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This study aimed to investigate the disease characteristics of familial Mediterranean fever (FMF) patients undergoing dose optimisation and discontinuation of canakinumab therapy. A total of 61 patients diagnosed with FMF and using canakinumab for the resistant disease were enrolled on this retrospective study. Patients' characteristics, disease activity, treatment response, dose optimisation, dose intervals, attack-free periods, drug-free periods and side effects were noted. Dose intervals were extended in patients who achieved remission without being bound by any protocol at the discretion of the rheumatology physician who followed up with the patients in the outpatient clinic. The drug was discontinued in some patients whose dose intervals were 2 months or longer and remained in remission for 6 months or longer. A total of 57 patients (56% female, median age 32.4 years) were included. The mean attack frequency before canakinumab was 3.4/6 months, while it was 1.2 at the last post-treatment visit (p 0.001). The median duration of canakinumab use was 46 months. After the first 6 months, the dosing interval was extended in 22 patients, and then treatment was discontinued in 12 of them who did not have an attack in the last 6 months. Three of the 12 patients whose treatment was discontinued started monthly treatment again after their attacks recurred. In the remaining ten patients, dose intervals were extended to 8-12 weeks after 6 months of monthly treatment. Nine patients are still being followed up without attacks and receive only colchicine therapy. Canakinumab is a safe and effective treatment, dose intervals may be extended, and follow-up without medication may be possible for eligible patients. However, there is a need for a consensus on dose optimisation or tapering.

Familial Mediterranean fever (FMF) is a hereditary auto-inflammatory disease resulting from mutations of the MEFV gene. The disease is characterised by recurrent attacks of abdominal pain and fever. Most FMF patients develop arthritis at some point in their life usually manifesting as self-limiting monoarthritis. On very rare occasions, arthritis in FMF can mimic septic arthritis (pseudo-septic arthritis) with very similar clinical and laboratory findings. We report a case of a young male patient who presented with recurrent attacks of prolonged monoarthritis. For 2 years, he had undergone multiple admissions and operations for drainage of suspected septic joints. The synovial aspiration showed culture-negative pus with very high synovial white blood cell counts highly suggestive of septic arthritis. The patient was later found to have FMF based on homozygous M694V mutation of the MEFV gene. He was treated with colchicine monotherapy with a quick improvement of arthritis and later good control of his disease. The literature review showed very few case reports with similar presentations, most of which responded well to colchicine. FMF can mimic septic arthritis resulting in unnecessary expensive and invasive interventions and prolonged courses of antibiotics. Pseudo-septic arthritis is usually associated with M694V homozygous mutation and can complicate FMF at any time throughout the disease course. It is important to consider FMF in the differential diagnosis of septic arthritis, particularly with a family history of FMF and in patients from communities with a high prevalence of MEFV gene mutation.

Familial Mediterranean fever (FMF) is a hereditary, autoinflammatory disease characterized by recurrent fever and serositis attacks. The disease onset occurs before 20 years of age in 90% of patients and rarely after the 4th decade. The aim of this study is to screen our FMF patient pool for patients with disease onset after age of 40 and to compare them to patients with early onset with regard to clinical and genetic features. The charts of 2020 patients registered in our FMF center in the years 2008-2017 were screened with regard to age of disease onset. Patients with disease onset after the age of 40 were considered as late-onset group (Group 1). The control group (Group 2) consisted of patients with a disease onset before the age of 20 who were randomly selected from the patient pool with twice the number of probands. Demographic, clinical and genetic data were recorded. Out of 2020 patients, the attacks of FMF had started after the fourth decade in 41 patients (2.02%), (Group 1). The male to female ratio was 1:1.7 in both groups. The delay of diagnosis was 5.6 ± 5.75 years in group 1, 10.7 ± 12.3 years in group 2. The only significant difference with regard to clinical features between two groups was the frequency of fever, which was present in 26 (63.4%) patients in group 1 and 67 (81.7%) in group 2 (p = 0.026). M694V mutation was more prevalent among early-onset group whereas exon 2 variants were more frequent in patients with late onset. The mean colchicine dose in the last 6 months was 1.38 ± 0.64 mg in group 1, and 1.61 ± 0.47 mg in group 2. FMF may start after 40 years of age in approximately 2% of the patients. Lower frequency of fever, lower daily colchicine dose and lower prevalence of exon 10 mutations point out that FMF patients with a disease onset after 40 years of age experience a milder disease compared to those with an onset before the second decade of life.

Objective We aimed to find out the asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence among pediatric patients with rheumatic diseases and healthy children and to compare them with each other. Methods Patients with familial Mediterranean fever (FMF), juvenile idiopathic arthritis (JIA), and juvenile systemic lupus erythematosus (jSLE) and healthy children as healthy control (HC) group who remained asymptomatic during the pandemic are examined by ELISA immunoglobulin (Ig) A and IgG tests in this cross-sectional study. Results Overall, 149 subjects (90 females) were included in the study. While IgA was positive in 15 subjects (10%) (HC: 8, jSLE: 3, FMF: 2, JIA: 2; p = 0.196), IgG was positive in 14 subjects (9.4%) (HC: 7, JIA: 5, FMF: 1, jSLE: 1; p = 0.156). Nineteen subjects (12.75%) were IgA or IgG positive (HC: 8, JIA: 5, jSLE: 3, FMF: 3; p = 0.644). Although not significant, seropositivity was more often in HC group. Both IgA and IgG positivity were not found to be related to age, sex, underlying rheumatic diseases, and received treatments of the patients. Conclusion We revealed that patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication such as biologic or conventional disease-modifying anti-rheumatic drugs, might have an asymptomatic SARS-CoV-2 infection, similarly to their healthy peers. Key points• Although it has been already known that children are most likely to have asymptomatic SARS-CoV-2 infection, there is a lack of data on the disease course of children with rheumatic disease.• There was no significant difference regarding the asymptomatic SARS-CoV-2 seropositivity rates between healthy children and the patients with childhood-onset rheumatic diseases.• Patients with childhood-onset rheumatic diseases, even if they receive immunosuppressive medication, might have asymptomatic SARS-CoV-2 infection, similarly to their healthy peers.

Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disease, caused by recessively inherited MEFV gene mutations. The most frequent MEFV mutations differ in penetrance and disease severity. We investigated the genotype-phenotype associations of the three most frequent MEFV gene mutations (M680I, M694V, and V726A) in Egyptian FMF children, regarding clinical features, severity, and colchicine response.We conducted a retrospective analysis of the medical registries of 500 FMF pediatric patients from Metropolitan Cairo between 2010 and 2015. The diagnosis was based on the Tel-Hashomer clinical diagnostic criteria. Clinical data and baseline investigations were collected. Mutation analysis was performed by the amplification-refractory mutation system (ARMS)-PCR method.Males represented 54% and ages ranged from 2 to 18 years. The most frequent symptoms were abdominal pain, fever, and arthralgia. Clinical features mostly associated with M694V mutation either homozygous or heterozygous whether simple, double, or triple. Of the patients, 94.6% completely responded to colchicine. Among patients benefiting from colchicine, 42.5% had M694V/V726A, 21.6% had M694V/V726A/M680I, and 21.1% had M694V genotype. Simple heterozygous M694V or V726A mutations conveyed a moderate phenotype in 57.1% and 50% of cases, respectively. Homozygous M694V mutation showed moderate and severe phenotypes in 21.7% and 65.2% of cases, respectively. Compound M694V/V726A mutation associated with moderate or severe disease in 48.3% and 33.8% of cases, respectively.This study encompasses the largest group of Egyptian pediatric FMF up to date to explore their genotype-phenotype associations. Our results support the notion that the genotype influences the phenotype as regards clinical manifestations, disease severity, and colchicine response.• This study encompasses the largest group of Egyptian pediatric patients affected by FMF up to date to explore their genotype-phenotype associations. • Our results support the notion that the genotype influences the phenotype as regards the clinical manifestations, the disease severity, and the response to colchicine treatment.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever and serositis. Periodic febrile attack can be managed with biologic medication in colchicine-resistant FMF patients, however, no reports or guidelines exist regarding the postoperative management of elective joint surgery in these patients. Although it is not clear how FMF attacks are triggered, they may be precipitated by stress including anesthesia or surgery. This study reports the case of a 51-year-old FMF patient who received total hip replacement under canakinumab (a specific interleukin-1β monoclonal antibody) treatment. He had highly active FMF, which was resistant to colchicine; however, his recurrent febrile attack with serositis was successfully controlled with canakinumab. Four months later from the start of canakinumab treatment, his hip osteoarthritis was required for total hip replacement (THR) because of the traumatic fracture. THR was successfully done and FMF attack was not occurred after this elective surgery. Discontinuation of canakinumab 3 weeks before surgery and resumption 6 weeks after led to favorable outcome without complications. This case addresses the differential management concerning stopping and restating of canakinumab in the perioperative setting in contrast to the other biologics such as tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) blocking agents. This case report suggests that canakinumab may represent a safe and effective therapy for the colchicine-resistant FMF, even in the patients requiring THR therapy.

Familial Mediterranean Fever (FMF) is a rare, hereditary, auto-inflammatory disease. The aims of this study were to explore the time trend and geographical distribution of hospitalizations in Spain from 2008 to 2015. We identified hospitalizations of FMF from the Spanish Minimum Basic Data Set at hospital discharge, using ICD-9-CM code 277.31. Age-specific and age-adjusted hospitalization rates were calculated. The time trend and the average percentage change were analyzed using Joinpoint regression. Standardized morbidity ratios were calculated and mapped by province. A total of 960 FMF-related hospitalizations (52% men) were identified across the period 2008–2015, with an increase in hospitalizations of 4.9% per year being detected (p < 0.05). The risk of hospitalization was higher than expected for the national total (SMR > 1) in 13 provinces (5 in the Mediterranean area), and lower (SMR < 1) in 14 provinces (3 in the Mediterranean area). There was an increase in hospitalizations of patients with FMF in Spain throughout the study period, with a risk of hospitalization that was higher, though not exclusively so, in provinces along the Mediterranean coast. These findings contribute to the visibility of FMF and provide useful information for health planning. Further research should take into account new population-based information, in order to continue monitoring this disease.

Objectives No studies examined the lower extremity–related anaerobic exercise capacity or functional status in adult patients with FMF. Methods Twenty-four patients with FMF (12 males) and 24 age–sex-matched healthy controls (13 males) were included in the study. Lower extremity–related anaerobic exercise capacity was assessed by using Wingate Anaerobic Test. Lower extremity–related functional status was examined by using 9-Step Stair Climb Test, 10-Repetition Chair Stand Test, and Six-Minute Walking Distance. Muscle strength of hip flexors, hip extensors, knee flexors, and knee extensors were evaluated by using a hand-held dynamometer. Results Patients with FMF had significantly poorer results in all anaerobic exercise capacity parameters and functional status assessments (P 0.05). Both average and peak anaerobic exercise capacities correlated significantly with all muscle strength measurements, 9-Step Stair Climb Test, 10-Repetition Chair Stand Test times, and Six-Minute Walk Distances (P Conclusion Lower extremity–related anaerobic exercise capacity and functional status seem to be diminished in adult patients with FMF. Evaluating these parameters may be beneficial for planning more appropriate and individualized treatment regimens such as patient education and exercise counselling for patients with FMF.

Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory disease. This study aimed to evaluate the risk of subclinical vascular damage in FMF children, and young adults, using both imaging and laboratory tests. Forty-five FMF patients (mean age 14.3 ± 9.5 years, 33 children) and 44 healthy controls(mean age 13.3 ± 8.6 years, 36 children) were included in the study. The patients were diagnosed according to Tel-Hashomer criteria, were positive for MEFV gene mutation, were treated with colchicine and were evaluated during an attack free-period. The arterial stiffness parameters studied were carotid-femoral pulse wave velocity (PWV), Augmentation Index (Aix), subendocardial viability ratio (SEVR) and carotid intima-media thickness (cIMT). Laboratory parameters, inflammation markers and lipid profile were also evaluated for all participants. There were no significant differences between patients and healthy individuals, as well as in our children population regarding PWV, SEVR, Aix and cIMT. However, significantly higher ESR, CRP and fibrinogen levels were detected in the total population of FMF patients and higher amyloid levels in FMF children, compared to controls. Atherogenic Index of Plasma was significantly higher both in the total patient population and in the subgroup of children, compared to controls. Furthermore, a significant positive correlation between Aix and CRP and a negative correlation between SEVR and ESR became apparent in the pediatric subgroup. Our study demonstrated no significant differences in vascular measurements between FMF patients and controls. The above could be attributed to the regular colchicine treatment, which seems to have a cardioprotective role against vascular damage.

The impact of the COVID-19 pandemic, and implemented restrictions on the frequency of pediatric rheumatic diseases remain unknown, while they have probably prevented common infections in children. We present the effects of the COVID-19 on our pediatric rheumatology practice in a main referral center. We retrospectively reviewed the medical records of patients presenting to pediatric rheumatology department in 4 years before March 2020 and compared it to the pandemic year (March 2020–March 2021). Since there was an overall decrease in patient numbers, we calculated the percentage according to the total number of that year. A total of 32,333 patients were evaluated. The mean annual number of patients decreased by 42% during the COVID-19 pandemic. When follow-up visits (25,156) were excluded, there were 2818 new diagnoses of rheumatic diseases. In the pre-pandemic period, familial Mediterranean fever (FMF) (n = 695, 28.1%) was the most frequent, whereas in the pandemic period multisystem inflammatory syndrome in children (MIS-C) (n = 68, 19.2%) was the most common diagnosis. There were no significant differences in the percentages of juvenile idiopathic arthritis, autoimmune diseases, rare autoinflammatory diseases, and other vasculitides. However, there was a significant decrease in patients diagnosed with FMF, IgA vasculitis (IgAV), acute rheumatic fever (ARF), classic Kawasaki disease (KD), and macrophage activation syndrome (MAS) (all p

Objectives The aims of this study were to describe the clinical features, comorbidities and outcome of systemic childhood polyarteritis nodosa (PAN) and to evaluate PAN-like diseases in differential diagnosis. Methods The study group consisted of patients who were diagnosed as PAN in a referral center in Turkey. The files of all patients were reviewed retrospectively. Disease activity was evaluated with pediatric vasculitis activity score (PVAS). Results A total of 19 (13 boys/six girls) patients were enrolled in the study. The mean age of patients was 10.37 ± 3.6 years. The mean duration of follow-up was 5.73 ± 3.74 years. Eight patients (42.1%) were also diagnosed with familial Mediterranean fever (FMF). The cutaneous involvement was higher in patients with PAN than those with FMF-associated PAN (p = .03). The median (min–max) PVAS at diagnosis was 5 (3–7). There was no correlation between PVAS scores at the time of diagnosis and age, clinical findings and relapse. CECR1 mutation was detected in one patient leading to deficiency of adenosine deaminase 2. Conclusion The clinical presentation is variable in children with PAN. PAN-like diseases characterized by necrotizing vasculitis should be considered. The possibility of FMF should be kept in mind if inflammation cannot be controlled.

OBJECTIVES To analyse the entity of retinal vasculitis, including frosted branch angiitis (FBA), or retina vascular occlusion in patients with familial Mediterranean fever (FMF). METHODS Retrospective collaborative case series using invitation by email to uveitis specialists around the Mediterranean basin. This series was combined with a literature review. Exclusion criteria included infectious diseases, Behcet's disease or other autoimmune diseases. RESULTS A total of 16 patients (21 eyes) had FMF and retinal vasculitis (FBA 11 patients, mild retinal vasculitis 5 patients). The mean age at onset of vasculitis was 29.5 ± 13.4 (range 9-62) with a female to male ratio of 9 to 7. In 19 eyes treated with various forms of corticosteroid and/or immunosuppression, the mean initial spectacle-corrected visual acuity improved from 6/194 to 6/10.5 at the last mean follow-up of 29.0 ± 34.9 months (p

Background/aim Compared to healthy controls, mean platelet volume (MPV) is frequently higher in patients with Familial Mediterranean fever (FMF) but lower in AA amyloidosis patients. The reason for the difference in MPV levels in FMF patients with and without AA amyloidosis is unclear. The aim of the study was to determine whether low MPV is unique to AA amyloidosis or MPV is similarly low in all glomerular diseases as a result of proteinuria and/or renal dysfunction. Materials and methods We compared pre-biopsy MPV levels of patients with AA amyloidosis secondary to FMF, to MPV levels of patients with membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS) and IgA nephropathy that all present with proteinuria and renal dysfunction. Results 703 patients (411 male, 292 female) were included in the study. Mean age was 42.6  14.3 years. There were 124 patients with AA amyloidosis, 224 patients with IgA nephropathy, 188 patients with membranous glomerulonephritis, and 167 patients wit h FSGS. Patients with AA amyloidosis had lower MPV levels compared to patients without AA amyloidosis (7.9  1.2 fL vs. 8.2  0.9 fL respectively, p = 0.008). Patients with AA amyloidosis had significantly lower MPV compared to patients with each of the othe r diagnoses. Independent predictors of MPV were platelet count (β = –0.321, p < 0.001) and CRP (β = – 0.134, p < 0.03). Conclusion This study is the largest study of MPV in patients with biopsy proven AA amyloidosis and confirms previous studies reporting low MPV in AA amyloidosis. This study indicates that low MPV in AA amyloidosis cannot be explained with proteinuria and renal dysfunction.

As an autosomal recessive autoinflammatory disease, treatment of Familial Mediterranean fever (FMF) has still gaps. Clinical studies are proving the safety and efficacy of colchicine in patients with FMF. However, there are very limited data on colchicine-resistant patients treated with canakinumab. This study presents the real-life experience of two rheumatology clinics choosing canakinumab in adult patients with FMF resistant to standard therapy. Treatment-resistant FMF patients with validated diagnoses enrolled from two rheumatology clinics. A special database was generated for the study and patients' demographic characteristics, FMF attack characteristics, adverse events seen during treatment, family history, MediterraneanFeVer (MEFV) mutations, and laboratory results recorded. Patients with missing dates were excluded from the analysis. PRAS score is used to assess the disease activity. A total of thirty colchicine and/or anakinra-resistant patients were enrolled to study. Twenty-one patients were female (70%) and the average disease duration was 21 years. The time from colchicine to anakinra was 4.27 years and the time to canakinumab was 1.52 years. Abdominal pain (100%), fever (93.3%), chest pain (56.7%) were the most prevailed findings. Morning stiffness, myalgia, low back pain, chest pain was the predominant musculoskeletal findings. Median colchicine dose was 2 mg/day (min–max 0.5–3 mg/day). The most common side effect during anakinra treatment, apart from treatment unresponsiveness, was injection site reactions. Before canakinumab treatment, the mean number of attacks was 8.3 in the 24 weeks, 4.33 in the third month of canakinumab treatment, and 1.56 at the last visit (p

Chest symptoms and pleural effusion due to serositis in familial Mediterranean fever (FMF) are occasionally misdiagnosed as acute pneumonia. However, the actual pulmonary involvement of FMF is extremely rare. A 67-year-old man was referred to our hospital due to repeated and transient anterior chest pain. Chest images revealed a moderate amount of pericardial fluid, slight bilateral pleural effusion, and infiltrations in both lower lung lobes. Colchicine treatment without antibiotics rapidly improved these symptoms and findings. Pericarditis, pleurisy and the response to colchicine indicated FMF. FMF should be considered as a causative disease of pulmonary infiltrations, especially if it occurs repeatedly.

Background/aim: Familial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia. Materials and methods: All patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine nonresponsiveness, amyloidosis, and persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using international severity score for FMF (ISSF) and autoinflammatory disease damage index (ADDI), respectively. Results: Among 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p > 0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p = 0.006 and 0.004, respectively). Conclusion: Our findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.

Light chain (AL) amyloidosis is a multisystem disorder with a high early mortality and diagnostic delays of >1 year from symptom onset. This retrospective observational study sought to characterize the clinical prodrome and diagnostic delay to inform early detection. We identified 1,523 adults with newly diagnosed AL amyloidosis in the Optum de-identified Clinformatics® Datamart US health care claims database as those with ≥2 new diagnosis codes for AL or other amyloidosis in 90 days with ≥1 multiple myeloma treatment within 730 days, excluding patients with prior hereditary or secondary amyloidosis and Familial Mediterranean Fever. We considered 34 signs/symptoms using diagnosis codes in all observable time on or before AL amyloidosis diagnosis. Sign/symptom prevalence was compared to that of 1:4 matched population controls. The overlap and sequence of signs/symptoms and the median time from first sign/symptom to AL amyloidosis diagnosis were explored. Health care utilization was summarized. The most common individual AL amyloidosis signs/symptoms were malaise/fatigue (61%) and dyspnea (59%). Cardiac signs/symptoms were observed in 77% of patients, followed by renal (62%) and nervous (59%) signs/symptoms. Multisystem involvement (≥3 systems) was present in 54%. Monoclonal gammopathy was detected in 29% before diagnosis. Median time from symptom onset to AL amyloidosis diagnosis was 2.7 years. Health care utilization was high between first AL amyloidosis signs/symptoms and diagnosis, with 50% visiting ≥5 physician types. AL amyloidosis patients have a lengthy and complex clinical prodrome. Novel approaches to early diagnosis are needed to improve outcomes.

Objectives To evaluate the incidence of hospitalization for coronavirus disease 2019 (COVID-19) in patients with FMF, as compared with the general population, and to compare the disease course between FMF inpatients, and age-, sex-, ethnicity- and comorbidity-matched non-FMF COVID-19 inpatients. Methods We used electronic medical records to obtain data about the total number of the insured population and the number of FMF patients in the two largest health management organizations in Jerusalem, Clalit and Meuhedet. The total number of COVID-19 inpatients at the Hadassah Medical Center, including those with FMF, for the period between 1 February 2020 and 10March 2021, was retrieved from the electronic medical records of Hadassah. COVID-19 course was compared between the FMF inpatient group and age-, sex-, ethnicity- and comorbidity-matched non-FMF COVID-19 inpatients. Each FMF inpatient was matched with two non-FMF controls. Results We found no statistically significant difference in the odds of hospitalization for COVID-19 between FMF patients and the non-FMF population (0.46% vs 0.41%, P = 0.73). Furthermore, we found similar disease severity and therapeutic approach in FMF COVID-19 inpatients and matched non-FMF COVID-19 inpatients. Conclusions Neither FMF nor baseline colchicine therapy, appear to affect the incidence of hospitalization for COVID-19 or the disease course, in terms of severity and therapeutic approach.

Current data demonstrated that severe cases of coronavirus-disease-19 (COVID-19) require treatment with antiviral therapy, dexamethasone, supportive care, as well as some anti-rheumatic drugs, among them, cytokine inhibitors and colchicine. Colchicine is an anti-inflammatory drug that is being used in rheumatology for many years to treat mostly gout, calcium pyrophosphate deposition disease, and Familial Mediterranean Fever. Here, we present for the first time, two patients suffering from gout being treated with colchicine, who were affected from severe acute respiratory coronavirus-2 (SARS-CoV-2) syndrome. Both patients presented with mild symptoms of COVID-19 expressed with myalgias, arthralgias, and sore throat, while laboratory investigations showed only high acute phase reactants. Four weeks later, both patients were free of symptoms with negative SARS-CoV-2 tests and without any complications. To our knowledge, there are no other studies of gout arthritis and SARS-CoV-2 infection published so far. Thus, our preliminary conclusion is that chronic use of colchicine may mitigate the clinical picture and disease course of COVID-19 in gout arthritis patients. Further studies with a large number of patients are needed to confirm the above beneficial effect of colchicine.

To determine the factors associated with colchicine resistance and the effect of colchicine resistance on health-related quality of life (QoL) in patients with familial Mediterranean fever (FMF).Demographic and clinical features, MEFV gene mutations, and Pras disease severity scores were recorded. QoL was assessed using the Short Form-36 (SF-36) and FMF-QoL scales. Colchicine resistance was defined as at least 1 attack per month for 6 months at the maximum tolerated dose of colchicine in fully compliant patients.The mean age of 118 patients (90 female, 28 male) with FMF was 38.4 ± 12.5 years. The percentage of colchicine-resistant patients was 19.5%. In univariable analysis, smoking (odds ratio [OR] = 2.885; 95% confidence interval [CI] = 1.104-7.539; P = 0.031), attack duration (OR = 1.955; 95% CI = 1.137-3.360; P = 0.015), presence of arthritis (OR = 5.235; 95% CI = 1.508-18.179; P = 0.009), and disease severity score (OR = 1.790; 95% CI = 1.334-2.402; P 0.001) were associated with colchicine resistance. The FMF-QoL and subscales of SF-36 except for role emotional and vitality, were different between colchicine-resistant and non-resistant patients (P 0.05).Smoking, attack duration, presence of arthritis, and disease severity were associated with colchicine resistance in fully compliant FMF patients. Colchicine-resistant patients had poorer health-related QoL.

Background Irritable bowel syndrome is a functional gastrointestinal disease. Visceral hypersensitivity is the most important pathophysiology in irritable bowel syndrome. Currently, diagnosis of irritable bowel syndrome is based on symptoms and exclusion of other organic diseases. Although the diagnosis of irritable bowel syndrome can be made based on the Rome IV criteria, one may speculate that complete exclusion of other organic diseases is not so easy, especially in cases uncontrolled with standard therapies. Case presentation We present herein a case of familial Mediterranean fever in a young Japanese patient who had been suffering from an irritable bowel syndrome-like clinical course. A 25-year-old Japanese male had been diagnosed as having diarrhea-predominant irritable bowel syndrome 5 years earlier. Unfortunately, standard therapies failed to improve irritable bowel syndrome symptoms. After careful medical history-taking, we understood that he had also experienced periodic fever since 10 years ago. Although no mutation was identified in the Mediterranean fever gene, not only periodic fever but abdominal symptoms improved completely after colchicine administration. He was therefore diagnosed as having familial Mediterranean fever and that the abdominal symptoms may be related to the disease. Conclusions Familial Mediterranean fever should be considered as a cause of irritable bowel syndrome-like symptoms.

To perform a systematic review and meta-analysis of studies reporting data on atherosclerosis and inflammatory markers in familial Mediterranean fever (FMF).EMBASE and PubMed databases were screened according to PRISMA guidelines from inception to January 2022 for articles reporting measurements of the intima media thickness (IMT) of carotid arteries and eventually carotid plaques; random effect meta-analyses for continuous outcomes and Peto's odds ratio for rare events were employed.The screening and selection search strategy yielded 18 case controls studies (16 full papers and 2 abstracts); the IMT was greater in FMF (n = 1112) than in controls (n = 901) (p 0.0001) with wide heterogeneity (IFMF is characterised by premature atherosclerosis expressed as a thicker intima media and a greater prevalence of carotid plaques, partially related to the C-reactive protein, as expected by the autoinflammatory nature of FMF. Key Points • Familial Mediterranean fever is characterised by premature atherosclerosis. • C-reactive protein relates to intima media thickness in keeping with the autoinflammatory nature Familial Mediterranean fever. • Targeting the inter-critical low-grade inflammation may be relevant to minimise the additional cardiovascular risk posed by premature atherosclerosis.

Familial Mediterranean fever (FMF) in gastrointestinal involvement has been considered rare, but resent reports suggest that FMF causes enterocolitis which is similar endoscopic findings to inflammatory bowel disease. The clinical characteristics and endoscopic findings of FMF with enterocolitis remain unclear. Here, we report a case of an FMF patient who had enterocolitis with stricture of the terminal ileum whose endoscopic and clinical features mimicked Crohn’s disease. A 23-year-old man who was diagnosed with FMF 10 years ago presented with abdominal pain and diarrhea. Colonoscopy showed terminal ileitis and aphthous colitis; however, these findings, including the histopathology, did not confirm Crohn’s disease. Therefore, we diagnosed FMF with enterocolitis and administered anti-interleukin-1β monoclonal antibody (canakinumab). The patient’s symptoms improved with treatment, but after 1 year, lower abdominal pain recurred. Colonoscopy revealed a stricture of the terminal ileum. Endoscopic balloon dilation relieved his symptoms. At present, he has been followed up without surgical treatment by endoscopic balloon dilation every 6 month. Clinicians should be aware that FMF accompanied with enterocolitis may resemble Crohn’s disease.

Background/aim: Familial Mediterranean fever (FMF) is a disease that is mainly diagnosed with clinical features. Several wellknown inflammatory markers increase in FMF. However, there is still a need for diagnostic tests for specifying FMF and monitoring inflammatory activity. CXCL16 is a chemokine produced by inflammatory cells that demonstrate efficacy in the acute phase response. In this study, we aimed to investigate the relationship between CXCL16 levels and FMF disease and to evaluate CXCL16 levels as a novel biomarker for FMF. Materials and methods: Fifty-three male patients diagnosed with FMF and sixty healthy individuals were included in this crosssectional study. Blood samples were taken in the first 24 h of the attack periods. Serum soluble CXCL16 was evaluated by enzyme-linked immunosorbent assay (ELISA) method. Results: CXCL16 (P < 0.001), erythrocyte sedimentation rate (P < 0.001), C-reactive protein (P < 0.001), and fibrinogen (P = 0.005) were significantly higher in FMF group than in control group. Receiver operating characteristic (ROC) curve analysis revealed a cut off value of CXCL16 as 2.68 ng/ml with 83% sensitivity and 68% specificity (P < 0.001). Logistic regression analysis indicated that high CXCL16 and erythrocyte sedimentation rate levels were predictive parameters for FMF disease (OR 8.31; 95% CI 2.59-26.62; p

Familial Mediterranean Fever (FMF), which is an autosomal recessive disease characterized by recurrent self-limiting fever, peritonitis, pleuritis, arthritis and erysipelas-like erythemas, has been common among ethnic groups such as Turkish, Armenian, Arabic and Jewish. The clinical presentation is caused by mutations in the MEFV gene encoding the Pyrin protein. In this study, we aimed to present a new mutation that has not been previously defined from the mutations in the MEFV gene which is responsible for the genetic pathology of familial Mediterranean fever and to evaluate the frequency of distribution of the MEFV gene mutation among different ethnic groups living in our region. In present retrospective study, a total of 2639 clinically suspected FMF patients who were referred to Hatay Mustafa Kemal University Hospital between 2010 and 2017 were recorded. MEFV gene mutations were observed using DNA sequence analysis. MEFV mutations were found in 2079 of the 2639 patients (78.7%) Among these patients 184 (6.97%) were homozygous, while 1365 (51.72%) were heterozygous. The most frequently observed mutation was R202Q (1319, 19.55%) followed by E148Q (n = 476, 7.05%), M694V (n = 439, 6.51%), V726A (n = 146, 2.16%) and M680I (n = 135, 2%). In a case clinically diagnosed as FMF, a new mutation called S145G (p. Ser145Gly, c.433A > G) was identified in exon 2 of the MEFV gene. Besides, addition of a new pathogenic MEFV variant to the literature, the relationship between the FMF clinic and homozygous form of R202Q, which was previously considered as a polymorphism, was highlighted.

Aim of this study is to investigate the course of coronavirus disease 2019 (COVID-19), in our cohort of familial Mediterranean fever (FMF) patients in means of mortality, admission to hospital and/or intensive care unit and length of hospital stay.A retrospective cohort was formed from patients who have previously been followed with a diagnosis of FMF. Patients of this cohort were retrospectively evaluated for a positive severe acute respiratory syndrome-coronavirus 2 (SARS-CoV 2) polymerized chain reaction (PCR) test result and information regarding hospitalisation, intensive care unit admission and mortality were collected from medical records.Out of a total 496 FMF patients, 34 were detected to have a positive SARS-CoV 2 PCR test. Eighty-five point three percent of these patients were under colchicine treatment and 17.6% were under interleukin (IL)—1 inhibitor treatment. Eight of the 34 patients (23.9%) were found to be hospitalized, one of them was admitted to the intensive care unit and died thereafter (2.9%). An increasing trend in the frequency of comorbid diseases (presence of at least one comorbidity 64.7% in all patients vs 75.0% in hospitalized patients) and IL-1 inhibitor usage (17.6% in all patients vs 50.0% in hospitalized patients) was observed in hospitalized patients.Rates of comorbid diseases and IL-1 inhibitor use for FMF were observed to be increased in FMF patients hospitalized for COVID-19.

Coronavirus disease 2019 (COVID-19) refers to the clinical picture of an important and severe infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Considering the current knowledge on the pathophysiology and clinical manifestations of COVID-19, it is safe to state that both COVID-19 and inflammatory rheumatic disorders cause a cytokine storm and merit treatment with anti-rheumatic drugs. Three patients, who were on regular follow-up due to the diagnosis of familial Mediterranean fever (FMF), contracted COVID-19 infection; and their pre-clinical and post-clinical data as well as laboratory, prognosis and treatment data were investigated. Effects of colchicine in FMF patients who contracted COVID-19 infection were presented in this study. All the cases recovered from COVID-19 without complications. The present study suggests that colchicine can positively affect the prognosis of COVID-19 in FMF patients; therefore, experience of rheumatologists in the use of anti-inflammatory drugs can be highly instrumental in management of COVID-19 patients.

Introduction Transition is a planned process of pediatric patients from child-centered to adult-oriented treatment. Transitional care for patients with chronic diseases is essential. The present study aimed to evaluate the readiness of patients with rheumatic diseases and their parents for transition process. Method This is a cross-sectional, single-center study. All patients and their parents were questioned about their awareness of and willingness to undergo transitional care. Transition Readiness Assessment Questionnaire (TRAQ) was applied to all the participants. TRAQ is a tool for measuring readiness for transitional care in adolescents with chronic diseases. TRAQ includes 20 items that are divided into 2 domains: self-management and self-advocacy. Results A total of 157 (87 girls/70 boys) patients and their parents were enrolled. Of them 64 were diagnosed with familial Mediterranean fever, 52 with juvenile idiopathic arthritis, 21 with systemic lupus erythematosus, and 20 with Behcet's disease. The median age of the patients was 16 years (15-18). However, all patients and parents accepted that transition to adult-oriented care is necessary; only one-third of them were aware about transitional care. Eighty (50.9%) patients and 147 (93.6%) of the parents stated that they were wishing to continue pediatric rheumatology treatment. The mean TRAQ self-management domain and self-advocacy domain total scores in the patients were 1.76 ± 0.51 and 1.72 ± 0.49, respectively (P = .48). The mean TRAQ total score was not different between patients and parents. When we assessed the factors affecting transition process, the TRAQ score was lower among patients with active disease, and requiring hospitalization during the previous year. Conclusion Assessment od the readiness of patients with chronic rheumatic diseases for transition care will increase the awareness of patients and their parents as well, and provide determination of the optimal time for transition.

Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease with potentially devastating effects on the kidney, and the chronic subclinical inflammation may also be deleterious. Further, proteinuria has been associated with chronic inflammatory states. Objective: We aimed to probe whether red cell distribution width (RDW) can be used as a reliable indicator of subclinical disease in FMF patients. Method: Ninety-nine children with FMF, according to the new pediatric FMF criteria, were included in the present study. All were attack-free at the time of the study. They were compared with 44 healthy age-matched controls. For all patients and controls, the following tests were done: Complete blood count (in the form of red cell count, leukocyte count, platelet count, hemoglobin, RDW and MCV), CRP, ESR, creatinine and an estimated glomerular filtration rate (e-GFR). For patients, serum and urine albumin and albumin/creatinine ratio were also determined. Group 1 consisted of 61 patients, who were not suffering from microalbuminuria, and Group 2 consisted of 38 patients who had confirmed albuminuria. Result: RDW and ESR were significantly higher in patients with FMF without microalbuminuria than in controls, while MCV was smaller in controls (p Conclusion: RDW can be used as an indicator of subclinical inflammation in children with FMF. The tests are easy to perform and cheaper than more sophisticated tests. Microalbuminuria may be silent and occur on the background of normal levels of acute-phase reactants. All cases must be routinely checked for microalbuminuria.

Background Tunneled catheters can be used as an alternative vascular access in patients with limited health expectancy,vascular access problems and several comorbidities. We aimed to present a patient with venous stenosis related- reversible acute Budd-Chiari syndrome after catheter malposition. Case presentation After changing of tunneled catheter insertion, 36-year old man was admitted to our hospital with sudden onset of nausea, fever, chills and worsening general condition In computed tomography (CT) imaging, a hypodense thrombus was observed in which the distal end of the catheter is at the level of drainage of the hepatic veins in the inferior vena cava and that blocked hepatic vein drainage around the catheter. The catheter was removed and a new catheter was inserted in the same session. Because patient’s general condition was good and without fever, he was discharged with advices on the 9th day of hospitalization. Conclusion Although catheter malposition and thrombosis are not a common complication, clinicians should be alert of these complications.

To evaluate the ethnic distribution of Israeli patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA).The medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel from March 2014 to March 2019 were retrospectively reviewed. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, and multiethnic. Findings were compared with patients with asthma under treatment at the same medical centers during the same period.The cohort included 303 patients with PFAPA and 475 with asthma. Among the patients with PFAPA, 178 (58.7%) were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 96 (33.0%) were multiethnic, and 17 (5.8%) were of non-Mediterranean descent (all Ashkenazi Jews). Patients with PFAPA had a significantly higher likelihood of being of Mediterranean descent than the patients with asthma (58.7% vs 35.8%; P .0001). The Mediterranean PFAPA subgroup had a significantly earlier disease onset than the non-Mediterranean subgroup (2.75 ± 1.7 vs 3.78 ± 1.9 years, P .04) and were younger at disease diagnosis (4.77 ± 2.3 vs 6.27 ± 2.9 years, P .04).PFAPA was significantly more common in patients of Mediterranean than non-Mediterranean descent. Further studies are needed to determine the genetic background of these findings.

Autoinflammatory diseases (AIDs) are disorders with an inborn error of innate immunity, characterized by recurrent episodes of fever and inflammatory attacks. The spectrum of AIDs is expanding, but there are no standardized clinical criteria for the diagnosis of the patients. This study aims at establishing the first autoinflammatory registry of an Iranian population focusing on the clinical and laboratory features that may help clinicians for a better understanding and diagnosis of these disorders. Clinical and laboratory characteristics of patients who were clinically and or genetically diagnosed with AIDs were collected for 15 years. The updated version of classification criteria from the Eurofever Registry was used for the clinical diagnosis. Twenty-eight patients (16 males and 12 females) with a mean±SD age of 28.03±14.49 years (from 2 to 68 years) entered this study. About 29% were genetically diagnosed. Familial Mediterranean fever (FMF) was the most common diagnosis of the patients. Fever duration episodes were between 1-10 days. Some of the clinical manifestations from the most to the least common were as follows: arthralgia and arthritis (80%), myalgia (76%), coughs and shortness of breath (68%), fatigue (60%), abdominal pain (56%), increased erythrocyte sedimentation rate(ESR) (48%), and splenomegaly (24%). Here, we presented the most common clinical manifestations of Iranian AIDs who have registered in our AID registry which would be a useful guide for managing the same patients and also designing the future studies.

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.

Familial Mediterranean fever is a hereditary autoinflammatory syndrome. The typical treatment for the disease is colchicine. However, a subset of patients are not responsive to colchicine. In this study, polymorphisms in the colchicine-binding site of the TUBB1 gene, which encodes a tubulin isoform specific to leukocytes, were investigated in patients with colchicine-resistant disease. FMF patients who were followed in the Department of Pediatric Rheumatology at Hacettepe University were included in this study. Colchicine resistance was defined as ongoing disease activity (>= 1 attack/month over 3 months or persistently elevated CRP) while taking the maximum tolerated dose of colchicine. A total of 62 Turkish FMF patients (42 colchicine-responsive and 20 colchicine-resistant) and a control group of healthy children were included in the study. DNA was extracted for analysis of TUBB1, and the colchicine binding site was sequenced. We did not observe A248T (rs148237574) or M257V (rs759579888), two variations that were previously associated with colchicine resistance in an in silico analysis. We did detect T274M (rs35565630), R306H (rs772479017), and R307H (rs6070697) variants in the FMF patients, but there was no statistically significant difference between the colchicine-responsive and colchicine-resistant groups. This is the first study to evaluate TUBB1 gene polymorphisms in the colchicine binding site in patients with FMF. Our data do not support the hypothesis that these polymorphisms are a possible cause of colchicine resistance in FMF patients.

Familial Mediterranean fever (FMF) is characterized by sporadic, recurrent attacks of fever and serosal inflammation. AA amyloidosis (AAA) is a disorder characterized by the extracellular tissue deposition of serum amyloid A protein (SAA). Azurocidin is a neutrophil-derived granule protein. We aimed to investigate the significance of azurocidin in FMF and AAA and the correlation between azurocidin levels and carotid artery intima media thickness (CA–IMT) and cardiovascular plaque existence. A sum of 52 FMF patients were enrolled in the study. FMF patients were composed of two groups. Group-1 included 30 patients with non-complicated FMF. Group-2 included 22 patients whom received renal transplantation due to FMF complicated with AAA and being followed up at stable state for at least one year. 24 healthy individuals who matched with FMF patients in terms of age and gender consisted the control group. We found statistically significant difference between patient and control groups in terms of urea (38.52 ± 19.96 mg/dl vs 29.08 ± 5.83 mg/dl; p = 0.003), creatinine (1.11 ± 0.39 mg/dl vs 0.91 ± 0.16 mg/dl; p = 0.002), serum uric acid (6.2 ± 2 mg/dl vs 4.5 ± 0.9 mg/dl; p

Chronic inflammation and proteinuria is a risk factor for cardiovascular disease (CVD) in patients with chronic kidney diseases and rheumatologic disorders. Our aim was to investigate the CVD events (CVDEs) and survival between the patients with FMF-related AA amyloidosis and glomerulonephropathies (GN) to define possible predictors for CVDEs. A prospective follow-up study with FMF-amyloidosis and glomerulonephropathy (GN) was performed and patients were followed for CVDEs. Flow-mediated dilatation (FMD), FGF-23, serum lipid, hsCRP levels, BMI and HOMA were assessed. A Cox regression analysis was performed to evaluate the risk factors for CVDEs. There were 107 patients in the FMF-amyloidosis group and 126 patients with GN group. Forty-seven CVDEs were observed during the 4.2-years follow up; all 28 patients in the FMF-amyloidosis group and 14/19 patients with GN developed CVDEs before the age of 40 (p = 0.002). CVD mortality was 2.8 times higher (95% CI 1.02–7.76) in patients with FMF-amyloidosis. Across both groups, FMD and FGF23 (p

Background Patients with rheumatological complaints may visit an emergency department (ED) because of an acute attack or complication. Because of the recent increased use of immunosuppressant drugs to treat rheumatic diseases, more patients with these conditions visit the ED with a complaint about an infection. However, there are little data on the ED visits of patients with rheumatological complaints. This study evaluated the ED visits of patients with inflammatory rheumatic diseases. Materials and methods A total of 2715 patients (1753 females, 962 males) who had been diagnosed with an inflammatory rheumatic disease and followed up at the rheumatology clinic of Yildirim Beyazit University, Ankara Ataturk Training and Research Hospital between April 2014 and April 2018 were included in the study. The demographic, clinical, and laboratory characteristics of the patients were obtained from the hospital patient records. The ED visits of these patients were classified into five triage groups (T1: critical, T2: very urgent, T3: urgent, T4: less urgent, T5: not urgent). Results Of the 2715 patients, 577 (21.3%) had visited the ED. The three most numerous groups who visited the ED were patients with rheumatoid arthritis (19.8%), ankylosing spondylitis (19.2%), and familial Mediterranean fever (15.9%). Of these 577 patients, 347 (60.1%) were discharged from the ED, 209 (36.2%) were hospitalized in the wards, and 21 (3.6%) were hospitalized in the intensive care unit (ICU). The 3 main reasons for visiting the ED were fever and malaise (n = 152, 26.3%), musculoskeletal complaints (n = 125, 21.7%), and abdominal pain (n = 89, 15.4%). The most numerous group of patients referred by the ED to the wards had vasculitis (n = 38, 17.9%), while the most numerous group of patients referred to the ICU had scleroderma (n = 7, 33.3%). Of the 21 patients who were referred by the ED to the ICU, 16 (76.1%) had respiratory system complaints. Of the 577 patients, 10 (1.7%) died. Eight of the 10 patients (80%) had a rheumatic disease and died after admission to the ICU. The other 2 patients had been diagnosed with pneumonia and myocardial infarction, respectively. Conclusions Our study found that visits to the ED by patients with inflammatory rheumatic diseases were classified as urgent or less urgent. Patients with rheumatoid arthritis were the most numerous ED visitors. Vasculitis was the most common cause of hospitalization in the wards and scleroderma was the most common cause of hospitalization in the ICU and death. This suggests that ED physicians should be aware of these patients.

Background Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease and is characterized by self-limiting episodes of fever and polyserositis. The aim of this study was to determine the atopic clinical findings associated with the MEFV gene. Methods A retrospective chart review was conducted of pediatric patients who had received a diagnosis of familial Mediterranean fever between August 2015 and November 2018. Results A total of 454 patients with familial Mediterranean fever were evaluated. The median age of diagnosis was 60 months (min–max: 6–228) and the percentage of patients who were male was 57.5%. A MEFV gene mutation was determined in 310 (68.3%) children. The most frequent genetic mutation was a R202Q heterozygote mutation, which was found in 95 patients (20.9%). When compared with MEFV-negative patients, elevation of serum amyloid A and fibrinogen levels during an episode of FMF was found to occur more frequently in MEFV-positive patients (p = 0.019 and 0.027, respectively). Male gender, cigarette exposure, and a younger diagnosis age were seen more frequently in patients who had episodes with fever (p = 0.039, 0.022, and 0.001, respectively). Chronic cough with sputum and persistent purulent rhinitis were more frequent in the group which did not experience fever episodes (p = 0.003 and 0.002, respectively). Conclusions While being a periodic fever syndrome, familial Mediterranean fever also presents as a multisystemic disease with heterogeneous clinical symptoms. Severe atopic diseases and recurrent respiratory tract infections are characteristic features of this disease.

Objectives FMF shows considerable variability in severity and type of clinical manifestations by geographic region, which are attributed to Mediterranean fever (MEFV) gene allelic heterogeneity, additional genetic modifiers and environmental factors. Considering the severe impact of MEFV mutation M694V on the FMF phenotype, this work aimed at investigating a possible disease modifying role of the serum amyloid A1 (SAA1) genotype in a cohort of 386 Armenian FMF patients homozygous for MEFV mutation M694V. Methods A cohort of 386 Armenian patients diagnosed with FMF based on the Tel-Hashomer criteria and carrying two MEFV M694V mutant alleles were included in this study. Fifty-two (13.40%) of these patients experienced their first attack at the age of ≥20 years (i.e. adult-onset FMF). MEFV and SAA1 analyses were performed by a commercial reverse-hybridization assay, and resulting genotypes were matched against the patients’ clinicodemographic profiles. Results Genotypic distribution of SAA1 alleles was significantly different between patients with an age of onset Conclusion We have identified a significant relationship between the SAA1β/β genotype and the age of disease onset in M694V homozygous FMF patients.

Objective Persistent inflammation is an insidious and less studied feature of FMF. We investigated clinical determinants of persistent inflammation and its associations with individual damage items. Methods This is a cross-sectional analysis of 917 FMF patients, who fulfilled the Tel Hashomer criteria and had at least 6 months’ follow-up. Patients were stratified based on whether they had persistent inflammation. We used logistic regression analysis to investigate independent predictors of persistent inflammation and the associated individual damage items. Results One hundred and forty-two (15%) patients had persistent inflammation. Active FMF (54%) was the most prominent reason for the persistent inflammation. Spondylarthritis (16%), other inflammatory arthritis (8%) and IBD (2%) were other frequent reasons. Male gender, history of exertional leg pain, inflammatory comorbidities, M694V homozygosity, colchicine resistance, lower education levels and musculoskeletal attack dominance were found to be the independent predictors of persistent inflammation. Earlier disease onset led to a tendency towards persistent inflammation. Patients with persistent inflammation were more likely to suffer damage. There is an increased risk of developing proteinuria, amyloidosis and renal insufficiency. Conclusion We identified, for the first time, the predictors of persistent inflammation in adult FMF patients and related individual damage items of the Autoinflammatory Disease Damage Index. Persistent inflammation is insidious and one of the chief causes of damage; therefore, especially patients with these predictors should be followed up more closely. If detected, underlying inflammatory comorbidities should be assessed meticulously as early detection and proper treatment strategies may favourably impact the natural history of the disease.

To make an accurate diagnosis of systemic autoinflammatory diseases (SAIDs), clinical and genetic analyses were performed in patients with unexplained fever.The clinical phenotype and genomic variants of 11 genes responsible for SAIDs were analyzed in 179 Japanese patients with unexplained fever. Genetic analysis was performed by next generation sequencing (NGS) on exons including exon-intron boundaries.Three cases met the diagnostic criteria for SAIDs other than familial Mediterranean fever (FMF). Considering 176 patients with unexplained fever, 43 cases (24.0%) were clinically diagnosed as FMF. Gene variants were found in 53 cases (30.1%) when searching for variants in the 10 disease genes other than theTwenty four percent of Japanese patients with unexplained fever were clinically diagnosed as FMF in this study. Low frequency but not pathogenic variants in genes other than

Introduction: Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome (MetS), insulin resistance (IR) and chronic inflammation. Although familial Mediterranean fever (FMF) patients have no symptoms in the periods between attacks, their subclinical inflammation continues. The aim of the present study was to determine the NAFLD frequency in FMF patients and to evaluate their MetS, IR and lipid profiles. Methods: The study included 54 FMF patients and 54 control subjects. The clinical and demographic characteristics of the subjects were recorded, and the patients’ Pras disease severity score was calculated. IR was determined using the homeostasis model assessment (HOMA) index. MetS was diagnosed using the revised National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP ATP III). Hepatic ultrasonography was used to diagnose NAFLD. Results: NAFLD was observed in 15 FMF patients (27.8%) and 14 controls (25.9%). The difference between the groups was not significant (p=0.828). Similarly, no significant difference was found between the two groups for MetS frequency and HOMA index levels. Fasting plasma glucose was significantly higher in FMF patients, whereas differences between the two groups were not significant for lipid levels and other parameters. When FMF patients with and without NAFLD were compared, no significant difference was found in Pras disease severity score, duration of the disease and daily colchicine dose. Conclusion: The present study showed that NAFLD frequency was not increased in FMF patients, and that patients’ MetS frequency, IR and lipid profiles were not different from control subjects.

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by frequent attacks and chronic inflammation. Subclinical inflammation continues during the attack-free period. Omentin is an anti-inflammatory adipokine, which plays important roles in the adjustments of glucose metabolism, cardiovascular homeostasis and atherosclerosis. The aim is to investigate the omentin levels in FMF patients and to assess the association with markers of subclinical inflammation in FMF patients such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).This cross-sectional study included 54 consecutive adult FMF patients (27 male, 27 female) and 28 healthy individuals (16 male, 12 female). The FMF patients were separated into 3 groups: (1) attack-free group, (2) active-attack group and (3) colchicine-resistant group. Serum omentin levels were compared between the FMF patients and the healthy control group.A significant difference was determined between the FMF patients and healthy control subjects in terms of omentin levels (108.05 (19.97-343.22) vs. 199.5 (42.98-339.41) p 0.05). SAA values were significantly higher in the FMF patients compared with the healthy control group. When the FMF patients were examined as separate groups, serum omentin values were lower in the colchicine-resistant group than in the groups without resistance (76.64 (19.77-224.33) vs. 186.47 (28.41-343.21) p = 0.006).FMF patients with colchicine resistance are associated with decreased omentin concentrations, probably mediated by inflammation-driven mechanisms. Key Points • Omentin is a type of adipokine which has an anti-inflammatory effect by inhibiting the inflammatory cytokine network. • Decreased omentin levels are associated with increased obesity, insulin resistance and comorbidities. • We report that omentin levels fluctuate in various diseases. In addition, we have focused on the levels of omentin in patients with FMF, as it may act as a biomarker for colchicine resistance.

Background Despite to PFAPA syndrome is considered a benign and self-limited condition in childhood its impact on patients and families can be remarkable in many cases. Currently, the therapeutic options for managing are non-specific and no consensus exists about the best treatment to use. Pidotimod has been suggested as a new potential treatment in PFAPA syndrome for its immunodulatory effects. We conducted a preliminary, prospective, controlled, open, cross-over trial to assess the efficacy and the safety of Pidotimod in the treatment of children with PFAPA syndrome. Methods 22 children with PFAPA syndrome were randomly allocated to treatment with pidotimod (with 2 vials of 400 mg daily) in combination with betamethasone 0.5–1 mg on need, based on parents/caregivers’ decision (group A) or betamethasone 0.5-1 mg on need, based on parents/caregivers’ decision (group B). Each treatment period was for 3 months (Phase 1), after that patients were switched to the other arm for other 3 months (Phase 2). Efficacy was expressed in terms of number of episodes of fever, pharyngitis, or aphthous stomatitis, as well as the additional use of betamethasone on need. Safety and tolerability of the Pidotimod were evaluated on the basis of the number and type of adverse events (AEs) recorded during the treatment. Results Patients receiving Pidotimod and use betametasone showed a significant decrease in frequency of fevers (p = 0.002); number of episodes of pharyngitis (p = 0.049); aphthous stomatitis (p = 0.036) as well as the betamethasone use on need (p = 0.007). Overall, 19/22 (86.4%) showed benefits from Pidotimod administration. The safety profile of Pidotimod was excellent as no serious adverse events have been reported in the treated groups. Conclusions We firstly showed that high dosage of Pidotimod could be an effective and safe to reduce the PFAPA attacks in children.

To develop a valid and reliable quality-of-life (QoL) scale in familial Mediterranean fever (FMF). After producing question pool by using psychometric methods, high-performance questions were obtained according to expert panel. The principal component analysis (PCA) was done with varimax rotation for factor analysis. The final version of the scale (FMF-QoL) was examined for reliability and validity. Internal consistency with Cronbach alpha was calculated. The face, content, convergent and discriminant validity were analyzed. PRAS score used to assess the disease activity. Spearman correlation coefficient (rho) was used to assess the convergent and discriminant validity. In our study, 123 FMF patients were recruited. According to the factor analysis the FMF-QoL were represented by 4 factor groups (eigenvalues >1) which were physical impact, social and recreational impact, psychological impact, and impact of sleep. All questions’ factor loadings after Varimax rotation were bigger than 0.5 and the cumulative variance of the scale was 68.11%. The strongest correlation of the FMF-QoL was found with other QoL scales like EUROHIS (rho: −0.64, p p p p p p p A valid, reliable, practical, not time-consuming FMF-specific QoL scale that can be used in the clinical follow-up and treatment of these patients was developed and validated.

Aim The aim of this study is to evaluate the clinical parameters, acute-phase reactants, side effects, genetic mutations among colchicine-resistant Familial Mediterranean fever (FMF) patients who received anti-interleukin-1 (anti-IL-1) treatment. We also evaluate the quality of life and school attendance among colchicine-resistant FMF patients, in relation to treatment with anti-IL-1. Introduction Familial Mediterranean fever is the most common inherited autoinflammatory disorder. Although the main treatment of FMF is colchicine, a small group of patients are resistant to colchicine treatment. Anti-IL-1 treatment is promising in colchicine-resistant patients due to excessive IL-1β production in pathogenesis. The aim of this study is to evaluate the quality of life and school attendance rates among colchicine-resistant FMF patients after anti-IL-1 treatment. Methods This is a single center retrospective study of 25 pediatric colchicine-resistant FMF patients treated with anti-IL-1 treatment. Autoinflammatory Disease Activity Index (AIDAI) was used for disease activity assessment. School attendance rates were evaluated before and after treatment. Results There were 25 patients with FMF (11 M/14 F) who were treated with anakinra or canakinumab for various indications (colchicine-resistant recurrent febrile attacks in 20, colchicine-related side effects in 2, subclinical inflammation in 3 patients). Only 3 patients developed side effects with anakinra (2 headache, 1 urticarial rash). There was a significant decrease in the frequency of attacks, acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein), AIDAI and physician's and patient's global assessment scores and improvement in school attendance rates. At the last follow-up, all patients were in remission, and only 3 had subclinical inflammation. Conclusion Anti-IL-1 treatment is quite effective in children with colchicine-resistant FMF patients, proven with improved AIDAI scores and school attendance rates. In the long term by lowering disease activation even development of amyloidosis may be prevented.

ObjectivesTo evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study.MethodsPatients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg.ResultsOf the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported.ConclusioncrFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.

Objective Familial Mediterranean Fever (FMF) is the most frequent autoinflammatory syndrome, and its frequency is reported to be increasing in Japan. We studied the clinical features and genetic background of patients with FMF in our hospital. Methods We analyzed the clinical features and genomic variants of MEFV, as well as 10 genes related to other autoinflammatory syndromes, in 22 Japanese patients with FMF. A genetic analysis was performed with a next generation sequencer. Results The patients were classified into the typical FMF (n=16) and atypical FMF (n=6) groups. Fever, abdominal pain, thoracic pain, and arthralgia were observed in 22, 12, 8, and 10 patients, respectively. MEFV variants were found in 19 patients (86.4%). Two cases had no MEFV variants and one case only had a variant in the 3′ untranslated region (3′-UTR) of MEFV. Genomic variants were found in genes other than MEFV in 7 patients (31.8%); however, none met the diagnostic criteria for autoinflammatory syndromes with disease-related gene variants, and all were classified as typical FMF. Moreover, none of the 6 patients with atypical FMF had any variants among the 10 disease-related genes. All cases in which the onset occurred before 20 years of age were classified as typical FMF. Conclusion The clinical features of FMF recorded in our hospital coincided with those from the Japanese national epidemiological survey of FMF in Japan. More than 30% of the patients with FMF had non-MEFV genes, related to other autoinflammatory syndromes, thereby suggesting that variants of these genes may act as a disease-modifier in FMF.