Familial Mediterranean Fever Research Articles

Successful treatment of two cases of acute myocarditis with colchicine.

Colchicine is an FDA-approved medicine that has been used for many years to prevent and treat gout flares as well as familial mediterranean fever. It is also used off-label to treat pericarditis, calcium pyrophosphate illness, and Behçet's syndrome. There are additional studies on the use of colchicine, which is accepted as the standard treatment for pericarditis in adults, post-pericardiotomy syndrome, post-operative and post-ablation atrial fibrillation, coronary artery disorders, prior to percutaneous coronary procedures, and myocarditis. Colchicine appears to be a promising oral cardiovascular treatment targeting the inflammatory axis, owing to its low cost and moderate side-effect profile. Our aim is to emphasise that colchicine treatment, which has a strong and effective anti-inflammatory effect profile, should be kept in mind in addition to conventional treatment in childhood myocarditis.

A young woman with fever and polyserositis caused by familial Mediterranean fever.

[See related commentary at www.cmaj.ca/lookup/doi/10.1503/cmaj.221652][1] KEY POINTS In 2015, a 28-year-old woman of Ashkenazi Jewish descent presented to the medical genetics clinic with concerns about flexible joints, easy bruising, stretchable skin, chronic back pain and mild scoliosis since

The Clinical Journey of a Patient with Familial Mediterranean Fever: One Gene, Three Diseases.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent self-limiting attacks of fever and serositis (Ben-Chetrit E and Levy M, Lancet 1998; 351: 659–664). The gain-of-function mutations in the responsible gene encoding pyrin, known as the MEditerranean FeVer (MEFV) gene, cause a reduction in the activation threshold of pyrin inflammasome triggering recurrent clinical attacks, subclinical inflammation, and a tendency for other inflammatory diseases (Jamilloux Y et al., Rheumatology (Oxford) 2018; 57: 100–111). Familial Mediterranean fever is more prevalently seen in the Middle Eastern communities. A relatively severe disease phenotype together with several diseases associated with FMF was frequently reported around this part of the world (Ben-Chetrit E and Yazici H, Clinical and Experimental Rheumatology 2019; 37 (Suppl 121): 18–22).

Serum amyloid A-A potential therapeutic target for hyper-inflammatory syndrome associated with COVID-19.

Serum amyloid-A (SAA) is associated with inflammatory disorders such as rheumatoid arthritis, Familial Mediterranean Fever, sarcoidosis, and vasculitis. There is accumulating evidence that SAA is a reliable biomarker for these autoinflammatory and rheumatic diseases and may contribute to their pathophysiology. Hyperinflammatory syndrome associated with COVID-19 is a complex interaction between infection and autoimmunity and elevation of SAA is strongly correlated with severity of the inflammation. In this review we highlight the involvement of SAA in these different inflammatory conditions, consider its potential role and discuss whether it could be a potential target for treatment of the hyperinflammatory state of COVID-19 with many potential advantages and fewer adverse effects. Additional studies linking SAA to the pathophysiology of COVID-19 hyper-inflammation and autoimmunity are needed to establish the causal relationship and the therapeutic potential of inhibitors of SAA activity.

Evaluation of the frequency of MEFV gene variants in patients with a pre-diagnosis of Familial Mediterranean Fever (FMF) in southeast Turkey.

Purpose: Familial Mediterranean Fever (FMF) is a hereditary auto inflammatory disease (MIM#249100). The most common symptoms are high fever, abdominal pain and arthralgia. FMF is the result of variations in the MEditerraneanFeVer (MEFV) gene, which is located on chromosome 16p13.3, consists of 10 exons and encodes the pyrin (marenostrin) protein. The frequency of MEFV gene variants that cause FMF varies according to ethnic groups, countries and even different regions in the same country. In this study, we aimed to determine the frequency and distribution of MEFV gene alterations that cause Familial Mediterranean fever in southeastern Turkey.
 Materials and Methods: A total of 6,660 patients with a prediagnosis of FMF, including 3,495 women and 3,165 men, were included in the study. Fragment analysis was performed to investigate the MEFV gene variations of the patients and the 19 most common variants in the Turkish population were examined.
 Results: We found at least one variation in 50.17% (3,341) of our 6,660 patients. In our patients, 108 different genotypes; in Exon 2, 3, 5 and 10 and we identified 16 different variations. We found 2,120 (63.21%) patients heterozygous, 693 (20.74%) compound heterozygotes, 275 (8.23%) homozygous and 261 (7.81%) complex genotypes. The 5 variants with the highest allele frequency are respectively; R202Q (27.84%), M694V (22.83%), E148Q (21.98%), V726A (7.42%), and M680I(G>C) (6.39%).
 Conclusion: We identified the most common prevalence of MEFV gene alteration in a large patient group in our region. High R202Q mutation rates were among the remarkable results of this study.

Apoptosis-associated speck-like protein containing a CARD (ASC), TNF Like Factor 1a(TL-1a) and B Cell Chemoattractant Chemokine Ligand 13(CXCL-13) expression profiles in familial Mediterranean fever (FMF) patients

Objectives: This study was carried out to compare the expression levels of ASC(Apoptosis Associated Speck Like Protein Containing a CARD), TL-1a(TNF Like Factor 1a) and CXCL 13(B Cell Chemoattractant Chemokine Ligand 13) genes in FMF patients According to Tell-Hashomer Criteria and Genetic analysis result in Düzce University Research and Application Hospital with healthy controls and to determine their clinical significance in FMF.
 Method: 36 patients (20 girls, 16 boys) and 12 healthy controls (7 girls, 5 boys) were included in the study. RNA was isolated from the peripheral blood of each individual and expression levels of ASC, TL-1a and CXCL 13 genes were determined. Routine biochemical parameters were also determined.
 Result: CXCL 13 and TL-1a gene expression levels were significantly increased in patients with FMF, the expression level of the ASC gene was found to be increased in FMF patients, but not significantly. 
 Conclusion: The expression levels of these genes may be related to the pathogenesis of the disease and these genes could be used as a marker in the early diagnosis of the disease.

Evaluation of Tuberculosis Risk under Interleukin-1 Inhibitor Agents in Patients with Autoinflammatory Diseases: Experience from a Region with Moderate Tuberculosis Prevalence

Abstract Background We aimed to investigate the rate of TBC reactivation in patients with autoinflammatory conditions who had been followed up under treatment with IL-1 antagonists in our clinic. We further aimed to evaluate whether latent TBC screening and isoniazid prophylaxis before IL-1 inhibitor treatment is beneficial in the prevention of reactivation. Patients and Methods This study was designed as a cross-sectional and observational study. It received the approval of the local ethics committee and was therefore performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Adult patients who had been followed up in our clinic under treatment with IL-1 antagonists were evaluated with regard to whether they had a TBC infection before and after these treatments and whether they had been screened for latent TBC infection before IL-1 antagonist treatment and received prophylaxis. Clinical and laboratory data were obtained from hospital records and via telephone interviews after the patients had given their verbal consent to participate. Results Fifty-nine patients under IL-1 antagonists were consecutively enrolled. 58 were under follow-up with the diagnosis of familial Mediterranean fever and one patient with a diagnosis of adult-onset Still’s disease. 35 patients (59.3%) were treated with anakinra and 24 (40.7%) were treated with canakinumab. 12 (50%) of the canakinumab users had previously received anakinra treatment and were switched to canakinumab due to side-effects or ineffectiveness. The number of patients who underwent latent tuberculosisc infection (LTBI) screening before treatment was 37 (62.7%); the number of patients who received prophylaxis was 13 (22%). None of the patients receiving IL-1 antagonists developed active tuberculosis. Conclusion Blocking the IL-1 pathway may be safe regarding the activation of LTBI or development of a new tuberculosis infection even in locations with a high geographical risk.

Kinesiophobia And Related Factors In Adult Patients With Familial Mediterranean Fever

Abstract Objective Kinesiophobia is a common problem in patients with rheumatic diseases and can cause physical inactivity, social isolation, disability, and poor quality of life. This study aimed to evaluate kinesiophobia and associated factors in patients with familial Mediterranean fever (FMF). Methods A total of 38 patients diagnosed with FMF volunteered to participate in the study. All patients were assessed using the Tampa Kinesiophobia Scale (TKS), the International Physical Activity Questionnaire (IPAQ), the Fatigue Severity Scale (FSS), and the Hospital Anxiety and Depression Scale (HADS). Results Thirty-three (86.8%) of the patients had TKS scores over 37, indicating high levels of kinesiophobia. The TKS score was positively correlated with the HADS depression score (r=0.530; p=0.001) and the FSS score (r=0.340; p=0.035) but was not significantly associated with age (r=0.102; p=0.543), disease duration (r=–0.110; p=0.511), body mass index (r=0.283; p=0.085), the HADS anxiety score (r=0.306; p=0.061), or the IPAQ score (r=–0.097; p=0.563). Conclusions Our sample of adult FMF patients showed high levels of kinesiophobia associated with fatigue and depression. Treatments focusing on kinesiophobia in FMF patients could help to increase the effectiveness of rehabilitation.

Familial Mediterranean Fever and Transverse Myelitis: A Causal Relation?

Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder characterized mainly by recurrent self-limited episodes of fever and polyserositis. FMF-related neurologic complication is an old debate, and the correlation between FMF and demyelinating disorders has been a matter of dispute for a long time. Few reports demonstrated a relationship between FMF and multiple sclerosis; however, the existence of a causal relationship between FMF and demyelinating disorders is still a puzzle. This report presents the first case of transverse myelitis following FMF attacks in which neurologic manifestations were resolved using colchicine treatment. Due to relapses of FMF, which were accompanied by transverse myelitis, rituximab was administered, which resulted in stabilizing disease activity. Accordingly, in the case of colchicine-resistant FMF and FMF-related demyelinating conditions, rituximab could be considered as a potential therapeutic option to alleviate both polyserositis and demyelinating manifestations.

Childhood-Onset Sacroiliitis: Causes and Correlation Between Clinical Findings and Magnetic Resonance Imaging.

The aims of this study were to describe disease associations of magnetic resonance imaging (MRI)-confirmed and clinically symptomatic sacroiliitis in pediatric patients with rheumatic diseases and to examine the relationship between patient characteristics and MRI findings of the sacroiliac joint (SIJ). Demographic and clinical data were extracted from the electronic medical records of the patients with sacroiliitis followed in the last 5 years. Active inflammatory and structural damage lesions of the SIJ-MRI were examined by the modified Spondyloarthritis Research Consortium of Canada scoring system, and correlation analysis of these results with clinical characteristics was evaluated. A total of 46 symptomatic patients were found to have MRI-proven sacroiliitis of 3 different etiologies: juvenile idiopathic arthritis (JIA) (n = 17), familial Mediterranean fever (FMF) (n = 14), and chronic nonbacterial osteomyelitis (CNO) (n = 8). Seven patients, FMF and JIA (n = 6) and FMF and CNO (n = 1), had a co-diagnosis that might cause sacroiliitis. Although inflammation scores and structural damage lesions did not statistically differ between the groups, capsulitis and enthesitis on the MRI were more frequently detected in the CNO group. There was a negative correlation between symptom onset and inflammation scores of bone marrow edema. Disease composite scores and acute phase reactants were correlated with MRI inflammation scores. We demonstrated that JIA, FMF, and CNO were the major rheumatic causes of sacroiliitis in children originating from the Mediterranean region. Quantitative MRI scoring tools can be used to assess the inflammation and damage of the SIJ in rheumatic diseases, show discrepancies between them, and have an important correlation with various clinical and laboratory features.

Diagnostic Value of Renal Duplex Doppler Ultrasonography in the Evaluation of Renal Amiloidosis Associated with Familial Mediterranean Fever

Diagnostic Value of Renal Duplex Doppler Ultrasonography in the Evaluation of Renal Amiloidosis Associated with Familial Mediterranean Fever

Dual Biologic Therapy in Patients with Familial Mediterranean Fever and Spondyloarthritis: Case-Based Review.

Patients with familial Mediterranean fever and spondylitis often fail to respond to conventional and biologic therapies. Achieving remission in these patients usually requires conventional and biologic treatment combinations. Combination of biologic agents may be a promising option for patients with familial Mediterranean fever and spondylitis who have refractory disease. Until recently, limited evidence existed regarding the efficacy and safety of this treatment strategy. To address this, our report presented a case series of 4 patients with familial Mediterranean fever and spondylitis who were resistant to standard treatments and in whom remission is achieved only with dual biologic therapy. The authors also conducted a literature search for studies that reported dual biological therapy in inflammatory diseases.

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

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. 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. 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. 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.

Importance of hematological markers in familial Mediterranean fever in terms of disease severity and amyloidosis.

There are limited follow-up parameters for familial Mediterranean fever (FMF) related to disease severity and amyloidosis. Some hematological markers are emerging to assess inflammation. In this study, we hypothesized that some hematological parameters could be used to determine disease severity and amyloidosis in FMF. We included 274 adult FMF patients, and evaluated the relationship between neutrophil lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR) and platelet-lymphocyte ratio (PLR), platelet counts and leukocyte counts, mean erythrocyte haemoglobin concentration (MCHC) and mean erythrocyte haemoglobin (MCH) with disease severity and amyloidosis. First, we classified patients according to disease severity and presence of amyloidosis. We then compared the parameters within the groups. In addition, we determined predictive cut-off values with ROC analysis. Finally, we correlated the change in ISSF scores with the change in hematological parameters of 52 patients with follow-up hematological indices after six months. The patients with severe-moderate group had higher CRP levels (p < 0.001), white blood cell (p = 0.002) and neutrophil counts (p = 0.004) and, conversely, lower MCHC levels (p = 0.001) than patients with mild disease severity. FMF patients with amyloidosis had higher neutrophil (p = 0.04) and monocyte count (p = 0.02), increased NLR (p = 0.01) and lower MLR (p = 0.02) levels than those without. In addition, MCHC levels were also lower in the severe-moderate group in the follow-up analyses after sixth months (p = 0.03). MCHC, neutrophil and monocyte counts, NLR, MLR may be associated with poor prognosis in FMF patients. These parameters can be used in conjunction with acute phase reactant and clinical features to assess disease status.

A case of Behçet's-like disease associated with trisomy 8-positive myelodysplastic syndrome presented periodic fever with MEFV E148Q variant.

Behçet's-like disease, which incompletely fulfils the criteria of Behçet's disease, is often associated with trisomy 8-positive myelodysplastic syndrome (MDS). We report a case of an 82-year-old man with these conditions carrying E148Q variant of MEFV gene who presented with periodic fever. The patient presented with joint pain, muscle pain, and episodes of periodic fever every two weeks for the past three months. On admission, painful erythema and fever were observed. Colonoscopy revealed erosion in the cecum and ascending colon. The patient had bicytopenia, and a bone marrow biopsy showed findings compatible with trisomy 8-positive unclassifiable MDS. Because the patient incompletely fulfilled the criteria for Behçet's disease, he was diagnosed with Behçet's-like disease associated with trisomy 8-positive MDS. Positron emission tomography-computed tomography performed during the fever revealed multiple muscle lesions consistent with the sites of pain. To examine the cause of the periodic fever attacks, MEFV gene was analysed, and the results revealed E148Q variant. Steroids were ineffective against periodic fever attacks. A daily dose of 0.5 mg colchicine was prescribed, but the effect was minimal, probably because of the insufficient dose due to renal dysfunction. Based on the diagnosis of atypical familial Mediterranean fever, canakinumab was added, which partially mitigated the periodic fever. This case suggests the importance of ruling out MDS when physicians see an elderly patient who present with Behçet-like disease. Although the significance of E148Q variant in the pathogenesis of periodic fever remains controversial, it may act as a disease modifier in accordance with trisomy 8-positive MDS.

MEFV gene mutation spectrum in patients with familial mediterranean fever

MEFV gene mutation spectrum in patients with familial mediterranean fever

Genotype-phenotype correlation in Jordanian children with genetically-proven familial Mediterranean fever: The effect of R202Q mutation

<h3>Background</h3> Familial Mediterranean fever (FMF) is a hereditary periodic fever syndrome inherited as an autosomal recessive pattern; nonetheless, patients with symptomatic heterozygous variants exist. This study aimed to review children with genetically-proven FMF, to describe their mutation maps and clinical characteristics, and to explore the genotype–phenotype correlation. <h3>Methods</h3> Medical charts of pediatric FMF patients who were diagnosed by both genetic mutation and clinical criteria and followed up at our hospital were reviewed. Demographic and clinical data, results of <i>MEFV</i> genetic testing, procedures, concomitant medical conditions, disease severity, and treatment response were recorded and analyzed. <h3>Results</h3> A total of 132 patients (71 females [54%]) were included in the final analysis. The average ages at presentation and diagnosis were 6.2 ± 3.1 and 7.6 ± 4.4 years, respectively. The most common clinical features were abdominal pain (n = 120, 91%), fever (n = 97, 73.5%), and arthritis (n = 75, 56.2%). Gastrointestinal endoscopy was the most frequently reported procedure (n = 27, 20.45%). The most common mutation was R202Q (n = 71, 53.8%), followed by E148Q (n = 36, 27.3%), M694V (n = 30, 22.7%), and V726A (n = 22, 16.7%). Two rare variants with potential pathogenicity were identified—namely, c.-15 and c.-330. A novel <i>MEFV</i> mutation (p. Lys629 Met) was noted. Abdominal pain, arthritis, arthralgia, and skin rashes were more common with the R202Q mutation. Patients with compound heterozygous mutations showed a higher rate of abdominal pain (94.1%) and exhibited the best response to colchicine (67.6%). Patients with complex alleles had the highest rate of fever (80%) and arthritis/arthralgia (70%). <h3>Conclusion</h3> FMF is endemic in Jordan. Genetic testing is important in FMF evaluation; however, the genotype–phenotype correlation needs further study. The R202Q mutation is possibly pathogenic and is associated with the manifestation of the full spectrum of FMF features; hence, it needs to be considered in the diagnosis of FMF patients in Jordan.

Quality of life in monogenic autoinflammatory diseases. A review.

Systemic autoinflammatory diseases (SAIDs) are a group of disorders related to defective regulation of the innate immune system. Recurrence of inflammation can severely affect the patients' outcomes with a direct or indirect impact on their physical and mental health and/or global quality of life (QoL). We therefore sought to identify currently available QoL studies for these diseases as well as measurement tools at our disposal. A systematic literature review was carried out with a focus on monogenic SAIDs. We inventoried the study designs developed in the selected publications, grouped them into similar topics, and listed the different outcome measures used for QoL. We recorded 53 bibliographic references evaluating the impact of monogenic SAIDs on the patients' QoL. These publications revealed 150 different study designs and 82 outcome measures used for their assessment. The best-explored topics were the overall patients' QoL, followed by the evaluation of their psychosocial and physical functioning. We found fair coverage of familial Mediterranean fever, poor investigation of the mixed hereditary recurrent fever (HRF) group, cryopyrin-associated periodic diseases and cherubism, and almost no study of the other monogenic SAIDs. This work revealed areas requiring further investigation such as homogenization of concepts, study of uncommon or more recent diseases, and development of more specific and validated outcome measures for SAIDs.

Co-occurrence of familial Mediterranean fever with systemic lupus erythematosus in South Asian population

Background and objectiveFamilial Mediterranean fever (FMF) and systemic lupus erythematosus (SLE) are autosomal recessive auto-inflammatory diseases, triggered by FMF-associated gene mutations and auto-antigens. The literature on the co-occurrence of these two disorders is limited to case reports and their correlation is considered rare. We investigated the proportion of FMF among SLE patients when compared with a healthy adult cohort in South Asia. MethodsFor this observational study, data from our institutional database were collected for the patients diagnosed with SLE. The control group was randomly selected from the database and were age- matched for SLE. The overall proportion of FMF among patients with and without SLE was considered. Student's t-test, Chi-square, and ANOVA were used for univariate analysis. ResultsThe study population included 3623 SLE patients and 14,492 controls. In the SLE group, there was a significantly higher proportion of FMF patients compared with the non-SLE group (1.29% vs. 0.79% respectively; p=0.015). SLE was prevalent in Pashtun's (50%) in the middle socioeconomic group while FMF was dominant in Punjabi's and Sindhi's (53%) in the low socioeconomic class. ConclusionThis investigation demonstrates that FMF is more prevalent in a South-Asian population cohort of SLE patients.

Co-occurrence of familial Mediterranean fever with systemic lupus erythematosus in South Asian population

Familial Mediterranean fever (FMF) and systemic lupus erythematosus (SLE) are autosomal recessive auto-inflammatory diseases, triggered by FMF-associated gene mutations and auto-antigens. The literature on the co-occurrence of these two disorders is limited to case reports and their correlation is considered rare. We investigated the proportion of FMF among SLE patients when compared with a healthy adult cohort in South Asia. For this observational study, data from our institutional database were collected for the patients diagnosed with SLE. The control group was randomly selected from the database and were age- matched for SLE. The overall proportion of FMF among patients with and without SLE was considered. Student's t -test, Chi-square, and ANOVA were used for univariate analysis. The study population included 3623 SLE patients and 14,492 controls. In the SLE group, there was a significantly higher proportion of FMF patients compared with the non-SLE group (1.29% vs. 0.79% respectively; p = 0.015). SLE was prevalent in Pashtun's (50%) in the middle socioeconomic group while FMF was dominant in Punjabi's and Sindhi's (53%) in the low socioeconomic class. This investigation demonstrates that FMF is more prevalent in a South-Asian population cohort of SLE patients. La fiebre mediterránea familiar (FMF) y el lupus eritematoso sistémico (LES) son enfermedades autoinflamatorias autosómicas recesivas, desencadenadas por mutaciones genéticas asociadas a la FMF y autoantígenos. La literatura sobre la coexistencia de estos dos trastornos se limita a informes de casos y su correlación se considera rara. Investigamos la proporción de FMF entre pacientes con LES en comparación con una cohorte de adultos sanos en el sudeste asiático. Para este estudio observacional se recolectaron datos de nuestra base de datos institucional para los pacientes diagnosticados con LES. El grupo control se seleccionó al azar de la base de datos y se emparejaron por edad y sexo para LES. Se consideró la proporción global de FMF entre pacientes con y sin LES. Se utilizaron la prueba t de Student, χ 2 y ANOVA para el análisis univariado. La población de estudio incluyó a 3.623 pacientes con LES y 14.492 controles. En el grupo de LES, hubo una proporción significativamente mayor de pacientes con FMF en comparación con el grupo sin LES (1,29 vs. 0,79%, respectivamente; p = 0,015). LES prevaleció en la región pastún (50%) en el grupo socioeconómico medio, mientras que FMF fue dominante en Punyab y Sind (53%) en la clase socioeconómica baja. Esta investigación demuestra que la FMF es más frecuente en una cohorte de pacientes con LES del sudeste asiático.