Experimental models in Familial Mediterranean Fever (FMF): Insights into pathophysiology and therapeutic strategies.

Familial Mediterranean Fever (FMF) is a recurrent polyserositis characterized by self-limiting episodes or attacks of fever along with serosal inflammation. It mainly impacts people of the Mediterranean and Middle Eastern basin. FMF is a recessive autoinflammatory condition caused by mutation in the MEFV gene located on chromosome 16p13. MEFV mutations lead to the activation of the pyrin inflammasome resulting in an uncontrolled release of IL-1ß. Various in vitro, in vivo and ex vivo experimental models have been developed to further comprehend the etiology and pathogenesis of FMF. These models have been proven to be clinically relevant to human FMF and can provide significant information about biological systems with respect to this condition. Additionally, these models have provided pertinent contributions to the development of potent therapeutic strategies against FMF. In this review, we describe the different experimental models utilized in FMF and we focus primarily on the most widely used models that have produced prominent insights into the pathophysiology of the disease.

Transition to Adult Care in Autoinflammatory Diseases: A Cohort of 111 French Patients.

BACKGROUND: Transitioning from pediatric to adult care is a critical step for individuals with autoinflammatory diseases, requiring effective programs to ensure continuity of care and disease management. Despite various recommendations, the effectiveness of transition programs, particularly in monogenic autoinflammatory diseases, remains understudied. METHODS: A single-center medical records review study was conducted at the French National Reference Center for Adult Autoinflammatory Diseases in Tenon Hospital from 2017 to 2023. All patients who had consulted for the first time between the ages of 15 and 30 years and had received care for an autoinflammatory disease during childhood were included. The patients were classified according to whether they had undergone a transition, defined as either no transition, simple transition (referral letter), or joint transition (pediatrician and adult physician consultation). RESULTS: One hundred eleven patients (median age, 18 years) were included. Patients who consulted without transition started adult follow-up and were followed up less regularly than those who underwent the transition process ( p < 0.001 and p = 0.028). In patients with familial Mediterranean fever, the absence of a formal transition was associated with poorer disease control at baseline ( p = 0.019). The type of transition did not impact disease control during follow-up. CONCLUSIONS: Participation in a transition program is associated with earlier and more regular follow-up in adulthood. Although transition type did not significantly impact disease control during follow-up in familial Mediterranean fever, the potential benefit of joint consultation extends beyond consultation frequency and disease outcomes, encompassing patient perspectives and self-management abilities. This study highlights the significance of collaborative transition programs in AIDs.

The effect of education given to Turkish adolescents with Familial Mediterranean fever on anxiety, depression, and quality of life.

To examine the effects of individual education given to Turkish adolescents with Familial Mediterranean fever (FMF) on anxiety, depression, and quality of life. The randomized controlled experimental study was performed on 70 adolescents aged 12-18 years who were diagnosed as having FMF between October 2021 and April 2022 in Turkey. The disease management education was offered individually to adolescents in the intervention group with a booklet entitled "FMF is under my control;" no intervention was applied to adolescents in the control group. The training booklet was prepared by the researchers in a multidisciplinary team and was finalized by taking expert opinions. In the data collection process, a personal information form, the State-Trait Anxiety Inventory for Children (STAI-CH), the children's depression inventory (CDI), and the Pediatric Quality of Life Inventory (PedsQL) were used. After applying the scales specified in the pretest, individual training was given and the posttest was performed 2 months later using the same scales. After the education, there was a statistically significant decrease in the mean CDI score of the intervention group (p < 0.05), whereas there were statistically significant increases in mean scores obtained on PedsQL and its sub-scales (p < 0.05). However, the decrease in the mean STAI-CH score of the intervention group was not statistically significant (p > 0.05). There was no statistically significant difference in the mean STAI-CH, CDI, and PedsQL scores of the control group after the education (p > 0.05).  Conclusion: The effectiveness of the individual education program for adolescents with FMF in improving quality of life and reducing levels of depression within the scope of disease management has been confirmed. It is recommended that all health professionals working with children with FMF regularly provide individual or group-planned education programs. What is Known: • The unpredictability of FMF attacks has a very negative effect on adolescents. • Individual education programs on FMF focus on children with a holistic approach. What is New: • To the best of our knowledge, this study is the first study to evaluate disease management education given to adolescents with FMF. • This is a pioneering study of the use of nurses in the education of adolescents with FMF and in fulfilling their educational roles.

Contribution of Arab Countries to Familial Mediterranean Fever Research: a PubMed-based bibliometric analysis.

Familial Mediterranean Fever (FMF) is an inherited autoinflammatory disease. One of the feared complications of FMF, amyloidosis is often correlated with an increased mortality rate. The severity of the disease is linked with different mutations in the MEFV gene that may favor different outcomes (amyloidosis, Bechet's disease…). Although several countries worldwide contribute remarkably to research related to FMF, Arab countries make up only a small part of this contribution. This study aims to estimate numerically the contribution of the Arab world to research conducted on FMF. PubMed is used to quantitate the number of FMF-related articles published by each Arab country from 2004 till 2019. The retrieved numbers are normalized with respect to each country's average population and average Gross Domestic Product (GDP) and are also compared to those of some non-Arab countries having high FMF prevalence. In comparison with some non-Arab countries, the Arab world has a minor contribution of 3.80% to the total FMF-related publications, faced by 24.93% solely by Turkey. Out of total research done by Arab countries, FMF-related articles constitute no more than 0.133%. When normalized against the average population, Tunisia ranks first, followed by Lebanon. Similarly, normalizing the retrieved numbers of articles against average GDP shows that Tunisia and Lebanon come first and second, respectively. Only 8 Arab countries published a total of 13 articles concerning amyloidosis which makes 4.7% of the total Arabic FMF published articles. This study reflects an undoubtable need for more research to be conducted on FMF by the Arab countries, which suffer greatly from immense shortage in research productivity, due to the many obstacles and limitations these countries face every day.

[Monogenic autoinflammatory diseases. An introduction on a translational mode to]. / Maladies auto-inflammatoires monogéniques. Une introduction sur un mode translationnel aux inflammasomopathies.

Autoinflammatory diseases refer to a broad spectrum of diseases that are primarily due to an abnormality in the regulation of natural immunity. Some are polygenic and highly influenced by the environment, others are monogenic. This article is devoted to a family of monogenic autoinflammatory diseases that is very important because it includes the emblematic Mediterranean familial fever, the first autoinflammatory disease described as such and which heavily affects the Eastern Mediterranean populations. We will discuss the regulatory mechanisms of inflammasomes and the impact of certain mutations on their function. General principles of treatment and diagnosis will also be discussed. Other autoinflammatory diseases (including type 1 interferonopathies and NF-?b and TNF-? axis abnormalities) deserve to be discussed later on.

: Les maladies auto-inflammatoires désignent une vaste gamme de maladies dues, avant tout, à une anomalie de régulation de l'immunité naturelle. Certaines sont polygéniques et très influencées par l'environnement, d'autres sont monogéniques. Cet article est consacré à une famille de maladies auto-inflammatoires monogéniques très importante car elle comprend l'emblématique fièvre familiale méditerranéenne, la première maladie auto- inflammatoire décrite comme telle et qui touche lourdement les populations de l'Est de la Méditerranée. Nous aborderons les mécanismes de régulation des inflammasomes et l'impact de certaines mutations sur leur fonctionnement. Les principes généraux du traitement et du diagnostic seront aussi abordés. Les autres maladies auto- inflammatoires, dont les interféronopathies de type 1 et les anomalies de l'axe NF-?b et du TNF-?, mériteraient d'être traitées ultérieurement.

Evaluation of caregiver burden and coping strategies in parents of paediatric familial Mediterranean fever patients in relation to illness severity, therapy and health-related quality of life.

PURPOSE: The study aimed to determine the caregiver burden and coping strategies in caregivers of familial Mediterranean fever (FMF) patients in relation to illness severity, therapy and health-related quality of life (HRQoL). METHODS: The study included 171 paediatric FMF patients and their caregivers (parents). The caregivers were asked to complete a socio-demographic form, the Zarit caregiver burden interview (ZCBI) and the Brief COPE. The patients and their caregivers were asked to complete the KINDer Lebensqualitätsfragebogen questionnaire (self-report and proxy report, respectively) for assessing HRQoL. The patients were categorised according to their disease activity (mild, moderate or severe) and the presence or absence of anti-IL-1 therapy. RESULTS: The mean ZCBI score of the caregivers was 44.7 ± 13.5. ZCBI and COPE scores did not differ significantly between the caregivers of FMF patients receiving and not receiving anti-IL-1 therapy. However, dysfunctional COPE (p = 0.039) and ZCBI (p = 0.021) scores showed a significant difference between the caregivers in relation to patient's disease severity. ZCBI scores were positively correlated with dysfunctional coping (p = 0.01). Self-reported HRQoL disease module scores were lower for the patients who received anti-IL-1 therapy than for those did not (p = 0.009). Proxy-reported (p < 0.001) and self-reported (p = 0.043) HRQoL disease module scores were lower for the patients with severe disease activity. CONCLUSIONS: As the caregiver burden increases, parents tend to use a dysfunctional coping strategy. Good control of disease activity with administration of medical therapy can reduce the disease severity, thereby decrease the caregiver burden, and secondly help to reduce the usage of dysfunctional coping in caregivers.

Twenty-Year Experience of a Single Referral Center on Pediatric Familial Mediterranean Fever: What Has Changed Over the Last Decade?

BACKGROUND/OBJECTIVE: Familial Mediterranean fever (FMF) is the most common autoinflammatory disease and is characterized by recurrent fever and serositis episodes. We aimed to share our 20-year FMF experience, clarify a phenotype-genotype correlation, and compare the characteristics and outcomes of pediatric FMF patients over the last 2 decades in this study. METHODS: This medical record review study included 714 pediatric FMF patients (340 females, 374 males), diagnosed by Tel Hashomer diagnostic criteria between January 2009 and January 2019 and followed up in our department. Demographic and disease characteristics, obtained from medical records of the patients, were compared between patients with M694V homozygosity and other genotypes and showed whether they were diagnosed before (n = 137) or after January 2010 (n = 577). χ2, Student t, and Mann-Whitney U tests were used to compare categorical and continuous variables between these groups. RESULTS: The most common symptoms were abdominal pain (92%), fever (89.5%), and arthralgia (64.5%). Mean ages at symptom onset and diagnosis were 5.16 ± 3.73 and 7.71 ± 3.87 years, respectively. M694V homozygosity was recorded in 111 patients (15.5%). Fever, arthralgia, arthritis, myalgia, erysipela-like erythema, colchicine resistance, and subclinical inflammation were more frequent, and mean disease severity score was higher in patients with M694V homozygosity. Fever, chest pain, and proteinuria were statistically more frequent in patients diagnosed before January 2010. Although M694V homozygosity rate was similar, patients diagnosed in the last decade had lower mean disease severity score. CONCLUSIONS: With this study, we speculate that although genotype and delay in diagnosis were similar, patients diagnosed in the last decade have a milder disease severity.

Anti-IL1 treatment in colchicine-resistant paediatric FMF patients: real life data from the HELIOS registry.

OBJECTIVES: FMF is a prototype of autoinflammatory diseases associated with excess IL1 production. Anti-IL1 treatments are the first-line alternatives in colchicine-resistant/intolerant FMF patients. We aimed to investigate the efficacy and safety of anti-IL1 treatment in paediatric FMF patients in our local [Hacettepe univErsity eLectronIc research fOrmS (HELIOS)] registry. METHODS: HELIOS is a web-based biologic drug registry for paediatric rheumatology patients. We have analysed the clinical features, disease activity parameters, treatment responses and safety outcomes in FMF patients treated with anti-IL1 agents. RESULTS: Forty paediatric FMF patients (34 continuous and six on-demand use) were included. Among the continuously treated group (61.7% female), the mean age at the start of colchicine was 5.55 (3.87) years. Age at onset of the anti-IL1 treatment was 11.47 (5.41) years with a mean follow-up duration of 3.87 (1.96) years. Apart from two, all patients had biallelic exon-10 mutations. We also gave anti-IL1 treatment on an on-demand basis in six patients. Anakinra was used as the first-line anti-IL1 treatment. During the last visit, six patients were treated with anakinra and 28 patients with canakinumab. Anti-IL1 treatment decreased the CRP levels and number and severity of the attacks. There were three hospitalizations reported due to mild infections. Eleven patients had local skin reactions, two patients had leucopenia with anakinra and one patient had thrombocytopenia with canakinumab. There was no malignancy or other severe adverse reactions. CONCLUSION: Anakinra and canakinumab are efficient and safe alternatives in colchicine-resistant or -intolerant paediatric FMF patients. We also, for the first time, report on-demand use of anti-IL1 in paediatric FMF patients.

Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever.

OBJECTIVE: FMF is an inherited autoinflammatory syndrome caused by mutations in the MEFV gene. MEFV variants are still largely classified as acvariant of uncertain significance, or with unresolved classification, posing significant challenges in FMF diagnosis. Rare Exome Variant Ensemble Learner (REVEL) is a recently developed variant metapredictor tool. To reduce the number of MEFV variants with ambiguous classification, we extracted REVEL scores for all missense variants present in the INFEVERS database, and analysed its correlation with expert-based classification and localization in the MEFV-encoded pyrin functional domains. METHODS: The data set of 216 MEFV missense variants was divided into four categories (likely benign, variant of uncertain significance, likely pathogenic and unresolved). Variants were plotted onto the pyrin protein, the distribution of REVEL scores in each category was computed and means, confidence intervals, and area under the receiver operating curve were calculated. RESULTS: We observed a non-random distribution of pathogenic variants along the pyrin functional domains. The REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases. Sensitivity, specificity and accuracy were calculated for different cut-off values of REVEL scores and a gene-specific-threshold of 0.298 was computed with confidence boundary limits. This cut-off value allowed us to propose a reclassification of 96 MEFV gene variants, thus reducing the variant of uncertain significance proportion from 61.6% to 17.6%. CONCLUSION: The combination of available expert information with sensitive predictor tools could result in a more accurate interpretation of clinical consequences of MEFV gene variants, and to a better genetic counselling and patient management.

A systematic literature review of efficacy, effectiveness and safety of biologic therapies for treatment of familial Mediterranean fever.

OBJECTIVES: To identify and summarize the existing evidence on the efficacy, effectiveness and safety of biologic therapies used, either as indicated or off-label, in the treatment of FMF. METHODS: A systematic literature review was conducted using Embase®, MEDLINE®, MEDLINE®-In Process, and Cochrane databases to identify randomized/non-randomized controlled trials (RCTs/non-RCTs) and real-world observational studies of FMF published as full-text articles (2000-September 2017) or conference abstracts (2014-September 2017). Studies with data for ≥1 biologic were included. Studies with <5 patients were excluded. RESULTS: Of the 3342 retrieved records, 67 publications, yielding 38 unique studies, were included. All studies were published after the year 2010, and the majority (21) were full-text articles. Most studies (33/38) were prospective/retrospective observational; three were double-blind, placebo-controlled RCTs (one each of anakinra, canakinumab and rilonacept); and two were non-RCTs (both canakinumab). Anakinra (26), canakinumab (21) and etanercept (6) were the most frequently used biologics across studies, whereas use of adalimumab, tocilizumab, rilonacept and infliximab was limited (1-2 studies). The available evidence suggested benefits of anakinra and canakinumab in FMF. CONCLUSION: Anti-IL-1 therapies (i.e. anakinra and canakinumab) appear to be effective and safe options in the treatment of overall FMF, including patients with colchicine resistance and FMF-related amyloidosis. There is a need for properly designed prospective or controlled studies to conclude the superiority of one anti-IL-1 therapy over another. Evidence on the use of TNF-α and IL-6 inhibitors is limited, and further research is suggested.

Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review

Familial Mediterranean fever (FMF) (OMIM #249100) is the most common hereditary autoinflammatory disease in the world. FMF is caused by gain of function mutations of MEFV gene which encodes an immune regulatory protein, pyrin. Over the last few years, we have witnessed several new developments in the pathogenesis, genetic testing, diagnosis, comorbidities, disease related damage and treatment approaches to FMF. Elucidation of some of the pathogenic mechanisms has led to the discovery of pathways involved in inflammatory, metabolic, cardiovascular and degenerative diseases. The use of next generation sequencing in FMF has revealed many new gene variants whose clinical significance may be clarified by developing functional assays and biomarkers. Clinically, although FMF is considered an episodic disease characterized by brief attacks, recent systematic studies have defined several associated chronic inflammatory conditions. Colchicine is the mainstay of FMF treatment, and interleukin (IL)-1 antagonists are the treatment of choice in refractory or intolerant cases. Experience of IL-1 antagonists, anakinra and canakinumab, is now available in thousands of colchicine resistant or intolerant FMF patients. In this contemporary review, we surveyed current FMF knowledge in the light of these recent advances.

Autoinflammation: Lessons from the study of familial Mediterranean fever.

Autoinflammatory disorders represent a heterogeneous group of systemic inflammatory diseases caused by genetic or acquired defects in key components of the innate immunity. Familial Mediterranean fever (FMF) is the most common among the other clinical phenotypes of the rare hereditary periodic fevers (HPFs) syndromes. FMF is associated with mutations in the MEFV gene encoding pyrin and is characterized by recurrent, often stress-provoked attacks of fever and serositis, but sometimes also by chronic subclinical inflammation. FMF is prevalent in Greece and other countries of the eastern Mediterranean region. Over the last 17 years, our group has focused on FMF as a model suitable for the research on innate immunity and particularly the role of neutrophils. Therefore, the study of Greek patients with FMF has yielded lessons across several levels: the epidemiology of the disease in Greece, the spectrum of its clinical manifestations and potential overlaps with other idiopathic inflammatory conditions, the demonstration of its rather complex and heterogeneous genetic background and the suggestion of a novel mechanism involved in the crosstalk between environmental stress and inflammation. Mechanistically, during FMF attack, neutrophils release chromatin structures called neutrophil extracellular traps (NETs), which are decorated with bioactive IL-1ß. REDD1 (regulated in development and DNA damage responses 1), that encodes a stress-related mTOR repressor, has been found to be the most significantly upregulated gene in neutrophils during disease attacks. Upon adrenergic stress, REDD1-induced autophagy triggers a pyrin-driven IL-1ß maturation, and the release of IL-1ß-bearing NETs. Consequently, not only the mode of action of IL-1ß-targeting therapies is explained, but also new treatment prospects emerge with the evaluation of old or the design of new drugs targeting autophagy-induced NETosis. Information gained from FMF studies may subsequently be applied in more complex but still relevant inflammatory conditions, such as adult-onset Still's disease, gout, ulcerative colitis and Behçet's disease.

Potential of miRNAs to predict and treat inflammation from the perspective of Familial Mediterranean Fever.

AIM: microRNAs (miRNAs) are small noncoding RNAs that play critical roles in physiological networks by regulating host genome expression at the post-transcriptional level. miRNAs are known to be key regulators of various biological processes in different types of immune cells, and they are known to regulate immunological functions. Differential expression of miRNAs has been documented in several diseases, including autoinflammatory and autoimmune diseases. This review aimed to focus on miRNAs and their association with autoimmune and autoinflammatory diseases. METHODS: All related literature was screened from PubMed, and we discussed the possible role of miRNAs in disease prediction and usage as therapeutic agents from the perspective of Familial Mediterranean Fever (FMF). CONCLUSIONS: FMF is an inherited autosomal recessive autoinflammatory disease caused by mutations in the MEditerranean FeVer (MEFV) gene, which encodes the protein pyrin. Recent studies have demonstrated that miRNAs may be effective in the pathogenesis of FMF and offer a potential explanation for phenotypic heterogeneity. Further understanding of the role of miRNAs in the pathogenesis of these diseases may help to identify molecular diagnostic markers, which may be important for the differential diagnosis of autoinflammatory diseases. Studies have shown that in the near future, traditional therapies in autoinflammatory diseases may be replaced with novel effective, miRNA-based therapies, such as the delivery of miRNA mimics or antagonists. These approaches may be important for predictive, preventive, and personalized medicine.

Evaluation of the Burden of Care and the Quality of Life in the Parents of Turkish Children with Familial Mediterranean Fever.

PURPOSE: This study aimed to determine the burden of care and the quality of life in caregivers of children with FMF. DESIGN AND METHODS: A cross-sectional study was conducted. Caregivers of the 109 children with FMF followed by a pediatric nephrology department were invited to join the study. Besides demographic information, the Zarit Care Burden Scale (ZCBS) and the World Health Organization Quality of Life Questionnaire-Short Form (WHOQOL-BREF) were used to collect data. Results for 90 patients were analyzed. RESULTS: The mean (±SD) ZCBS score of the caregivers was 44.78 ±â€¯13.55. Care burden of the caregivers according to the ZCBS was categorized as; 61.1% (n = 55) mild, 25.6% (n = 23) moderate, and 13.3% (n = 12) severe. Although single caregivers were perceived as having a relatively higher burden than those who were married (80% and 36%), this difference was not significant. There were no statistically significant differences between ZCBS categories concerning caregivers' gender, educational status, and having comorbidities (p > 0.05). Also, there were no significant correlations between ZCBS and the WHOQOL-BREF domains (p > 0.05). CONCLUSION: This study showed that the quality of life of the caregivers of children with FMF was not adversely affected, but a significant number of caregivers perceived care burden in moderate severity. Attention should be paid to the needs of caregivers, and they should be provided with adequate social, economic, physical, and psychological support. PRACTICE IMPLICATION: Responsive strategies to support caregivers' should be taken as means of social, economic, physical, and psychological needs.

[Evidence-based treatment recommendations for familial Mediterranean fever : A joint statement by the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. / Evidenzbasierte Therapieempfehlungen für das familiäre Mittelmeerfieber : Eine gemeinsame Stellungnahme der Gesellschaft für Kinder- und Jugendrheumatologie und der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Familial Mediterranean fever (FMF) in Germany is a rare, genetically linked disease of childhood and adolescence, which is characterized by recurrent febrile episodes and clinical signs of peritonitis, pleuritis and arthritis. Treatment with colchicine is effective and well-tolerated in the majority of patients; however, some patients do not sufficiently respond to this treatment or are intolerant to colchicine. For these patients first-line treatment with biologics which block interleukin-1 can be used. OBJECTIVE: The aim was to formulate evidence-based treatment recommendations for patients with an insufficient response and intolerance to colchicine treatment. METHODS: Based on a literature search and the European League Against Rheumatism (EULAR) recommendations on FMF from 2016 the appointed members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Rheumatology (DGRh) convened to work out and form a consensus in a joint statement on evidence-based treatment recommendations on FMF. RESULTS: After intensive discussions all decisions were in concordance. A total of 5 superordinate principles and 10 recommendations were agreed upon. DISCUSSION: The joint activities of the GKJR and the DGRh were successfully concluded in a timely manner. The recommendations form a good basis for optimal treatment of all age groups of patients with FMF.

A novel assessment tool for clinical care of patients with autoinflammatory disease: juvenile autoinflammatory disease multidimensional assessment report.

OBJECTIVES: To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care. METHODS: The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report. RESULTS: 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989). CONCLUSIONS: The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.

[Case report of a combination of periodic disease and irritable bowel syndrome].

The article reports a case of atypical picture of a combination of periodic disease and irritable bowel syndrome in a 52 year old patient.

Familial Mediterranean fever with a single MEFV mutation: comparison of rare and common mutations in a Turkish paediatric cohort.

OBJECTIVES: Presence of common MEFV gene mutations strengthened the diagnosis of FMF in addition to the typical clinical characteristics of FMF. However, there are also rare mutations. P369S, A744S, R761H, K695R, F479L are the main rare mutations in Turkish population. We aimed to evaluate FMF patients with a single allele MEFV mutation and to compare patients with common and rare mutations. METHODS: We retrospectively reviewed the medical records of FMF patients with a single allele mutation who were followed up between 2008 and 2013 in six centres. We compared the patients with rare and common mutations for disease severity score, frequent exacerbations ( >1 attack per month), long attack period (>3 day), symptoms, age at the onset of symptoms, gender, consanguinity, and family history. RESULTS: Two hundred and seventeen patients (M/F=101/116) with the diagnosis of FMF and single mutation were included. Heterozygote mutations were defined as common (M694V, V726A, M68OI) and rare mutations (A744S, P369S, K695R, R761H, F479L). Sixty-seven patients (27 males, 40 females) had one single rare mutation and 150 (74 males, 76 females) had one single common mutation. No difference was found between the rare and common mutations with respect to the disease severity score. There was no significant difference between common and rare heterozygote form of mutations in terms of disease severity. CONCLUSIONS: Patients with typical characteristics of FMF, with some rare mutations (A744S, P369S) should be treated in the same manner as patients with a common mutation.

Resolution of polyserositis after removal of appendix mucinous cystadenoma.

Mucinous cystadenoma is a rare benign neoplasm and is usually discovered incidentally. Pleuritis and pericarditis, inflammation of the pleura and pericardium, may represent manifestations of autoimmune disorders especially in female subjects. We report a patient with polyserositis that was resolved after removal of the mucinous cystadenoma. To the best of our knowledge, this is a first report describing pleuritis and pericarditis as an initial presentation of mucinous cystadenoma of an appendix. A forty-year-old Caucasian female patient with a history of pleuritis and recurrent pericarditis was admitted to the hospital due to acute abdomen. At that time she was taking indomethacin and colchicine due to pericarditis that was controlled only with the combination of these two drugs. The patient had elevated erythrocyte sedimentation rate (ESR), increased C-reactive protein (CRP) and normocytic anemia. Immunological tests, including antinuclear antibody, anti-neutrophil cytoplasmic antibody, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies, were repeatedly negative. Emergency surgery revealed acute appendicitis with perforation and subsequent diffuse peritonitis. Histopathological examination showed acute appendicitis and mucinous cystadenoma. Following the surgery the patient did not take any drugs. Fourteen months later the patient was symptom free. Pleuritis and pericarditis in female patients are most often associated with autoimmune diseases. We assume that increased ESR and CRP with anemia detected in the patient may reflect the altered immunity that is due to mucinous cystadenoma. We believe that this report has a broader clinical impact, implying that benign tumor could alter immunity, which can lead to unusual presentation such as polyserositis.

Patient with Recurrent Polyserositis (Familial Mediterranean Fever).

Familial Mediterranean fever (FMF) is a hereditary autosomal recessive ,systemic, auto-inflammatory disorder characterized by sporadic, unpredictable attacks of fever and serosal inflammation. FMF is caused by mutations in MEFV, a gene located on the short arm of chromosome 16 (16p13) which encodes a protein 'Pyrin'. The disorder has been given various names including familial paroxysmal polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, and periodic disease or periodic fever, As the name indicates, FMF occurs within families and is much more common in individuals of Mediterranean descent than in persons of any other ethnicity. It has been described in several ethnic groups including Sephardic Jews, Armenians, Turks, North Africans, Arabs, Greeks, and Italians. However, the disease is not restricted to these groups and sporadic cases have been reported. Diagnosis is usually clinical and it classically presents with unprovoked, recurrent attacks of fever and painful polyserositis mainly affecting the peritoneum (most common), synovium, and pleura that usually (but not always) begin in childhood. We present a atypical case of FMF with type 1 Diabetes Mellitus and FMF who had no fever, Mediterranean ancestory or family history and discuss his clinical features,diagnosis and management.