COVID-19 in familial Mediterranean fever: Clinical course and complications related to primary disease.

OBJECTIVES: To evaluate the impact of familial Mediterranean fever (FMF) features on the clinical course and outcomes of coronavirus disease 2019 (COVID-19) and clinical course of FMF after COVID-19. METHODS: Consecutive FMF patients with COVID-19 were enrolled from three referral hospitals. Clinical features of FMF and detailed COVID-19 information were obtained from patient interviews and medical records. RESULTS: Seventy-three FMF patients were included in the study. 94.5% of patients had clinical symptoms of COVID-19. We found 24.7% hospitalization, 12.3% respiratory support, 4.1% intensive care unit admission, 6.8% complication, and 1.4% mortality rate in patients. The risk factors of hospitalization for respiratory support were male gender [OR: 7.167 (95% CI: 1.368-37.535)], greater age [OR: 1.067 (95% CI: 1.016-1.121)], and non-adherence to colchicine treatment before the infection [OR: 7.5 (95% CI: 1.348-41.722)]. One-third of patients had reported attacks after COVID-19. The patterns of triggered attacks were fever, peritonitis, pleuritis, transient arthritis, chronic knee mono-arthritis, and protracted febrile myalgia. CONCLUSIONS: FMF characteristics were not associated with worse outcomes of COVID-19. Colchicine non-adherence was the risk factor of hospitalization for oxygen support. The rate of FMF attacks after COVID-19 is prominently increased, with some of them being protracted and destructive.

Efficacy and safety of tofacitinib in rheumatoid arthritis-associated interstitial lung disease: TReasure real-life data.

OBJECTIVES: Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is a major concern in RA. These patients have been included in clinical trials and in the post-marketing setting of RA patients using tofacitinib. We aimed to assess the real-life efficacy and safety of tofacitinib in patients with RA-ILD. METHODS: RA patients with ILD diagnosis based on the HRCT images of the lungs from eight different centres recruited to study. As a control group, RA patients without ILD under tofacitinib were included. Demographic data, patients' characteristics, available pulmonary function tests regarding RA and RA-ILD at the visit in which tofacitinib was initiated and for the last follow-up visit under tofacitinib were recorded. Reasons for tofacitinib discontinuation were also recorded. Drug retention rates were compared by log-rank test. p-value <0.05 was considered statistically significant. RESULTS: A total of 47(42.6% male) RA patients with RA-ILD and a control group of 387 (17.8% male) patients without RA-ILD were included in analysis. After the median of 12 (9-19) months follow-up, mean FEV1%; 82.1 vs. 82.8 (pre/post-treatment, respectively, p=0.08), mean FVC%; 79.8 vs. 82.8 (pre/post-treatment, respectively, p=0.014) were stable and worsening was observed in 2/18 (11.1%) patients. Retention rates were similar (p=0.21, log-rank). In RA-ILD group, most common cause of drug discontinuation was infections (6.3 vs. 2.4 per 100 patient-years). CONCLUSIONS: Treatment strategy of RA-ILD patients is still based on small observational studies. A high rate of discontinuation due to infections was observed in RA-ILD patients under tofacitinib; however, RA-ILD patients were older than RA patients without ILD.

Compliance of Familial Mediterranean Fever Patients With Regular Follow-up Visits and Associated Factors.

BACKGROUND: Follow-up is crucial to detect asymptomatic complications of familial Mediterranean fever (FMF). The current European League Against Rheumatism recommendations state that patients with FMF should be evaluated at least every 6 months to monitor attacks, acute phase response, and proteinuria. OBJECTIVES: This study aimed to assess compliance of FMF patients with regular follow-up visits and the associated factors. METHODS: Adult patients with a diagnosis of FMF who had their initial visit at least over 1 year ago were included. Demographic and socioeconomic data, family history, and comorbid diseases were obtained from medical records. The International Severity Score for FMF and the Autoinflammatory Disease Damage Index scores were calculated. We defined patients as "compliant with follow-up visits" both if they had at least 2 visits during the previous year and a compatible physician's assessment. The characteristics of the compliant and noncompliant patients were compared, and multivariable logistic regression analysis was used to determine the factors influencing visit compliance. RESULTS: Four hundred seventy-four patients with FMF were included. Two hundred thirty (48.5%) were compliant, and 244 (51.5%) were noncompliant with follow-up visits. A family history of FMF in parents, the absence of a family history of FMF in siblings, treatment with biologic agents, concomitant medication use, multisite involvement during FMF attacks, and treatment satisfaction were independent predictors of visit compliance. CONCLUSIONS: Only half of the patients with FMF were compliant with follow-up visits. Better strategies should be implemented to increase the compliance of FMF patients. Identifying independent predictors would help to build one.

Diagnostic utility of serum biomarkers in large vessel vasculitis and their correlation with positron emission tomography.

OBJECTIVES: To investigate the association between vascular inflammation, as detected by positron emission tomography (PET) imaging and interleukin-6 (IL-6), pentraxin3, and B-cell-activating factor (BAFF) in subjects with LVV. METHODS: The study included newly diagnosed giant cell arteritis (GCA, n = 27) or Takayasu arteritis (n = 9) patients and healthy control (HC, n = 31) subjects. PET scan and blood samples were obtained before the introduction of treatments. IL-6, PTX3, and BAFF levels were determined quantitatively by enzyme-linked immunosorbent assay kits. RESULTS: Thirty-six patients with LVV (20 females, 16 males; age 64.5 ± 16.6 years) and 31 HC (14 females, 17 males; age 37.1 ± 9.6 years) were included. Serum levels of IL-6, PTX3, and BAFF were increased in patients with newly diagnosed LVV compared with healthy control subjects. In receiver operating characteristics (ROC) analysis, serum IL-6 and BAFF provided excellent discrimination of newly diagnosed LVV patients from HC (area under the ROC curve of >0.90 and >0.80, respectively). None of the inflammatory markers correlated with vascular inflammatory activity determined by PET scanning. CONCLUSIONS: Our results suggest that IL-6 and BAFF may serve as markers of large vessel vasculitis, while PTX3 is not useful. None of the inflammatory markers correlated with PET assessed vasculitis activity.

Predictors of persistent inflammation in familial Mediterranean fever and association with damage.

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.

Prognostic value of interleukin-18 and its association with other inflammatory markers and disease severity in COVID-19.

BACKGROUND: The effectual immune response is crucial to defeat viral infections. However, exuberant immune response with features of macrophage activation syndrome (MAS) lead detrimental consequences in COVID-19 patients. Interleukin (IL)-18 is one of the leading cytokines in MAS which has not been studied in COVID-19. OBJECTIVE: To investigate the association of IL-18 with the other inflammatory markers and disease severity in COVID-19 for predicting disease prognosis. METHODS: Patients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled into the study. Data on demographic and clinical characteristics, and laboratory values of CRP, ferritin, d-dimer and procalcitonin were measured on admission. Patients were followed up prospectively with a standardized approach until hospital discharge or death. Individuals were classified as asymptomatic, mild and severe pneumonia according to their clinical, laboratory and radiological characteristics. Worse outcome was defined as requirement of intensive care unit (ICU) admission or death. Blood samples were collected at enrollment and serum levels of IL-6 and IL-18 were determined by ELISA. Association between IL-18 and other inflammatory markers and prognosis were analyzed. RESULTS: There were 58 COVID-19 patients (50% male) with a median age of 43 (min 22-max 81) years. Twenty age and sex matched healthy subjects were served as control group. The study population was divided into three groups according to disease severity: asymptomatic (n = 20), mild pneumonia group (n = 27) and a severe group (n = 11). During follow up nine (15.5%) patients required ICU admission and three of them were died eventually. Serum IL-18 were correlated with other inflammatory markers and biochemical markers of organ injury; creatinine, liver enzymes and troponin. Serum IL-18 levels were remarkably higher in COVID-19 patients compared to healthy subjects with being highest in severe pneumonia group (p < 0.001). IL-18 serum concentrations were almost four-fold higher in patients with worse outcome compared to good outcome (p < 0.001). Serum IL-18 above the cut off value of 576 pg/mL on admission was associated with 11.7 fold increased risk of ICU admission. CONCLUSIONS: The serum concentrations of IL-18 correlate with other inflammatory markers and reflect disease severity. Results of the present study shed light on role of IL-18 on COVID-19 pathogenesis and might provide an evidence for the clinical trials on IL-18 antagonists for the treatment of severe COVID-19 patients.

Long-term safety and efficacy of anakinra and canakinumab in patients with familial Mediterranean fever: a single-centre real-life study with 101 patients.

OBJECTIVES: Anakinra and canakinumab are the most commonly used agents in colchicine resistant/intolerant patients. In this study we investigated long-term efficacy and safety of anakinra and canakinumab. METHODS: In this retrospective study, we enrolled 101 adult patients with familial Mediterranean fever (FMF). Clinical and laboratory parameters before and after treatment with anakinra/canakinumab and the side effects observed during the treatment were recorded. All patients received anakinra initially and switched to canakinumab, in case of inadequate response/intolerance. RESULTS: The median (IQR) duration of treatment with anti-IL-1 agents was 35 (24-47.5) months. 101 patients were treated with anakinra and 27 patients with canakinumab. The autoinflammatory diseases activity and attacks decreased with both anakinra and canakinumab. Anakinra was effective in decreasing proteinuria and canakinumab was not effective in decreasing proteinuria in anakinra unresponsive patients. The modified FMF score was achieved in 76.2% of anakinra and 88.9% of canakinumab group. Injection site reactions (ISRs, n:15) was the most common reason of discontinuation of anakinra and most of ISRs developed in first 3 months of treatment. One severe skin rash, two anaphylactic reactions and one severe neutropenia were observed with anakinra; in the first, eighth, twelfth and fiftieth months, respectively. No severe side effects or side effect-related discontinuation of canakinumab were observed. CONCLUSIONS: Anakinra and canakinumab seem to be effective in long-term management of FMF patients. Canakinumab had a favourable safety/tolerability profile. Anakinra is also generally safe, but the serious side effects that may be observed in the short and long-term use should be taken into account.

Diagnostic Role of 18F-Fluorodeoxyglucose Positron Emission Tomography for the Evaluation of Patients With Inflammation of Unknown Origin.

BACKGROUND: Sometimes, the underlying causes of inflammation cannot be established despite meticulous investigation, including medical history, physical examination, laboratory tests, and radiologic procedures. Rheumatologists are often faced with patients whose condition is known as inflammation of unknown origin (IUO). Differential diagnosis of IUO is diverse, and investigation of these cases is challenging and time-consuming. OBJECTIVE: The study aimed to assess the diagnostic role of positron emission tomography/computed tomography (PET/CT) in the evaluation of patients with IUO. METHODS: The study sample consisted of 97 adult patients with IUO who have not been previously diagnosed with an infectious, inflammatory, or malignant disease. The necessary data were collected from January 2015 to June 2018 with a 6-month follow-up period. The patients were screened using PET/CT after a specific diagnosis could not be established with detailed laboratory and radiologic evaluations. RESULTS: A final diagnosis was established at follow-up, and 47 (54%) of the 97 patients had inflammatory diseases, 30 (34.4%) had malignancies, and 10 (11.4%) had infections. Despite meticulous investigation, 10 patients were left undiagnosed in the follow-up. PET/CT aided diagnosis in 59 patients (60.8%), but it was not helpful in 38 patients (39.2%). PET/CT was positive in 30 (63%) of the 47 patients with inflammatory diseases, whose final diagnosis was inflammatory rheumatic disease, as follows: large-vessel vasculitis in 19 patients, polymyalgia rheumatica in 7 patients, and seronegative arthritis or other rare miscellaneous diseases in 4 patients. The sensitivity of PET/CT was 67% with a specificity and diagnostic accuracy of 100% and 71%, respectively. CONCLUSIONS: Investigation of the underlying etiology of IUO is time-consuming and challenging. PET/CT may help identify the final diagnosis more quickly by locating an obscure inflammatory site; thus, it may reduce the number of unnecessary biopsies, diagnostic time, anxiety, work loss, morbidity, and mortality.

Folfirinox versus gemcitabine-cisplatin combination as first-line therapy in treatment of pancreaticobiliary cancer

Background/aim: The purpose of this study was to compare efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine-cisplatin as first-line therapy in patients with pancreatic cancer. Materials and methods: Pancreaticobiliary cancer patients who had Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating greater severity of illness) were evaluated to receive folfirinox or gemcitabine plus cisplatin. The primary endpoints were progression-free and overall survival time. Safety analysis was also evaluated as secondary measures. Results: There were 32 patients in the folfirinox group and 36 patients in the gemcitabine-cisplatin group. The median overall survival was 18.1 months (7.5­28.7) in the folfirinox group as compared with 9.7 months (6.5­13) in the gemcitabine-cisplatin group (p = 0.009). Median progression-free survival was 16.2 months (9­23.4) in the folfirinox group and 6.9 months (6.1­7.6) in the gemcitabine- cisplatin group (p = 0.001). Conclusion: Folfirinox is an option for the first-line treatment of patients with pancreatic cancer and good performance status.

Decreased exercise capacity, strength, physical activity level and quality of life in adult patients with familial Mediterranean fever

Background: Familial Mediterranean fever (FMF) is a systemic autoinflammatory disease that causes recurrent attacks of fever, polyserositis, arthritis or skin eruptions, resulting in pain in the abdomen, muscles, joints and chest. All of these might lead to a reduction in exercise capacity, muscle strength, physical activity level (PAL) and quality of life (QoL). Therefore, assesment of these parameters are important. The aim of this study was to assess exercise capacity, muscle strength, PAL, and QoL in patients with FMF as compared to controls. Materials and methods: A total of 40 subjects with FMF and 36 healthy control subjects participated in the study. The 6-minute walk test (6MWT) was used to assess exercise capacity. Muscle strength measurements for shoulder flexors, extensors and abductors, hip flexors, extensors and abductors, knee flexors and extensors, and ankle dorsiflexors were evaluated by hand-held dynamometer. PAL was assessed using the International Physical Activity Questionnaire-Short Form (IPAQ-SF). QoL was investigated by Nottingham Health Profile (NHP). Results: Significant differences were found between patients and healthy subjects for 6MWT (p = 0.003), muscle strength of ankle dorsiflexors (p = 0.001), hip flexors (p = 0.047), extensors (p = 0.003) and abductors (p = 0.004), total scores of IPAQ-SF (p = 0.004), and pain (p < 0.001), physical mobility (p < 0.001) and energy level (p = 0.026) subscales of NHP. However, there were no significant differences between groups for the shoulder flexion (p = 0.089), extension (p = 0.440) and abduction (p = 0.232), hand grip strength (p = 0.160) , and knee flexion (p = 0.744) and extension (p = 0.155) muscle strength and emotional reaction (p = 0.088), sleep (p = 0.070) and social isolation (p = 0.086) subsets of NHP. Conclusion: Subjects with FMF demonstrated lower exercise capacity, muscle strength, PAL and QoL than healthy peers. Therefore, it is important to evaluate and improve these parameters in patients with FMF.

Appendectomy history is associated with severe disease and colchicine resistance in adult familial Mediterranean fever patients

Background/aim: Peritonitis attacks of Familial Mediterranean Fever (FMF) usually requires emergency medical admissions and it's hard to distinguish a typical abdominal attack from surgical causes of acute abdomen. Therefore, history of abdominal surgery, particularly appendectomy, is very common in patients with FMF. However, history of appendectomy might also give some clues about the course of FMF in the adulthood. This study was to determine whether the history of appendectomy help to anticipate disease course of FMF in the adulthood. Materials and methods: All patients recruited from FMF in Central Anatolia (FiCA) cohort, comprising 971 adult subjects. All patients fulfilled the Tel Hashomer criteria. Demographic data, FMF disease characteristics, co-morbid conditions, past medical history, surgical history and disease complications were meticulously questioned and laboratory features and genotype data (if available) were recruited from patient files. Results: Appendectomy history was evident in 240 (24.7%) subjects. Disease onset was earlier and peritonitis is strikingly more prevalent (97.1% vs. 89.6%, p < 0.001) in appendectomized patients. These patients had reported almost two fold more frequent attacks in the last year compared to appendix intact patients (median 3.5 vs. 2 attacks, p = 0.001) without a difference in frequency of musculoskeletal and skin attacks. Severe disease was more common (10% vs. 5.9%, p = 0.038) due to involvement of more attack sites throughout the life and more frequent attacks. Appendectomy patients had used higher daily doses of colchicine to control disease (1.43 ± 0.6 mg vs. 1.27 ± 0.52 mg, p = 0.002) but colchicine resistance was also more common in these patients, 15% vs. 6.7% respectively, p < 0.001. Conclusion: Appendectomy history is common in FMF patients and associated with frequent serositis attacks in adulthood. These patients require higher colchicine doses with a lower rate of response and more need for Interleukin-1 antagonist therapies.

Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

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.

Diaphragmatic muscle thickness and diaphragmatic function are reduced in patients with systemic lupus erythematosus compared to those with primary Sjögren's syndrome.

INTRODUCTION: Systemic lupus erythematosus (SLE) is associated with an increased risk of pulmonary infections, as well as a rare condition known as shrinking lung syndrome (SLS). The diaphragm has an important role to play in lung physiology and might also play a role in these adverse events. Here, we aimed to investigate whether SLE patients have impairment in their diaphragmatic muscle thickness and function with respect to another connective-tissue disease: primary Sjögren's syndrome (pSS). METHOD: Patients diagnosed with SLE who were in remission or who had minimal disease activity and had at least one year of follow-up were included in this study. Patients with known lung pathology and smokers were excluded. Patients with pSS constituted the second experimental group. Ultrasonographic evaluation of the diaphragmatic muscle was conducted by an experienced independent sonographer at three time points, diaphragmatic thickness during deep and quiet inspiration and maximum expiration being measured. Diaphragmatic muscle function was evaluated with maximum expiratory pressure (MEP) and maximum inspiratory pressure (MIP). RESULTS: A total of 115 patients were studied (n = 39 SLE; n = 76 pSS). The mean ± standard deviation (SD) thickness of the diaphragmatic muscles during quiet inspiration was significantly reduced in patients with SLE compared to patients with pSS (2.32 mm vs. 2.81 mm; p < 0.05). Similarly, the thickness during deep inspiration and at maximum deep expiration were significantly lower in SLE patients (2.88 mm vs. 3.29 mm and 1.92 mm vs. 2.33 mm, respectively; p < 0.01). MIPs and MEPs, defined as the percentages of expected values, were significantly lower in patients with SLE compared to those with pSS (80% vs. 92% and 76% vs. 120%, respectively; p < 0.05). Diaphragmatic muscle thickness during deep inspiration demonstrated a moderate correlation with MIP (r = 0.434; p = 0.001). CONCLUSION: SLE patients had reduced diaphragmatic muscle thickness compared to those with pSS, which was associated with impaired functional tests. Further prospective studies are needed to investigate whether structural and functional impairments in diaphragmatic muscle play a role in an increased risk of pulmonary infections and SLS in patients with SLE.

Factors associated with damage in patients with familial Mediterranean fever.

OBJECTIVES: Defining predictors of damage would improve patient care. We applied damage indexes to patients with familial Mediterranean fever (FMF) and identified the predictors of damage. METHODS: This is a cross-sectional analysis of 926 FMF patients, who fulfilled the Tel-Hashomer criteria and had at least six months of follow-up. Patients were stratified according to their damage status (damage vs. no damage) defined with autoinflammatory disease damage index (ADDI) and modified ADDI (excluding musculoskeletal pain). We used logistic regression analysis to investigate independent predictors of damage for both indexes. RESULTS: Mean disease duration was 21.6±11.9 years. 527 patients (57%) had damage according to ADDI. Median ADDI score was 1 (0-11). Most common FMF-related damages were observed in musculoskeletal, reproductive and kidney domains. Female gender, inflammatory comorbidity, colchicine resistance, colchicine nonadherence, musculoskeletal attack dominance, diagnostic delay, follow-up time, and smoking history remained independent predictors of damage according to ADDI score. The rate of patients with damage defined by modified ADDI was only to 23%. M694V/M694V homozygosity, female gender, musculoskeletal attack dominance, colchicine resistance, persistent inflammation, follow up time and family history of amyloidosis were found to be predictors of damage according to modified ADDI score. CONCLUSIONS: Our study is the first to apply comprehensive damage indexes to FMF patients and identified predictors of damage. Factors linked to a severe FMF phenotype, including M694V homozygosity and persistent inflammation, were associated with only modified ADDI. Our findings justify the concerns about musculoskeletal pain and might point to the need for re-evaluation of ADDI for FMF patients.

Tofacitinib for the treatment for colchicine-resistant familial Mediterranean fever: case-based review.

Familial Mediterranean fever is characterized by self-limited attacks of serositis and arthritis. However, substantial number of patients suffer from chronic complications of this disease, primarily involving musculoskeletal system. Treatment for these complications is challenging due to limited evidence. Interleukin-1 (IL-1) antagonists, tocilizumab and anti-tumor necrosis factor (anti-TNF) agents are off-label treatment options for the management of chronic manifestations of FMF, such as secondary (AA) amyloidosis, chronic arthritis and sacroiliitis. This paper presents a case series of four FMF patients who are refractory to IL-1 antagonists, anti-TNF agents and tocilizumab, who responded well to tofacitinib. The authors also conducted a comprehensive literature search for studies investigating tofacitinib use in FMF patients. Although still limited, current data suggest that tofacitinib could be a useful treatment option for FMF patients with associated inflammatory comorbid conditions and chronic manifestations of disease.

Familial Mediterranean fever is associated with a wide spectrum of inflammatory disorders: results from a large cohort study.

Familial Mediterranean fever (FMF) is characterized by recurrent short-lived/self-limiting inflammatory attacks. Besides these, a substantial number of patients with FMF present with a variety of other inflammatory diseases; however, this issue has not been systematically studied previously. Hence, we aimed to investigate the frequency of inflammatory comorbid diseases in a large FMF cohort. All patients were recruited from "FMF in Central Anatolia (FiCA) Cohort", comprising 971 (mean age 35.3 ± 12 years, 61.5% female) adult subjects. All patients fulfilled Tel Hashomer criteria. Demographic data, FMF disease characteristics, MEFV gene mutations, and comorbid inflammatory diseases were meticulously questioned, and laboratory features and genotype data were retrieved from hospital records. There were comorbid inflammatory diseases in 205 (21.1%) patients. The most common inflammatory disease was spondyloarthritis (12.9%). Other remarkable inflammatory disorders were psoriasis, immunoglobulin A vasculitis/Henoch-Schönlein purpura, Behçet's disease and inflammatory bowel diseases. Cryptogenic organizing pneumonia is a newly defined entity in our cohort which is seemed to be associated with FMF (0.3%). Number of patients with persistent inflammation was higher in those with comorbid diseases (p < 0.001). Our results suggest that FMF is commonly associated with other inflammatory diseases. Therefore, clinicians should be cautious about comorbid inflammatory diseases in FMF patients, particularly in those with persistent inflammation. Identification of pathogenic pathways linking FMF to these diseases warrants further investigations.

Effectiveness of Canakinumab in Colchicine- and Anakinra-Resistant or -Intolerant Adult Familial Mediterranean Fever Patients: A Single-Center Real-Life Study.

OBJECTIVE: We aimed to present our single-center real-life experience of canakinumab use in adult patients with familial Mediterranean fever (FMF). METHODS: Data were derived from the Gazi FMF cohort, which was established in 2010. From that year, all patients with FMF were registered. The impact of FMF on their lives was tracked by either an FMF diary or mobile phone application (FMF-AIDD, free to download in App Store and Google Play). The records of patients who were treated with canakinumab were reviewed. RESULTS: Twenty-three adult patients with FMF (65% female) were enrolled in this study. The median age was 32 years (min-max, 24-58 years), and the disease duration was 26 years (14-59 years). A total of 86% of patients harbored homozygous or compound heterozygous exon 10 MEFV mutations. Indications for interleukin 1 inhibitor use were colchicine resistance (n = 12) or intolerance (n = 2), amyloidosis (n = 7), and chronic manifestations of the disease (n = 2). All patients used anakinra before. The median duration of canakinumab use was 7 months (min-max, 1-44 months). Pre- and post-canakinumab periods were compared. Attack severity, duration, frequency, C-reactive protein level, and erythrocyte sedimentation rate were significantly improved (p ≤ 0.01), whereas serum creatinine and alanine aminotransferase levels remained the same (p = 0.27 and p = 0.74, respectively). Canakinumab achieved complete disease remission in 14 patients (60%). Canakinumab was discontinued in 7 patients. The reasons for discontinuation were pregnancy (n = 2), dominance of axial spondyloarthropathy (n = 2), inflammatory bowel disease, patient's refusal, and weight gain. CONCLUSIONS: Canakinumab is effective in the prevention of FMF bouts without severe adverse effects. Treatment with canakinumab in an individualized dose and interval may be a reasonable choice for colchicine- and anakinra-resistant or -intolerant adult patients with FMF and those with chronic manifestations of disease.

Colchicine intolerance in FMF patients and primary obstacles for optimal dosing

Background/aim: Colchicine is the mainstay of treatment in FMF. However, in daily practice it is not easy to maintain effective colchicine doses in a substantial number of patients due to its side effects. In this study, we aimed to investigate prevalence and risk factors for colchicine side effects that limit optimal drug dosing and cause permanent discontinuation. Materials and methods: All patients were recruited from "FMF in Central Anatolia" (FiCA) cohort, 915 adults with a minimum follow- up time of 6 months during which they had obeyed all treatment instructions. Demographic and anthropometric data, FMF disease characteristics, disease severity, complications, and treatment features were recorded on a web-based registry. Prevalence of colchicine intolerance and characteristics of intolerant patients were analyzed. Results: Effective colchicine doses cannot be maintained in 172 (18.7%) subjects. Main side effects that limit optimal dosing were as follows: diarrhea in 99 (10.8%), elevation in transaminases in 54 (5.9%), leukopenia in 10 (%1.1), renal impairment in 14 (1.3%), myopathy in five (0.5%), and allergic skin reaction in two. Colchicine had to be permanently ceased in 18 (2%) patients because of serious toxicity. Male sex and obesity were found to be associated with liver toxicity, and having a normal body weight was associated with diarrhea. Chronic inflammation and proteinuria were more common in colchicine-intolerant patients, and they had reported more frequent attacks compared to those tolerating optimal doses. Conclusion: Colchicine intolerance is an important problem in daily clinical practice, mainly due to diarrhea and liver toxicity. Suboptimal colchicine dosing is associated with complications.