the need for biological therapy, and whether surgery was performed for CD. RESULTS: Eight (3.8%) of 210 CD patients have concomitant FMF, which is 35 to 40 times higher than expected in an endemic region for FMF. Baseline demographic parameters, location/behavior of the CD, and initial therapeutic regimens were similar between the 2 groups. The prevalence of peripheral arthritis was significantly higher in CD-FMF group (37.5% vs. 10.4%, respectively, P =0.04). A significantly greater proportion of the CD-FMF patients had received biological therapy (50% vs. 11.9%; P =0.012). Steroid dependence and CD-related hospitalization rates in the CD-FMF group were relatively higher but were not statistically significant (37.5% vs. 15.3 and 62.5% vs. 41.1%). CONCLUSIONS: Our findings indicate that the disease course of CD tends to be more severe in patients with coexisting FMF.

Do we consider enough the presence of triggering factors in the evaluation of patients with FMF? Triggering factors are highly prevalent in colchicine-resistant FMF patients.

The aim of the study is to investigate the frequency of triggering factors in colchicine-resistant and -responsive Familial Mediterranean Fever (FMF) patients as well as the effect of  interleukin (IL)-1 antagonist treatment on the triggering factors. Both colchicine-resistant (patients on IL-1 antagonist treatment) and colchicine-responsive (patients on colchicine who had ≤ 3 attacks in the last year) patients were questioned for the presence of 12 different triggering factors, including exposure to cold, emotional stress, fatigue, physical activity, menstruation (for females), sleeplessness, prolonged standing, long-duration travel, high-fat diet intake, starvation, infection, and trauma. Colchicine-resistant patients were questioned for the presence of triggering factors for two time periods, before and after treatment with IL-1 antagonists. We studied 28 colchicine-resistant and 35 colchicine-responsive patients. Overall 77.8% of patients had at least one triggering factor. Triggering factors were associated with 28.5% of the total number of attacks. More than half of the patients (57.1%) declared that they had avoided these conditions. The frequency of triggering factors was higher in the colchicine-resistant group as compared to the colchicine-responsive group (89.3% vs 68.6%; p = 0.04). In colchicine-resistant FMF patients, the frequency of triggering factors (89.3% vs 32.1%) and the percentage of attacks initiated by triggering factors (27.8 vs 14.4%; p < 0.001) were decreased after treatment with IL-1 antagonists. In this study, triggering factors were more frequent in colchicine-resistant patients as compared to colchicine-responsive patients. Treatment with IL-1 antagonists seems to increase the endurance of colchicine-resistant patients in stressful conditions.

Cancer incidence in Familial Mediterranean Fever: A retrospective analysis.

OBJECTIVES: Familial Mediterranean Fever (FMF) is the most common hereditary monogenic fever syndrome that is characterized by recurrent attacks of fever and polyserositis. Anti-inflammatory drugs, with colchicine being the first-line therapy, have been used in the management of FMF. This study aims to evaluate the risk of cancer in Turkish FMF patients. METHODS: We retrospectively screened the cancer-related outcomes of our study group which consisted of Turkish FMF patients registered at our division. Cancer estimates of the Turkish population were published by the Turkish Ministry of Health in the Turkey Cancer Statistics Report 2018. Standardized incidence rates (SIR) were calculated to compare the cancer incidence observed in our study group with the expected cancer incidence of the Turkish population. Subgroup analyses were conducted on the subgroups, based on gender and usage of biological agents. RESULTS: Our study included 1734 FMF patients, 1054 (60.8 %) of whom were females. The total follow-up was 68,784 person-years. Cancer was observed in 35 (2 %) of these patients. Turkish FMF patients had a significantly lower incidence of cancer, compared with the overall Turkish population [SIR 0.64 (95 % CI 0.46-0.89), p < 0.01]. No significant association was found between cancer and biological agent therapies in FMF patients. CONCLUSIONS: Findings from our study indicate that the risk of cancer was decreased by 36 % in Turkish patients with FMF, compared with the outcomes of the overall Turkish population. Life-long exposure to anti-inflammatory drugs, primarily colchicine, may be the underlying reason for this outcome. Further studies are needed for the confirmation and explanation of this association.

French protocol for the diagnosis and management of familial Mediterranean fever.

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood associated with abdominal and/or thoracic pain lasting an average of 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.

Evaluation of Gastrointestinal System Complaints and Comorbidities in Pediatric Familial Mediterranean Fever Patients.

OBJECTIVE: Familial Mediterranean fever (FMF) is the most prevalent hereditary autoinflammatory disease among children. Abdominal pain and various gastrointestinal system (GIS) manifestations may arise directly from FMF or concomitantly with FMF. This study aimed to evaluate GIS complaints and findings other than classic peritonitis attacks in patients with FMF and to interpret concomitant GIS and hepatic disorders in these patients. METHODS: The medical and genetic findings of patients with FMF who attended our clinic between December 2011 and December 2021 were reviewed. Gastrointestinal system symptoms, liver function tests, abdominal images, and endoscopic and histopathological data were extracted from medical records. RESULTS: A total of 576 pediatric patients (female, 52.3%) diagnosed with FMF were included. Among them, almost one-fifth displayed GIS complaints, such as abdominal pain, defecation problems, and dyspepsia, distinct from typical FMF attacks. High serum aminotransferase levels were detected in 18.4% of the patients, with viral infections being the most common cause of moderate/severe hypertransaminasemia. In addition, during follow-up, 26.9% of them were referred to the pediatric gastroenterology department. At least 1 gastroenterological and hepatobiliary disorder was detected in 17.5% of the patients because of organic and functional GIS disorders or hepatobiliary disorders, such as gastroesophageal reflux disease, esophagitis, functional dyspepsia, and inflammatory bowel diseases. CONCLUSION: Various GIS and hepatic disorders can be encountered in children with FMF. The spectrum of these complaints and pathologies can range from frequently observed health problems to more severe diseases.

Genetic and clinical features of familial mediterranean fever (FMF) in a homogeneous cohort of patients from South-Eastern Italy.

Familial Mediterranean Fever (FMF) is linked with the MEFV gene and is the commonest among monogenic autoinflammatory diseases, with high prevalence in the Mediterranean basin. Although the clinical presentation of FMF has a major role in diagnosis, genotype/phenotype correlations and the role of "benign" gene variants (as R202Q) appear highly variable and incompletely clear, making difficult to select the most effective strategy in the management of patients. Aim of the present study was to investigate the clinical presentation and the genetic background in a homogenous cohort of patients from Apulia (south eastern Italy). We investigated 217 patients with a clinical suspect of autoinflammatory diseases, who were characterized for the occurrence of specific symptoms and with next generation sequencing by a 4-gene panel including MEFV, MVK, NLRP3 and TNFRSF1A. A genetic change was identified in 122 (53.7%) patients, with 161 different MEFV variants recorded in 100 individuals, 10 variants in NLRP3, and 6 each in TNFRSF1A and MVK. The benign variant R202Q was largely prevalent (41.6% of all MEFV variants). When patients were selected according the number of pathogenic MEFV variants (0, 1, or 2 pathogenic variants), results failed to show significant links between the frequency of symptoms and the number of pathogenic variants. Only family history and Pras score (indicative for severity of disease) predicted the presence of pathogenic variants, as compared with carriers of variants considered of uncertain significance or benign. Fever >38 °C and arthralgias appeared more frequently in R202Q-positive patients than in non-R202Q carriers. These two subgroups showed comparable duration of fever, occurrence of myalgia, abdominal and chest pain, Pras, and IFFS scores. In conclusion, results confirm that FMF manifests in mild form in non-middle eastern patients. This possibility partly affects the reliability of clinical criteria/scores. Furthermore, the presence of the R202Q variant might not be completely neutral in selected groups of patients.

Increased risk for stroke in patients with familial Mediterranean fever: results from a large population-based study.

OBJECTIVE: The association between chronic inflammatory conditions and cardiovascular disease is well established. Considering FMF, few studies exist investigating the risk of ischaemic heart disease, and none address the risk of stroke. We aimed to evaluate the incidence and risk for stroke in FMF patients compared with the general population. METHODS: A retrospective cohort study using the electronic database of Clalit Health Services (CHS), the largest health organization in Israel. All FMF patients diagnosed between 2000 and 2016 were included and matched with control according to age, gender and place of residence. Follow-up continued until the first diagnosis of stroke or death. The incidence of stroke was compared between the groups using univariate and multivariate models adjusting for cardiovascular risk-factors. RESULTS: A total of 9769 FMF patients and a similar number of controls were followed up for a median period of 12.5 years. The mean age at the beginning of the follow-up was 25.7 years. In total, 208 FMF patients were diagnosed with stroke compared with 148 controls, resulting in an incidence rate (per 10 000 persons-years) of 19.8 (95% CI 17.2, 22.7) and 13.9 (95% CI 11.8, 16.4), respectively, and a crude HR of 1.42 (95% CI 1.15-1.76; P < 0.001). In a multivariate analysis, FMF patients who developed amyloidosis with related or non-related renal failure demonstrated significant stroke risk (HR = 2.16; 95% CI 1.38, 3.38; P < 0.001), as well as for those who did not develop these complications (HR = 1.32; 95% CI 1.04, 1.67; P < 0.05). CONCLUSION: FMF patients are at increased risk for stroke regardless of known complications.

Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease.

OBJECTIVES: The aim of this study was to investigate the clinical associations of the second allele mutations and the effect of genotype and presenting features on colchicine resistance in children with familial Mediterranean fever (FMF), carrying at least one M694V variant. METHODS: The medical records of the patients diagnosed with FMF, in whom at least one allele M694V mutation was detected, were reviewed. Patients were grouped according to the genotype as M694V homozygotes, compound heterozygote M694V with an exon 10 mutation, compound heterozygote M694V with a variant of unknown significance (VUS), and M694V heterozygotes. Disease severity was assessed with the International Severity Scoring System for FMF. RESULTS: Among the 141 patients included, homozygote M694V (43.3%) was the most frequent MEFV genotype. Clinical manifestations of FMF at diagnosis were not significantly different according to genotypic alterations except homozygote M694V. Besides, homozygous M694V was associated with a more severe disease, with more frequent comorbidities and colchicine-resistant disease. A lower disease severity score was observed in compound heterozygotes with VUS than in M694V heterozygotes (median 1 vs 2, p = 0.006). Regression analysis revealed that homozygous M694V, arthritis, and frequency of attacks were associated with an increased risk of colchicine-resistant disease. CONCLUSIONS: Clinical manifestations of FMF at diagnosis with a M694V allele were predominantly influenced by the M694V rather than the second allele mutations. Although homozygous M694V was associated with the most severe form, the presence of compound heterozygosity with a VUS did not affect disease severity or clinical features. Homozygous M694V confers the highest risk of colchicine-resistant disease.

Renal involvement in familial Mediterranean fever in an Algerian population.

The objectives of this study were to investigate the clinical biological and histological renal involvement secondary to familial Mediterranean fever (FMF), the epidemiological data, genetics of our patients and their evolution under treatment. We prospectively studied 58 Algerian patients admitted in our nephrology department from January 2012 to January 2021. The diagnosis of nephropathy was suspected clinically and biologically and confirmed histologically. All our patients were tested for MEFV mutations. Results: 58 patients, 30 males and 28 females, mean age 31.68 ± 12.71; 3 (5.17%) chronic dialysis patients and 55 (94.82%) referred to the nephrology department for renal biopsy with renal symptomatology consisting of nephrotic syndrome in 50 (94. 73%), associated with renal failure 27 (47.36%), mainly primary in 23 (34.5%), secondary to seronegative lupus 13 (22.4%), Crohn's disease 9 (14.5%), sarcoidosis 3 (5.26%), and lymphoma 1 (1.7%); 29 (50%) were from consangineous marriages, the histological study found AA amyloidosis in 52 (89.6%); the genetic study confirmed the diagnosis of FMF in 58 (100%). The evolution of the patients: 20 (34.48%) followed in consultation, 25 (43.10%) in hemodialysis and 13 (22.41%) deceased. Conclusion: Renal involvement was the revealing complication in the diagnosis of FMF which exists in our country, and is still underdiagnosed.

Immunogenic Potential of the Mediterranean Fever Gene in Patients with Coronavirus Disease: A Cross-Sectional Study.

Background: In December 2019, an outbreak of pneumonia caused by the novel coronavirus disease 2019 (COVID-19) became a pandemic and caused a global health crisis. This study evaluates the immunogenic potential of the Mediterranean fever (MEFV) gene in patients with COVID-19. Methods: A cross-sectional study was conducted from March to April 2020 in various COVID-19 referral centers in Ardabil, Iran. Blood samples of 50 hospitalized patients with confirmed COVID-19 were evaluated for MEFV gene mutation using the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) and Sanger sequencing. Statistical analysis was performed using SPSS software, version 22.0. Results: Mutations of the MEFV gene were found in 6 (12%) of the patients. All mutations were heterozygous, and no homozygous or compound heterozygous forms were detected. The total mutant allele frequency was 6% and the carrier rate was 12%. The most common allele of the MEFV variant was E148Q, detected in 3 (6%) patients. No mutant variant of the MEFV gene was detected in deceased patients. None of the mutation carriers had familial Mediterranean fever (FMF) symptoms or a family history of FMF. Conclusion: MEFV gene mutations may have immunogenic potential in patients with COVID-19. A preprint version of this article has already been published at https://www.researchsquare.com/article/rs-69373/latest.pdf.

Clinical and functional impact of central sensitization on patients with familial Mediterranean fever: a cross-sectional study.

This study aimed to investigate the frequency of CS and its clinical and functional effects on familial Mediterranean fever (FMF). A hundred FMF patients were included in this study. The presence of CS was investigated by the central sensitization inventory (CSI). In addition to the detailed clinical features of patients and genetic mutations, quality of life, disability, sleep disorders, depression, anxiety, and fibromyalgia frequency were examined to evaluate the negative effects of CS on the individual. Patients were divided into groups according to the presence and severity of CS, and their results were compared. Correlation and multivariate regression analysis were performed to investigate the association of CS  with selected demographic and clinical parameters. The mean CSI was 37.72 (SD: 19.35), and thirty-eight (38%) patients had CS. Sacroiliitis occurred in 11 patients (11%), amyloidosis in 3 (3%), and erysipelas-like erythema in 11 (11%). The most prevalent genetic mutation was M694/any compound heterogeneous (35.7%), followed by M69V homogeneous (30%). Regarding comparing the patients with and without CS, the number of attacks, disease activity, daily colchicine dose, and all investigated comorbidities were significantly higher in the patients with CS (p < 0.05). In regression analysis, gender, colchicine dose and sleep disturbance were detected as related parameters with CS (OR (95% CI): 6.05 (1.39; 26.32), p: 0.017, OR (95% CI): 6.69 (1.65; 27.18), p: 0.008, OR (95% CI): 1.35 (1.35; 1.59), p: 0.001, respectively). Concomitant pain sensitization appears to be related to FMF patients' clinical and functional characteristics. These results suggest taking into consideration CS in the management of FMF patients.

Occurrence of familial Mediterranean fever in haemophilia patients.

INTRODUCTION: This is the first study of simultaneous occurrences of Familial Mediterranean Fever (FMF) in patients with haemophilia. AIM: The aim was to investigate the frequency and clinical characteristics of FMF in patients with severe haemophilia. METHODS: Our study included 30 patients with severe haemophilia (26 haemophilia A and four haemophilia B). All 30 patients are screened for MEFV genotypes in FMF according to the new Eurofever/PRINTO diagnostic criteria. All cohorts were genetically tested for FMF and thrombophilia. RESULTS: Eight (26%) of 30 haemophilic patients were diagnosed with FMF. Six different heterozygous FMF mutations including M694V (n = 2), E148Q (n = 2), V726A(n = 1), P369S (n = 1), E148Q/K695R (n = 1) and E148Q/M694I (n = 1) were identified. Seven had haemophilia A and only one had haemophilia B. Four (50%) patients had a positive family history and three of them had extraarticular findings specific to FMF. Only one haemophilia B patient received colchicine. Target joints in the knee, ankle, and elbow were identified in three FMF patients. The number of target joints in eight patients with FMF was significantly lower than in twenty-two patients without FMF (p < .05). The annual number of suspected joint bleedings in FMF patients admitted to the hospital was 40; however, 15 (37.5%) were documented bleedings in ultrasounds. Hereditary thrombophilia was detected in seven of eight patients. CONCLUSION: Our data indicate that screening for FMF may be useful in patients with haemophilia who develop arthritis without prominent bleeding and have a positive family history in many Mediterranean countries, including Turkey.

R202Q prevalence in clinically diagnosed Familial Mediterranean Fever patients: 9 years of data analysis from 1570 patients living Central Black Sea region, Turkey.

INTRODUCTION: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limiting fever, peritonitis, arthritis, and erysipelas-like-erythema, common among ethnic groups such as Turkish, Armenian, Arab, and Jewish. The disease is caused by mutations in the MEFV gene encoding the Pyrin. This study examines the genotypes of FMF patients from Amasya, Turkey. METHOD: According to the Tel Hashomer criteria, one thousand five hundred seventy patients (871 female, 699 male, mean age 21.2 ± 15.5 years) living in Amasya Province and the surroundings were screened for sequence variants in the entire MEFV gene. Besides, mutation types and alleles were evaluated with clinical findings. RESULTS: MEFV mutations and polymorphisms were found in 1413 of the 1570 patients (90%). Among these patients, 5 (0.3%) were double homozygous, 152 (9.7%) were homozygous, 373 (23.8%) were double heterozygous, and 882 (56.2%) were heterozygous. The most frequent genotype was R202Q (960, 43.5%) followed by M694V (n = 412, 18.7%), E148Q (n = 321, 14.6%), and M680I (n = 200, 9.1%). The most common clinical symptoms were abdominal pain (96.4%) and fever (91.3%). CONCLUSIONS: The fact that the R202Q genotype, which is compatible with the known FMF clinic, is frequently seen shows that it should be included in routine molecular screenings of the patients. Functional studies of the R202Q variant pyrin protein should be performed to understand FMF better. Finally, it is unclear whether the R202Q genotype might be regarded as a mutation while being approved as a polymorphism in the inFevers database.

Comparison of demographic, clinic and radiological features of patients with axial spondyloarthritis accompanying familial Mediterranean fever to patients with each condition alone.

OBJECTIVE: To compare the demographic, clinical, and radiological features of patients with axial spondyloarthritis (axSpA) accompanying familial Mediterranean fever (FMF) to patients with each condition alone. METHOD: Hacettepe University Hospital database was screened regarding ICD-10 codes for FMF (E85.0) and axSpA (M45). The diagnosis of FMF was confirmed by Tel-Hashomer criteria, and axSpA by the presence of sacroiliitis according to the modified New York criteria or active sacroiliitis on magnetic resonance imaging. As control groups, 136 gender-matched, consequent FMF patients without axSpA and 102 consequent axSpA patients without FMF previously treated with any biological agents were included in the analysis. RESULTS: In patients with FMF + axSpA compared to the axSpA group, age at axSpA symptom onset and age at diagnosis were lower [median with interquartile range (IQR): 21 (17-30) vs 27 (21-37), p < 0.001; 23 (21-38) vs 32 (24-43) years, p = 0.001], moderate to severe hip disease and total hip replacement were more prevalent (23.4% vs 4.7%, p < 0.001; 11.2% vs 2.8%, p = 0.016). In patients with FMF + axSpA compared to the FMF group, age at FMF symptom onset and age at diagnosis were higher [13 (6-30) vs 11 (5-18), p = 0.057; 23 (13-33) vs 18 (10-31) years, p = 0.033] and amyloidosis was more prevalent (6.6% vs 2.2%, p = 0.076). Although the M694V variant (in one or two alleles) was more prevalent in the FMF + axSpA group, the difference was not statistically significant. CONCLUSION: In patients with FMF + axSpA, the age of onset of axSpA was significantly earlier, moderate to severe hip involvement and amyloidosis were more common than in patients with each condition alone.

Increased risk of venous thromboembolism among patients with familial Mediterranean fever.

INTRODUCTION: Familial Mediterranean Fever (FMF) is an auto inflammatory disease characterized by acute febrile attacks, serositis, arthritis and skin rash. Previous studies have identified an association between venous thromboembolism (VTE) and various inflammatory and autoimmune disorders, driven in large part by inflammatory processes. Despite these established associations, there remains a paucity of data linking FMF to VTE. The purpose of this study is to evaluate the association between VTE in patients with FMF compared to matched controls. METHOD: A population based cross-sectional study was performed utilizing the electronic medical database of Israel's largest healthcare provider, Clalit Health Services. Using this database, we looked at the prevalence of VTE in a cohort of FMF patients compared to matched controls. Univariate logistic regression was used to evaluate the association between FMF and VTE. Multivariate analysis was conducted to adjust for age, sex, socioeconomic status and comorbidities associated with VTE. RESULTS: A total of 6534 FMF patients were identified and matched with an equal number of controls. In univariate analysis the cumulative percent of VTE was higher in FMF patient compared to matched controls (FMF 3%, Control 2%). In a multivariate logistic regression analysis FMF was found to be independently associated with VTE (HR 1.96, P < 0.001). CONCLUSION: FMF is associated with increased risk of VTE. This association is likely the result of a chronic and persisting inflammatory state. Physicians should be aware of this sequela and care must be undertaken to control unbalanced disease.

The frequency of fibromyalgia in familial Mediterranean fever and its impact on the quality of life.

BACKGROUND AND AIM: Concomitant fibromyalgia syndrome (FMS) has been known to be more frequent in patients with several rheumatic diseases. In this study, our aim was to investigate the prevalence of FMS in patients with familial Mediterranean fever (FMF), to analyze the possible factors related to this frequency, and to evaluate the impact of FMS on the functionality and quality of life (QoL) of the patients with FMF. PATIENTS AND METHODS: One hundred cases with FMF and 100 controls were included to this case-control study. FMS coincidence was investigated in all participants according to revised 2016 classification criteria. Demographic features, FMF disease duration, FMF gene mutations, drugs used, attack frequency per year, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum fibrinogen levels were recorded. FMF disease severity was assessed by International Severity Scoring System for Familial Mediterranean Fever (ISSF). For the assessments of QoL and functioning, FMF-QoL, Short form 36 (SF-36), and Health Assessment Questionnaire-Disability Index (HAQ-DI) were used, and for the assessment of FMS impact, the fibromyalgia impact questionnaire (FIQ) were used. RESULTS: We found an FMS frequency of 33% in patients with FMF in our study using the current FMS classification criteria. This result was significantly higher than in age- and gender-similar controls (6% FMS frequency; P < 0.05). The number of woman patients and FMF disease duration were significantly higher in patients with FMF + FMS than in patients with only FMF (P < 0.001). There was no significant difference in ISSF scores, ESR, CRP, and fibrinogen levels, management regimens, and FMF gene mutation distributions between FMF + FMS and FMF groups. FMF attack frequency was reported as significantly higher in FMF + FMS patients than in others (P < 0.000). In spite of similar FMF-QoL scores, there were significant differences in HAQ-DI and SF-36 scores between groups (P < 0.05). Higher impact of FMS presented negative correlation with functioning and general health, and positive correlation with QoL in FMF + FMS (P < 0.05). CONCLUSION: Concomitant FMS was a common clinical problem in patients with FMF regardless of the severity and characteristics of FMF. The FMS impact may affect function and QoL in patients of FMF. Considerations of the FMS component in the management of FMF may contribute to the holistic approach to FMF.

Seasonal residual activity in adult familial Mediterranean fever: a longitudinal observational study.

Although it is assumed that cold exposure triggers inflammation in patients with familial Mediterranean fever (FMF), seasonal differences in FMF have not yet been investigated. This study aims to investigate the association of seasonal changes with the frequency of attacks, disease severity, and subclinical inflammation in FMF. This longitudinal study examined adult patients with FMF on an established treatment followed up for at least 1 year in Istanbul. Clinical characteristics, medications, intraseasonal attacks counts, arthralgia and arthritis, disease severity, and the subclinical inflammation parameters were recorded covering four seasons. Friedman's and Cochran's Q tests were used to analyze changes in the above-mentioned data over seasons. Additionally, all attacks experienced in each season were added, and interseasonal differences were compared with the Chi-square goodness-of-fit test. Data for 240 observations (60 patients) were analyzed. The mean age and disease duration were 39.78 (SD 11.91) and 10 (IQR 6-22.75) years, respectively. The comparison of medians for four seasons did not show any statistical differences in terms of attack frequency, disease severity parameters, markers of subclinical inflammation, and the presence of arthralgia and arthritis. The total number of intraseasonal attacks experienced by patients differed among the seasons (p = 0.023), with a higher count in winter. Adult individuals with established FMF are more likely to experience attacks in winter than summer, but this difference may not be seen in the general parameters of disease activity/severity. This result supports the notion that there is a pronounced residual activity in winter.

Spondyloarthritis in familial Mediterranean fever: a cohort study.

Familial Mediterranean fever (FMF) and spondyloarthritis (SpA) may show several common signs. This study aimed to evaluate the frequency of SpA and its manifestations in FMF, the impact of SpA on FMF, and the associations of non-episodic findings (heel enthesitis, protracted arthritis, and sacroiliitis) with the FMF features. Demographic, clinical, imaging, and genetic data were retrieved from medical records of the patients with adult FMF. To identify patients who met the classification criteria for SpA, data including rheumatologic inquiry were recorded. Patients with SpA and those who did not meet the criteria were compared in terms of FMF features. Regression analyses were performed to determine the factors that were most associated with sacroiliitis, enthesitis, and protracted arthritis. Of the 283 patients with FMF, 74 (26.1%) met the SpA criteria (64 axial, 10 peripheral); and 65 (22.9%) patients had sacroiliitis, 27 (9.5%) protracted arthritis, and 61 (21.6%) heel enthesitis. Patients with SpA were older and had more FMF severity, and heel pain rate than those without; however, genetic features, CRP, resistance to colchicine, and heel enthesitis did not differ. A meaningful number of patients without SpA had also displayed heel enthesitis, protracted arthritis, inflammatory back pain, heel pain, family history of SpA, and elevated CRP. Age was found to be the main predictor of heel enthesitis and protracted arthritis was linked with FMF severity. A significant number of patients with FMF meet the peripheral SpA classification criteria as well as axial SpA. SpA and its shared manifestations with FMF may have an impact on FMF.