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Objective: Prodrome is defined by manifestations that precede a familial Mediterranean fever (FMF) attack and predict its emergence. We aimed to determine the frequency, characteristics, and clinical determinants of prodrome in patients with FMF.Method: This cross-sectional study was conducted in a tertiary rheumatology clinic. During the clinical interview, all patients completed a standardized questionnaire about the pre-attack period. Prodrome was defined as the presence of any recurrent pre-attack manifestation occurring at least 4 h before an attack. Patients were classified according to whether they had prodrome of any kind of attack.Results: The study enrolled 401 patients aged 37.7 ± 11.0 years (mean ± sd). Male gender, M694V/M694V, homozygous MEFV mutation, peritonitis, pleuritis, and arthritis were more frequent in prodrome-positive patients. Altogether, 141 patients (35.2%) had prodrome. Male gender and ever having attack types of peritonitis or arthritis were independent clinical determinants of prodrome [relative risk (95% confidence interval): 1.72 (1.07-2.76), p = 0.02; 4.27 (1.80-10.1), p = 0.001; 1.77 (1.04-3.04), p = 0.04, respectively]. Age, MEFV mutations, pleuritis, and erysipelas-like erythema were not clinical determinants.Conclusions: All FMF patients, particularly males and patients who had peritonitis or arthritis at any time, should be questioned about prodrome. Prodrome should be analysed in terms of elucidating the pathogenesis of FMF and as an opportunity for a secondary prevention strategy for impending attacks. This study may shed light on prodrome for future cytokine or drug studies with the purpose of developing new cost-effective treatment protocols irrespective of colchicine resistance. [ABSTRACT FROM AUTHOR]

Objectives: Post-thrombotic syndrome (PTS) is a frequent and important consequence of deep vein thrombosis (DVT) for Behcet`s disease (BD) patients. Although various clinical scales are used to diagnose PTS, Villalta scale was accepted as the standard tool to diagnose and grade the severity of PTS. Poor quality of life (Qol) in the general population was defined for patients with PTS, however, studies in BD patients with PTS is limited. Our aim was to compare the performance of different scales to assess venous disease in BD patients with a history of DVT and to assess the relationship with quality of life. Methods: Patients with BD ( n = 194, M/F:157/37, age:39.1 ± 9.5 years) with a DVT history were investigated. Villalta, VCSS,CEAP scale and SF 36,Veines scales were used to assess venous disease and QoL respectively. Results: Among BD patients, 120 (61.9 %) patients were classified as having PTS by Villalta and of patients 18% had severe PTS. Half of patients with CEAP score <4 were classified as having PTS. Also, 42% of patients with CEAP>4 and almost two third of VCSS classified severe CVD patients was grouped in severe PTS by Villalta scale. VCSS and Villalta classified PTS patients had decreased disease specific and general Qol scores compared to the patients without PTS. Also, severe PTS group (by VCSS) had decreased veines QoL scores and PCS compared to mild/moderate group. Conclusion: BD patients with DVT have a high risk of PTS. Our results show that both Villalta scale and VCSS should be used to assess venous disease BD patients with DVT. However, VCSS classified severity of PTS can show better correlation with venous disease -specific QoL., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Polymyalgia rheumatica associated amyloidosis is an extremely rare condition that can be rapidly progressive with high morbidity and mortality and management is challenging. Tocilizumab is a monoclonal anti IL-6 receptor antibody which is in the therapeutic arsenal of polymyalgia rheumatica. The efficiency of tocilizumab in improvement of polymyalgia rheumatica activity score and decreasing steroid dose is well established, while efficiency in polymyalgia rheumatica associated amyloidosis has not been published. Herein, we reported a polymyalgia rheumatica patient with AA amyloidosis who was treated effectively with tocilizumab., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Introduction: Anti-tumor necrosis factor (anti-TNF) agents are commonly used in treatment of axial spondyloarthritis (axSpA), but clinical and radiological improvement is not achieved in all patients. We aimed to investigate the impact of anti-TNFs on inflammatory and noninflammatory parameters in patients with axSpA., Methods: In this longitudinal study, 30 biologic naïve axSpA patients with high disease activity and 30 healthy controls were enrolled. All patients were treated with anti-TNF agents for 6 months. ASDAS-CRP, BASDAI, BASFI, BASMI, patient and physician global assessments were evaluated. C-reactive protein, COX2, TNF-α IL-6, IL-17, IL-22, IL-23, IL-33, sclerostin, dickkopf-1, and noggin levels were evaluated at baseline and at 6 months of anti-TNF treatment., Results: At baseline, axSpA patients had significantly higher median (IQR) TNF-α levels, 34.4 (31.4-37.03) vs. 18.1 (12.1-28.4) pg/ml (p < 0.001), and lower DKK1, 446.7 (356.9-529.3) vs. 1088.7 (951.7-1244.4) pg/ml, and sclerostin, 312.4 (140.8-412.7) vs. 412.3 (295.4-512.8) pg/ml, compared to healthy controls (all p < 0.001). The median (IQR) serum levels of IL-17, IL-22, and IL-33 increased significantly after 6 months of anti-TNF treatment, from 93.3 (85.1-104.8) to 102.1 (86.6-114.6) pg/ml (p = 0.026), 159.2 (151.9-178.4) to 183.5 (156.3-304.6) pg/ml (p = 0.033), and 127.8 (106.6-186.1) to 147.06 (128.5-213.4) pg/ml (p = 0.016), respectively. Sclerostin and DKK-1 levels increased significantly after anti-TNF treatment from 312.4 (140.8-412.7) to 405.1 (276.3-452.5) pg/ml (p = 0.018) and 446.7 (356.9-529.3) to 881.3 (663.1-972.2) pg/ml (p < 0.001), while there was no significant change in noggin level., Conclusions: Many inflammatory cytokines increase after anti-TNF treatment and noggin is not affected by anti-TNF treatment in AxSpA. Noggin might be a therapeutic target in patients with axSpA., Key Points: • Anti-TNF therapy is not sufficient for complete blockage of the inflammatory process in axial spondyloarthritis. • The increase in IL-17, IL-22, and IL-33 may decrease the efficiency of anti-TNF therapy. • Noggin might be a therapeutic target as a complementary or alternative approach to anti-TNF therapy in axial spondyloarthritis., (© 2022. International League of Associations for Rheumatology (ILAR).)

Background: Comedication with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) during treatment with tumour necrosis factor inhibitors (TNFi) is extensively used in psoriatic arthritis (PsA), although the additive benefit remains unclear. We aimed to compare treatment outcomes in patients with PsA treated with TNFi and csDMARD comedication versus TNFi monotherapy., Methods: Patients with PsA from 13 European countries who initiated a first TNFi in 2006-2017 were included. Country-specific comparisons of 1 year TNFi retention were performed by csDMARD comedication status, together with HRs for TNFi discontinuation (comedication vs monotherapy), adjusted for age, sex, calendar year, disease duration and Disease Activity Score with 28 joints (DAS28). Adjusted ORs of clinical remission (based on DAS28) at 12 months were calculated. Between-country heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Secondary analyses stratified according to TNFi subtype (adalimumab/infliximab/etanercept) and restricted to methotrexate as comedication were performed., Results: In total, 15 332 patients were included (62% comedication, 38% monotherapy). TNFi retention varied across countries, with significant heterogeneity precluding a combined estimate. Comedication was associated with better remission rates, pooled OR 1.25 (1.12-1.41). Methotrexate comedication was associated with improved remission for adalimumab (OR 1.45 (1.23-1.72)) and infliximab (OR 1.55 (1.21-1.98)) and improved retention for infliximab. No effect of comedication was demonstrated for etanercept., Conclusion: This large observational study suggests that, as used in clinical practice, csDMARD and TNFi comedication are associated with improved remission rates, and specifically, comedication with methotrexate increases remission rates for both adalimumab and infliximab., Competing Interests: Competing interests: BeG reports grants from BMS, grants from Pfizer, grants from AbbVie, outside the submitted work. AC reports consultancy and speaker fees from Abbvie, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer. MP-S reports speaker and research fees from Gilead, Janssen, MSD and Sanofi. KE reports consulting fees from Lilly, Biogene, Sobi, Pfizer and Gilead. HR reports personal fees from AbbVie, personal fees from Roche, personal fees from Pfizer, outside the submitted work. BjG reports other from Novartis, other from Amgen, outside the submitted work. GTJ reports grants from AbbVie, grants from Pfizer, grants from UCB, grants from Celgene / Amgen, grants from GSK, outside the submitted work. CC reports speaker fees and grants from AbbVie, Amgen, Egis, Novartis, Pfizer and UCB. RI reports speaker fee from Abbvie, Amgen, Novartis, Pfizer, Lilly and UCB. JZ reports speaker and consulting fees from Elli-Lilly, Abbvie, Novartis and UCB. SY reports speaker fees from Abbvie, MSD, Novartis, UCB, Sanofi and Pfizer. BM reports grants and personal fees from Novartis, outside the submitted work. ZR reports speaker fees, consultancy fees and support to biorx.si registry by, AbbVie, Amgen, Biogen, Eli Lilly, Janssen, Medias, Medis, MSD, Novartis, OPH Oktal Pharma, Sandoz and Pfizer. MTreports speaker fees, consultancy fees and support to biorx.si registry by, AbbVie, Amgen, Biogen, Eli Lilly, Janssen, Medias, Medis, MSD, Novartis, OPH Oktal Pharma, Sandoz and Pfizer. FI reports consultancy fees and/or speaker honoraria from Pfizer, AbbVie, MSD, BMS, Lilly, Novartis, Sanofi, Celgene and UCB, outside this work. MJS reports personal fees from Abbvie, Novartis and Pfizer, outside the submitted work. PA-R reports research grant (paid to academic research institute) from Novartis. LMØ reports grants from Novartis, during the conduct of the study. MØ reports grants, personal fees and non-financial support from AbbVie, grants, personal fees and non-financial support from BMS, personal fees from Boehringer-Ingelheim, personal fees from Eli Lilly, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from Merck, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from UCB, grants and personal fees from Celgene, personal fees from Sanofi, personal fees from Regeneron, grants, personal fees and non-financial support from Novartis, personal fees from Gilead, outside the submitted work. LJ reports lecture and consulting fees from Pfizer, Abbvie, Novartis, Eli-Lily and Janssen. JA reports grants from Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB, outside the submitted work. MN reports research and consulting fees from Abbvie, Celgene, Eli-Lilly, Janssen, Novartis and Pfizer., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Deep vein thrombosis (DVT) of the lower extremities is the most common form of vascular involvement in Behçet disease (BD), frequently leading to post-thrombotic syndrome (PTS) as a disabling complication. We have described the clinical characteristics and predictors of PTS presence among patients with BD and lower extremity DVT. We also used venous Doppler ultrasound (US) examinations in our assessment., Methods: Patients with BD (n = 205; 166 men, 39 women; age 39 ± 9.5 years) and a history of DVT were investigated. The Villalta scale was used to assess the presence and severity of PTS. Doppler US examinations were performed within 1 week of the clinical evaluation. The total number of vessels with reflux, thrombi, recanalization, and collateral vessels were calculated., Results: Of the 205 patients with BD, 62% had had PTS and 18% had had severe PTS. Patients with PTS had had greater reflux (P = .054) and thrombosis (P = .02) scores compared with patients without PTS. Treatment with anticoagulation (AC), immunosuppressive (IS) therapy, or AC combined with IS drugs did not affect the occurrence of PTS. However, patients treated with IS therapy, with or without AC drugs, had a decreased incidence of severe PTS compared with the AC-only group (P = .017). Patients treated with AC plus IS agents also had increased collateral scores compared with patients treated with only IS drugs. Interferon-α use seemed to provide better recanalization scores compared with azathioprine only (1.0 [range, 0-14] vs 2.5 [range, 0-10]; P = .010)., Conclusions: Patients with BD and DVT have a high risk of developing severe PTS. IS treatment decreases the development of severe PTS. AC therapy might influence the course of PTS by increasing the collateral scores, and the use of interferon-α also increased recanalization scores. Routine assessment with Doppler US examinations could be helpful in the prediction of severe PTS., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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.

Introduction: Familial Mediterranean fever (FMF) is characterized by recurrent attacks of fever, serositis, and arthritis. Some patients suffer from associated inflammatory conditions and damage related to FMF that may potentially impair work productivity which have not been studied to date., Methods: Consecutive FMF patients who were attending a tertiary referral center and age-and sex-matched healthy subjects enrolled into the study. Disease activity was assessed with autoinflammatory disease activity index (AIDAI) and patient global assessment. Damage was evaluated using Autoinflammatory Disease Damage Index (ADDI). Quality of life (QoL) and work productivity were determined with 36-Item Short Form Health Survey (SF-36) and Work Productivity and Activity Impairment Specific Health Problem v2.0 (WPAI:SHP), respectively., Results: There were 111 FMF patients, 60 female (54%), mean age 32.7±8.7 years. There were significant impairments in all domains of the SF-36 QoL in FMF patients. Of the 111 patients enrolled, 65 (58.6%) were employed in a paid work. Mean% ±SD impairment in work productivity both assessed as absenteeism (9.3±23.2% vs. 0.7±2.6, p=0.013) and presenteeism (35.2±32.6% vs. 9.6±14.7, p<0.001) were significantly higher in FMF patients compared to healthy subjects. Impairment in work productivity was correlated with the number of attacks, disease activity, colchicine resistance, and disease-associated damage. Impairment was most significant in colchicine-resistant FMF patients but lower in those on interleukin (IL)-1 antagonist treatments., Conclusions: FMF causes significant work impairment and reduced QoL which is associated with disease activity and damage. The use of IL-1 antagonists may help to improve work productivity and QoL in FMF patients with frequent attacks. Key points • Work productivity is impaired in patients with FMF. • Disease activity was an independent predictor for impaired work productivity. • IL-1 antagonists may improve work productivity and quality of life in FMF patients with frequent attacks.

Objective: To identify the biotinidase (BTD) gene mutations in patients with biotinidase deficiency in our region; and to determine the phenotype-genotype correlations in the presence of clinical findings., Study Design: Descriptive study., Place and Duration of Study: Department of Medical Genetics and Pediatric Metabolism Outpatient Clinic, Faculty of Medicine, Harran University, between January 2018 and June 2020., Methodology: Two hundred and nine patients, who were found positive for biotinidase deficiency in heel blood screening, were included. Genomic DNA was isolated from peripheral blood. Next-generation DNA sequencing analysis was performed using primers covering the exon regions of the BTD gene. The results were analysed by the mutation surveyor programme., Results: The most common mutation was c.1330 G>C (p.D444H) and the second most common mutation was c.470 G>A (p.R157H). The majority of the mutations are missense; and they are especially located in the exon 4. The most frequent mutations were found to be D444H and R157H with a rate of 66.66% in symptomatic patients., Conclusion: Common mutations in BTD deficiencies were indentified. Associating them with phenotype-genotype data will assist clinicians in better genetic counselling and management in the future by implementing prevention programmes. Key Words: Biotinidase deficiency, BTD gene, Newborn screening, Inherited metabolic disease, Newborn screening programme.

Competing Interests: The authors declare no conflict of interest.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.