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Objective: To determine the SpA prevalence and identify its associated factors in Crohn's disease (CD) patients receiving a systematically rheumatological and imaging assessment, including magnetic resonance imaging (MRI) of the sacroiliac joints and spine., Methods: CD patients either naive to biologics or without them for three months prior enrollment were recruited in a subgroup of the German Spondyloarthritis Inception Cohort (GESPIC-Crohn). A structured assessment of SpA manifestations was performed by a rheumatologist, including MRI of sacroiliac joints and spine. Demographic and clinical parameters including disease activity in CD (Harvey Bradshaw Index-HBI) and SpA (C-reactive protein - CRP, Bath Ankylosing Spondylitis Disease Activity Index, and Ankylosing Spondylitis Disease Activity Score) were collected. Univariable and multivariable logistic regression analyses were performed to identify factors associated with the presence of SpA., Results: A total of 103 patients with CD were included in the cohort. The mean CD disease duration was 1.3±2.4years and 95.1% were naïve to biologics. The most frequent musculoskeletal manifestation was back pain (65.0%), followed by chronic back pain (50.5%), and arthralgia (43.7%). Prevalence of SpA was 19.4% with slightly higher proportion of axial SpA than peripheral SpA, and higher proportion of radiographic axial SpA (7.4%) than non-radiographic axial SpA (2.8%). Changes in MRI compatible with axial SpA were found in 15 (14.7%) patients, of which 9 (81.1%) patients had the clinical diagnosis of axial SpA. HLA-B27 positivity (OR 9.02, CI 95% 2.29-35.55) and higher disease activity of CD as reflected by the HBI (OR 1.14, 95%CI 1.01-1.30) were significant and independently associated with the presence of SpA., Conclusion: SpA was present in nearly one out of five patients with CD and it was associated with the expression of HLA-B27 and a higher clinical activity of CD. Our findings raise awareness to rheumatologists and gastroenterologists on the high concomitance between both diseases and may help to reduce the delay in SpA diagnosis., (Copyright © 2022 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To investigate the longitudinal association between radiographic sacroiliitis progression and treatment with tumor necrosis factor inhibitors (TNFi) in patients with early axial spondyloarthritis (SpA) in a long-term inception cohort., Methods: We included patients from the German Spondyloarthritis Inception Cohort who underwent radiographic assessment of the sacroiliac joints at baseline and at least once more during the 10-year follow-up. Two central readers scored the radiographs according to the modified New York criteria for ankylosing spondylitis. The sacroiliac sum score was calculated as a mean of the scores determined by both readers. TNFi use was assessed according to exposure in the current and/or previous 2-year radiographic interval. The association between TNFi use and radiographic sacroiliitis progression was examined by longitudinal generalized estimating equation analysis with adjustment for potential confounders., Results: In this long-term inception cohort, 10-year follow-up data on 737 radiographic intervals assessed in 301 patients with axial SpA (166 patients with nonradiographic axial SpA and 135 patients with radiographic axial SpA) were obtained. Having received ≥12 months of treatment with TNFi in the previous 2-year radiographic interval was associated with a significant decrease in the sacroiliitis sum score (β = -0.09 [95% confidence interval (95% CI) -0.18, -0.003]; analyses adjusted for age, sex, symptom duration, HLA-B27 status, Bath Ankylosing Spondylitis Disease Activity Index score, C-reactive protein, and nonsteroidal antiinflammatory drug intake). In contrast, among patients receiving TNFi in the current radiographic interval, there was no significant association with change in the sacroiliitis sum score (β = 0.05 [95% CI -0.05, 0.14]). This effect of having received ≥12 months of treatment with TNFi in the previous 2-year radiographic interval was stronger in patients with nonradiographic axial SpA as compared to patients with radiographic axial SpA (β = -0.16 [95% CI -0.28, -0.03] versus β = -0.04 [95% CI -0.15, 0.07])., Conclusion: Treatment with TNFi was associated with the reduction in radiographic sacroiliitis progression in patients with axial SpA. This effect became evident between 2 and 4 years after treatment was initiated., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: The Simplified Disease Activity Index (SDAI) is a recommended composite score for assessing the remission status in patients with rheumatoid arthritis (RA). However, determination of C-reactive protein (CRP) levels takes several hours and sometimes days and limits the use of the SDAI in the clinical setting. The aim of this study was to validate the SDAI using a quick quantitative C-reactive protein (qCRP) assay (as SDAI-Q) in RA patients., Design: This is a multicenter, prospective, cross-sectional pilot study in RA patients., Methods: Adult patients (⩾18 years) with a clinical diagnosis of RA were recruited between January 2020 and September 2020 from five rheumatologic centers located in Berlin, Germany. SDAI, SDAI-Q, Clinical Disease Activity Index (CDAI), and DAS28 scores comprising CRP, qCRP, or erythrocyte sedimentation rate (ESR) were calculated. The agreement of disease activity categories was analyzed using cross tabulations and weighted Cohen's kappa. The agreement of numerical values was analyzed with Bland-Altman plots and intraclass correlation coefficients (ICCs)., Results: Overall, 100 RA patients were included in the statistical analysis. The mean value of qCRP (7.89 ± 16.98 mg/l) was slightly higher than that of routine laboratory CRP (6.97 ± 15.02 mg/l). Comparing SDAI and SDAI-Q, all patients were assigned to identical disease activity categories. Agreement of disease activity categories by CDAI and SDAI/SDAI-Q was observed in 93% with a weighted Cohen's kappa of 0.929 (95% confidence interval (CI) = 0.878; 0.981)., Conclusion: The SDAI-Q showed an absolute agreement regarding the assignment of disease activity categories in comparison with the conventional SDAI. Therefore, the SDAI-Q may facilitate the application of a treat-to-target concept in clinical trials and clinical routine as a quickly available disease activity score incorporating CRP as an objective parameter., (© The Author(s), 2022.)

Objective: The objective of the current study was to analyse the association between treatment with tumour necrosis factor inhibitors (TNFi) and radiographic spinal progression in patients with axial spondyloarthritis (axSpA) from a long-term inception cohort., Methods: A total of 243 patients with axSpA from the German Spondyloarthritis Inception Cohort with at least two sets of spinal radiographs obtained at least 2 years apart during a 10-year follow-up were included. Spinal radiographs were evaluated by three trained and calibrated readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The association between the current TNFi, previous TNFi and radiographic spinal progression defined as the absolute mSASSS change score over 2 years was analysed using longitudinal generalised estimating equations analysis., Results: TNFi treatment in the current 2-year interval was not associated with retardation of radiographic spinal progression (β=-0.02 (95% CI -0.37 to 0.34) and -0.17 (95% CI -0.54 to 0.20) for any and ≥12 months treatment duration, respectively, adjusted for sex, the Ankylosing Spondylitis Disease Activity Score, smoking, presence of definite radiographic sacroiliitis, mSASSS at baseline and non-steroidal anti-inflammatory drug intake). TNFi treatment in the previous 2-year interval, was, however, significantly associated with reduction of mSASSS progression, which was especially evident in patients who received TNFi in the previous and in the current intervals: β=-0.58 (95% CI -1.02 to -0.13), adjusted for the same variables., Conclusion: TNFi treatment was associated with a time-shifted effect on radiographic spinal progression in axSpA that became evident between years 2 and 4 after treatment initiation., Competing Interests: Competing interests: VRR: reports grants and personal fees from Falk e.V., consulting fees from AbbVie. FP: reports grants and personal fees from Novartis and Lilly, and personal fees from AbbVie, AMGEN, BMS, Celgene, MSD, Pfizer, Roche, UCB, and Janssen. MP: reports personal fees from Novartis and UCB. JR: reports personal fees from Novartis and UCB. HH: reports consulting fees from Boehringer, Janssen, MSD, Novartis, Sobi; personal fees from MSD, Janssen, Roche, Pfizer, Novartis, AbbVie, and Sobi. JS: reports consulting fees from: AbbVie, Lilly, Merck, Novartis, UCB; consulting fees from: Abbvie, Lilly, Merck, Novartis, UCB; speaker fees from: Abbvie, Janssen, Lilly, Merck, Novartis, UCB; personal fees from: AbbVie. MR: reports personal fees from: Abbvie, Janssen, Eli Lilly, Novartis, Galapagos, Pfizer, and UCB; speaker fees from: Abbvie, Boehringer Ingelheim, Celgene, Chugai, BMS, Eli Lilly, Janssen, Novartis, Pfizer, UCB. DP: reports research support from: AbbVie, Eli Lilly, MSD, Novartis, Pfizer; consulting fees from: AbbVie, Biocad, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB; speaker fees from: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, and UCB., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe the clinical characteristics of neuro-Behçet's syndrome (NBS) and to define the factors associated with relapses and poor outcome., Methods: Among 2118 patients with Behçet's syndrome who fulfilled the international study group criteria, 208 (9.8%) patients had NBS. Retrospective data of 125 NBS patients (55.5% male; mean age 37.2 ± 11.8 years) were analysed. We divided patients into two subgroups, either parenchymal (p-NBS) or non-parenchymal (np-NBS), according to international consensus recommendations for NBS. We assessed the predictor factors associated with relapse and poor outcome-which was defined as a modified Rankin score (mRS) ≥ 3 at last follow-up and/or death-using Cox and logistic regression analyses, respectively., Results: In total, 79 (63.2%) patients presented with p-NBS and 46 (36.8%) presented with np-NBS. Ocular involvement was more common in p-NBS than np-NBS (55.7% vs. 37.0%, p = 0.04), whereas vascular involvement excluding cerebral vein thrombosis was more frequent in patients with np-NBS (19.0% vs. 52.2%, p < 0.001). Forty-two patients (33.6%) experienced at least one relapse. Factors associated with relapse were BS diagnosis at a younger age and cranial nerve dysfunction (HR 0.96 95% CI 0.93-0.99 and 2.36 95% CI 1.23-4.52, respectively). After a median of 68 (Q1-Q3: 25-125) months, 23 patients (18.4%) had a poor outcome. Indicators of a poor outcome were higher initial mRS and the progressive p-NBS type (OR 8.28 95% CI 1.04-66.20 and 33.57 95% CI 5.99-188.21, respectively)., Conclusion: Our findings indicate that clinical characteristics and prognosis differ between NBS subgroups, of which patients with p-NBS have worse outcomes., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The objective of the study was to validate the Ankylosing Spondylitis Disease Activity Score (ASDAS) based on a quick quantitative C-reactive protein (qCRP) assay (ASDAS-Q) in a multicentre, prospective, cross-sectional study in patients with axial spondyloarthritis (axial SpA)., Methods: Disease activity assessment was performed in prospectively recruited patients with axial SpA. Routine laboratory CRP was determined in the central laboratory of each study centre, while quick qCRP and erythrocyte sedimentation rate (ESR) were measured locally. Consequently, ASDAS-CRP, ASDAS-Q using the qCRP and ASDAS-ESR were calculated. The absolute agreement on the disease activity category ascertainment was analysed with cross-tabulations and weighted Cohen's kappa. Bland-Altman plots and intraclass correlation coefficients (ICCs) were used to analyse the criterion validity., Results: Overall, 251 axial SpA patients were included in the analysis. The mean qCRP value (6.34 ± 11.13 mg/l) was higher than that of routine laboratory CRP (5.26 ± 9.35 mg/l). The ICC for routine laboratory CRP versus qCRP was 0.985 [95% confidence interval (CI): 0.972-0.991]. Comparing ASDAS-Q with ASDAS-CRP, 242 of 251 (96.4%) patients were assigned to the same disease activity categories with a weighted Cohen's kappa of 0.966 (95% CI: 0.943-0.988) and ICC of 0.997 (95% CI: 0.994-0.999)., Conclusions: ASDAS-Q showed an almost perfect agreement with ASDAS-CRP in the assignment to specific disease activity categories. Consequently, ASDAS-Q using the qCRP value can be applied as an accurate and quickly available alternative to ASDAS-CRP, thus facilitating the implementation of the treat-to-target concept in clinical trials and clinical routine., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FP: reports grants and personal fees from Novartis, Lilly and UCB and personal fees from AbbVie, AMGEN, BMS, Hexal, MSD, Pfizer and Roche all outside the presented work. JBJ: reports personal fees from AbbVie, Affibody, BMS, Gilead, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis and UCB all outside the presented work. GRB: reports personal fees from AbbVie, Lilly, Janssen, Novartis, Amgen and Pfizer all outside the presented work. HH: reports personal fees from from Janssen, AbbVie, MSD, Pfizer, Novartis and Roche all outside the presented work. KK: reports personal fees from AbbVie, Lilly, Roche, Novartis, Sanofi and Galapagos all outside the presented work. BM: reports personal fees from UCB, Amgen, Gilead and Hexal Sandoz all outside the presented work. DP: reports grants and personal fees from AbbVie, Eli Lilly, MSD, Novartis and Pfizer, and personal fees from Bristol-Myers Squibb, Roche, UCB, Biocad, GlaxoSmithKline and Gilead all outside the presented work. JS, HCB, HK, SL, MP, VRR, MT, MV and SZ have nothing to disclose., (© The Author(s), 2022.)

Objectives: To describe demographic and clinical characteristics of vascular involvement in patients with Behçet's syndrome (BS) and to evaluate associations with such involvement., Methods: We retrospectively evaluated records of 2118 BS patients. In total, 460 patients diagnosed with superficial thrombophlebitis (ST) and/or major vascular events (venous and/or arterial involvements) were included in current analysis. Isolated ST with no accompanying deep venous thrombosis might be accepted as part of skin involvement; therefore, we defined two different outcomes for vascular involvement ("any vascular event" and "major vascular events") and performed univariable and multivariable logistic regression to assess factors associated with these outcome variables., Results: Overall, 68 (14.8%) patients had isolated ST, and 392 (85.2%) had major vascular events. The mean age of vascular BS was 33.8 (SD: 10.5) years and median follow-up was 13.9 (Q1-Q3: 8.3-22.9) years. The primary sites of major vascular events were deep venous thrombosis (n=358, 77.8%), pulmonary arterial involvement (n=66, 14.3%), extrapulmonary arterial involvement (n=52, 11.3%), and intracardiac thrombosis (n=14, 3.0%), respectively. Male sex was significantly associated with a higher risk for both outcome variables. When it was added to analysis, ST itself was the strongest explanatory variable that was associated with major vascular events in all multivariable models (ORs=11.9, 12.0, 13.0, and 18.9). While HLA-B51 was significantly associated with any vascular event, there was no similar observation for major vascular events., Conclusion: Male sex is a well-known risk factor for major vascular events in BS, but our study established that presence of ST was the strongest risk factor., (Copyright © 2021 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Behçet syndrome (BS) is a multisystemic chronic vasculitic disease. Among previous studies, although there are some that showed increased risk of subclinical atherosclerosis in BS, there are also others that showed the opposite. The objective of this study is to evaluate subclinical atherosclerosis in BS by using the cutoff value for intima-media thickness in the 2013 European Society of Cardiology/European Society of Hypertension guideline., Methods: We conducted a cross-sectional analysis of 100 BS patients and 30 healthy volunteers at a single center in a 4-month period. All ultrasound scans were performed in a blind manner to the clinical assessment, and they were carried out by the same researcher by a B-mode ultrasonography., Result: When we grouped the patients based on the presence of subclinical atherosclerosis, the frequency of subclinical atherosclerosis in the BS patients was found to be higher than that in the healthy controls (32% and 7%, respectively; p = 0.006). When a cutoff is used for carotid intima-media thickness, increased atherosclerosis risk is observed in BS patients with vascular involvement (p = 0.043)., Conclusions: Although higher inflammation and increased atherosclerosis in vascular BS patients were expected, this situation was not supported much in previous studies. We think that this may have been caused by mere comparison of numerical data, and usage of a cutoff value could be more significant in distinguishing what is normal and what is abnormal as in several medical parameters., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To demonstrate the effects of rituximab (RTX) in patients with rheumatoid arthritis-related interstitial lung disease (RA-ILD)., Methods: A total of 165 patients who used RTX for the management of rheumatoid arthritis were retrospectively scrutinised. Among these, 26 patients diagnosed with RA-ILD were analysed (61.5% male, mean age at RTX infusion 61.4 ± 6.5 years). To evaluate the efficacy of RTX on lung response, patients with pulmonary function test results and/or thorax computed tomography (chest-CT) of pre- and post-RTX were compared. Disease progression was defined as either a decline of ≥10% in forced vital capacity (FVC) and/or a decline of ≥15% in diffusion capacity of carbon monoxide (DLCO), or an increase of parenchymal involvement on chest-CT images according to the radiologists' assessment., Results: Among 26 patients, the most common radiologic pattern was usual interstitial pneumonia (42.3%), followed by non-specific interstitial pneumonia (38.5%). Data for lung response was available in 20 patients. Median pre- and post- RTX DLCO values were 71.0% (60.0-77.0) and 63.0% (47.0-74.0), respectively (p= 0.06). Median pre- and post-RTX FVC values were 74.0% (61.0-99.0) and 84.0% (63.0-100.0), respectively (p= 0.28). Overall, stabilization or regression of RA-ILD was provided in 13 (65.0%) patients, whereas 7 patients had progressive RA-ILD. Post-RTX, 5 patients were diagnosed with RA-ILD., Conclusion: Our results suggest that RTX is effective in achieving stabilization or even improvement of RA-ILD. However, considering that it does not cause regression in every patient and some develop RA-ILD under RTX, we still need more effective treatment options., Competing Interests: Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article., (Copyright: © 2021 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Background: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microangiopathy, inflammation, fibrosis. Interstitial lung disease (ILD) is common among SSc patients., Objective: This study aims to define the clinical, laboratory, and serologic characteristics of SSc patients with ILD and to present the frequency of chest computed tomography features., Methods: Two hundred twenty-six SSc patients who applied to the Rheumatology Department between January 2007 and August 2019 were retrospectively examined. A total of 100 SSc patients with ILD (44.2%) were determined. Clinical, laboratory, and serological features of SSc patients with and without ILD were compared., Result: Both groups had similar characteristics in terms of age and sex. The duration of disease (p=0.001) and follow-up time (p=0.001) were longer in SSc patients with ILD. Multivariable logistic regression analysis indicated that the duration of disease (OR: 1.06 (1.01-1.13), p=0.029), presence of gastrointestinal system involvement (OR: 3.29 (1.28-8.46), p=0.013) and anti-SCL70-positivity (OR: 6.04 (2.35-15.49), p <0.001) were associated with ILD. There was an inverse relationship between Anti-CENP-B positivity and the presence of ILD (p=0.001). The assessment regarding the chest computed tomography characteristics of interstitial pneumonia patterns were as follows: 82.5% non-specific interstitial pneumonia, 14.4% usual interstitial pneumonia, and 2.1% desquamative interstitial pneumonia. The most frequent abnormal findings included ground-glass opacification (88.7%), reticulation (64.9%), traction bronchiectasis (57.7%), septal thickening (52.6%) and honeycombing (28.9%)., Conclusion: We have shown a relationship between anti-SCL70, disease duration, gastrointestinal system involvement, and ILD in SSc patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research., Design: Prospective, multicenter, multinational, cross-sectional study., Methods and Analyses: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of ⩽10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information., Ethics: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Registration: ClinicalTrials.gov ID: NCT04434885., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DP: reports grants and personal fees from AbbVie, Eli Lilly, MSD, Novartis and Pfizer, and personal fees from Bristol Myers Squibb, Roche, UCB, Biocad, GlaxoSmithKline and Gilead. XB: reports grants and personal fees from AbbVie and Novartis, and personal fees BMS, Chugai, Eli Lilly, MSD, Pfizer, UCB, Galapagos and Gilead. FVdB: received speaker and/or consultancy fees from AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer and UCB. JB: has received honoraria for talks, advisory boards, paid consultancies and grants for studies from Abbvie (Abbott), Amgen, Baxter, Biogen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Fresenius, GlaxoSmithKline, Gilead, Hexal, Janssen, Lilly, Medac, MSD (Schering-Plough), Mylan, Mundipharma, Novartis, Pfizer (Wyeth, Hospira), Roche, Sanofi-Aventis and UCB. LCC: reports grant/research support from Abbvie, Amgen, Celgene, Lilly, Novartis, Pfizer and honoraria from Abbvie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Galapagos, Gilead, GSK, Janssen, Lilly, Medac, Novartis, Pfizer and UCB. VC: reports honoraria and/or research grants from Abbvie, Amgen, BMS, Eli Lilly, Janssen, Novartis, Pfizer and UCB, and is supported by a Pfizer Chair Rheumatology Research Award from the Department of Medicine, University of Toronto; spouse is an employee of AstraZeneca. TD: reports personal fees from Novartis Pharma, MSD and Canon MS, outside the submitted work. FAvG: reports grants from Stichting vrienden van Sole Mio, Stichting ASAS, UCB and Novartis and honoraria from Novartis, MSD, Abb Vie and Bristol Myers Squibb. LSG: reports grants and personal fees from UCB and Pfizer, and personal fees from AbbVie, Eli Lilly, Janssen and Novartis. NG: Employed by Abcuro, Inc; stockholder UCB. ABG: received honoraria as an advisory board member and consultant for AnaptsysBio, Avotres Therapeutics, Beiersdorf, Boehringer Ingelheim, Bristol Myers Squibb Co., Incyte, GSK, Janssen, LEO Pharma, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical Industries, Inc., UCB, Dermavant and Xbiotech. ABG has received research / educational grants from Boehringer Ingelheim, Incyte, Janssen, Novartis, UCB, Xbiotech and Sun Pharma. DvdH: reports personal fees from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB Pharma, outside the submitted work; and Director of Imaging Rheumatology bv. PSH: received consulting fees (Eli Lilly) and fees for educational services (Pfizer, Novartis, Janssen). KGAH: reports lecture fees from AbbVie, MSD, Pfizer and Novartis. DJ: Although not directly related to this manuscript, DJ has received research grants, educational grants and/or speaker honoraria from AbbVie, Amgen, Biogen, BMS, Celgene, Celltrion, Eli Lilly, Gilead, GSK, Janssen, MSD, Novartis, Pfizer, Roche, Sandoz, Sanofi and UCB. DJ acknowledges that his research time is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-42001) and Cambridge Arthritis Research Endeavour (CARE). RGL: has acted as a paid consultant for Calyx, CARE Arthritis, IA Group, Novartis and Pfizer. WPM: is Chief Medical Officer of CARE Arthritis Ltd and has acted as a paid consultant/participated in advisory boards for AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB; received research and/or educational grants from AbbVie, Novartis, Pfizer and UCB; and received speaker fees from AbbVie, Janssen, Novartis, Pfizer and UCB. PM: reports grants and personal fees from AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sun and UCB, and personal fees from Boehringer Ingelheim and GlaxoSmithKline. PN: reports consulting / speaker fees from Abbvie, Bristol Myers Squibb, Gilead, Janssen, Novartis, Lilly, Pfizer, Celgene, Roche, Boehringer, Sanofi, Merck, outside the submitted work. FP: reports grants and personal fees from Novartis, Lilly and UCB, and personal fees from AbbVie, AMGEN, BMS, Hexal, MSD, Pfizer and Roche. MP: reports personal fees from Novartis. DDG: Grant support from Abbvie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and UBC, and consulting fees from Abbvie, Amgen, BMS, Galapagos, Gilead, Eli Lilly, Janssen, Novartis, Pfizer and UCB. JS: has nothing to disclose. MT: has nothing to disclose., (© The Author(s), 2021.)

Introduction: Psoriatic arthritis (PsA) is an inflammatory disease characterised by synovitis, enthesitis, dactylitis and axial involvement. The prevalence of axial involvement ranges from 25% to 70% in this patient group. Treatment recommendations for axial PsA were mainly extrapolated from guidelines for axial spondyloarthritis, and the main treatment options are non-steroidal anti-inflammatory drugs and biological disease-modifying antirheumatic drugs (tumour necrosis factor, IL-17 and IL-23 inhibitors). Tofacitinib was approved for the treatment of PsA and its efficacy on axial inflammation has been demonstrated in a phase II study of ankylosing spondylitis (AS). This prospective study aims to evaluate the efficacy of tofacitinib in reducing inflammation in the sacroiliac joints (SIJs) and spine on MRI in patients with axial disease of their PsA presenting with active axial involvement compatible with axial PsA., Methods and Analyses: This is a randomised, double-blind, placebo-controlled, multicentre clinical trial in patients with axial PsA who have evidence of axial involvement, active disease as defined by a Bath AS Disease Activity Index score of ≥4 and active inflammation on MRI of the SIJs and/or spine as assessed by and independent central reader. The study includes a 6-week screening period, a 24-week treatment period, which consist of a 12-week placebo-controlled double-blind treatment period followed by a 12-week active treatment period with tofacitinib for all participants, and a safety follow-up period of 4 weeks. At baseline, 80 subjects shall be randomised (1:1) to receive either tofacitinib or matching placebo for a 12-week double-blind treatment period. At week 12, an MRI of the whole spine and SIJs will be performed to evaluate the primary study endpoint., Ethics and Dissemination: The study will be performed according to the ethical principles of the Declaration of Helsinki and the German drug law. The independent ethics committees of each centre approved the ethical, scientific and medical appropriateness of the study before it was conducted., Trial Registration Number: NCT04062695; ClinicalTrials.gov and EudraCT No: 2018-004254-22; European Union Clinical Trials Register., Competing Interests: Competing interests: FP: research grants from Novartis; speaker and consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche and UCB Pharma. MT: has nothing to disclose. BM: travel cost, speaker and/or consulting fees from Amgen, Bristol-Myers Squibb, Gilead, Sandoz Hexal and Stadapharm. VR-R: has nothing to disclose. MV: has nothing to disclose. DP: research grants from AbbVie, MSD, Novartis, and Pfizer; speaker and/or consulting fees from AbbVie, Biocad, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKlein, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, and UCB Pharma., (© 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: To evaluate the diagnostic value of SpA parameters and their combination for the diagnosis of axial SpA in patients with an a priori different probability of the diagnosis., Methods: A total of 361 patients with chronic back pain and suspicion of axial SpA (181 referred by primary care physicians or orthopaedists, 180 recruited via an online screening tool) received a structured rheumatologic examination, which resulted into a diagnosis or exclusion of axial SpA. The prevalence of axial SpA indicating the pre-test probability was 40% in the physician-referred subgroup and 20% in the online screening subgroup. Sensitivities, specificities and likelihood ratios for SpA features were determined in both subgroups and the respective post-test probabilities of axial SpA were calculated., Results: The relative diagnostic value of single SpA features varied substantially between the groups with different referral pathways. For instance, HLA-B27 positivity increased the probability of the presence of axial SpA by 35% to 55% in online-screened patients and by 22% to 62% in physician-referred patients. The absence of HLA-B27 resulted in a sharp decrease in the probability of the presence of axial SpA in physician-referred patients (from 40% to 6%). This decrease was less sharp in the online screening group (from 20% to 10%). These differences were especially relevant in patients with a small number (one to two) of positive SpA features., Conclusion: The diagnostic value of SpA features varies in different patient populations, which should be considered in the diagnostic approach., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: High mobility group box- 1 (HMGB- 1) is a nuclear protein acting as a proinflammatory molecule. The serum HMGB- 1 levels were found elevated in chronic inflammatory diseases. In this cross-sectional study, serum HMGB- 1 levels in Behcet's disease (BD) patients and healthy controls (HC) were studied. Also, its association with disease activity scores and clinical findings were evaluated., Methods: Ninety BD patients and 50 age-sex matched HC were included in the study. Disease activity scores were assessed by Behcet Disease Current Activity Form (BDCAF) and Behcet Syndrome Activity Score (BSAS). Serum HMGB- 1 levels were measured using a commercial ELISA kit. A p value of < 0.05 was considered to be statistically significant., Results: Serum HMGB- 1 levels were significantly higher in BD than in HC (43.26 pg/mL and 16.73 pg/mL; p < 0.001, respectively). Serum HMGB- 1 levels were statistically significantly associated with presence of erythema nodosum (EN) and genital ulcers in the last one month prior to recruitment (p = 0.041 and p < 0.001, respectively). BDCAF and BSAS scores were positively correlated with serum HMGB- 1 level ( p = 0.03 and p = 0.02, respectively)., Discussion: HMGB - 1 may play a role in the development of BD. Also, due to its positive correlation with disease activity indices, it can be used as a novel disease activity parameter in BD.

Objective: To report the clinical characteristics of pulmonary artery involvement (PAI) in patients with Behçet's syndrome (BS) and to define the predictors of relapses., Methods: We performed retrospective analysis of BS patients with PAI who fulfilled international study group criteria. Among 460 patients with vascular Behçet's syndrome (VBS), 66 were diagnosed with PAI. For final analyses, 61 patients with PAI were included who had at least 2 follow-up visits (72.1% male, mean age at BS diagnosis 29.34 ± 10.1 years). The patient data were recorded. Relapse was defined as the reoccurrence of vascular event in any vascular structure. Factors associated with relapse were assessed by logistic regression analysis., Results: There were no differences considering demographic and clinical features of the patients with and without PAI in the VBS group, except that intracardiac thrombosis was more common in the patients with PAI (19.7% vs 0.3%). Among 61 patients, 50 (82.0%) had isolated pulmonary artery thrombosis (PAT), whereas 11 (18.0%) had pulmonary artery aneurysm with or without PAT. Twenty-four (39.3%) patients experienced vascular relapse during median follow-up of 65.9 (Q1-Q3: 20.1-109.0) months. To define the factors associated with relapses, patients with isolated PAT were analysed. On multivariable logistic regression analysis, older age at BS diagnosis and anticoagulation usage seemed to be protective (OR: 0.92, 95% CI 0.86-1.02, OR: 0.34, 95% CI 0.09-1.33, respectively)., Conclusion: Our results indicate a higher frequency of intracardiac thrombosis in BS patients with PAI and possible efficacy of anticoagulation usage in preventing relapses. Key Points • This study shows that intracardiac and intracranial thromboses are seen more frequently in patients with PAI and the prevalence of pulmonary artery thrombosis has been increasing in the case of PAI. Furthermore, our report indicates that anticoagulation might be effective in preventing further vascular relapses., (© 2021. International League of Associations for Rheumatology (ILAR).)

Background and Aims: Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking., Approach and Results: We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score-matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 × the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19., Conclusions: This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19., (© 2021 by the American Association for the Study of Liver Diseases.)

Background: Radiographs of the sacroiliac joints are commonly used for the diagnosis and classification of axial spondyloarthritis. The aim of this study was to develop and validate an artificial neural network for the detection of definite radiographic sacroiliitis as a manifestation of axial spondyloarthritis (axSpA)., Methods: Conventional radiographs of the sacroiliac joints obtained in two independent studies of patients with axSpA were used. The first cohort comprised 1553 radiographs and was split into training (n = 1324) and validation (n = 229) sets. The second cohort comprised 458 radiographs and was used as an independent test dataset. All radiographs were assessed in a central reading session, and the final decision on the presence or absence of definite radiographic sacroiliitis was used as a reference. The performance of the neural network was evaluated by calculating areas under the receiver operating characteristic curves (AUCs) as well as sensitivity and specificity. Cohen's kappa and the absolute agreement were used to assess the agreement between the neural network and the human readers., Results: The neural network achieved an excellent performance in the detection of definite radiographic sacroiliitis with an AUC of 0.97 and 0.94 for the validation and test datasets, respectively. Sensitivity and specificity for the cut-off weighting both measurements equally were 88% and 95% for the validation and 92% and 81% for the test set. The Cohen's kappa between the neural network and the reference judgements were 0.79 and 0.72 for the validation and test sets with an absolute agreement of 90% and 88%, respectively., Conclusion: Deep artificial neural networks enable the accurate detection of definite radiographic sacroiliitis relevant for the diagnosis and classification of axSpA.

Background and Aim: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC)., Methods: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints., Results: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P < 0.001) and seropositive for anti-mitochondrial antibodies (88% vs 84%, P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8% vs 43.6%, P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76 vs 1.98 × upper limit of normal [ULN], P = 0.006), aspartate aminotransferase (1.29 vs 1.50 × ULN, P < 0.001), and total bilirubin (0.53 vs 0.58 × ULN, P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3% vs 16.1%, P = 0.07) and Paris II response (71.4% vs 69.4%, P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8% vs 90.7%, P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjögren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome., Conclusions: Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: Calprotectin is an inflammatory biomarker which assesses disease activity in rheumatoid arthritis (RA). The objective of this study was to test whether serum calprotectin is associated with clinical and ultrasonographic disease activity in patients with RA, and to analyse its predicting value for disease activity evaluation despite normal C-Reactive protein (CRP) levels., Methods: We included 80 patients with RA and 30 healthy subjects. Patients were examined clinically and by ultrasound, (US7 score) along with laboratory parameters (calprotectin, CRP, erythrocyte sedimentation rate [ESR]). Disease activity scores (DAS28) were calculated to assess disease activity. Firstly, patients were divided into four subgroups according to the DAS28-ESR (high, moderate, low disease activity, and remission), then into two subgroups; group-1 (DAS-28≤3.2) and group-2 (DAS28>3.2). The predicting value of calprotectin for disease activity in patients with normal CRP was analysed with univariate and multivariate analysis and receiver operating characteristic curves., Results: Calprotectin levels were higher in RA patients than controls (96.3±45.9 ng/ml, 54.7±50.0 ng/ml, respectively; p<0.001). Calprotectin levels were 74.8±45.5 ng/ml in group-1 (n=37) and 114.7±37.9 ng/ml in group-2 (n=43) (p<0.001). In univariate analyses, calprotectin was significantly correlated with clinical, laboratory, and ultrasound parameters (p<0.05), and was a better predictor of power doppler synovitis than CRP in multivariate analysis (OR=1.014; 95%CI 1.002-1.027; p=0.024). The discriminatory capacity for calprotectin to distinguish ultrasonographically active disease in patients with normal CRP levels using AUC was 0.75 (95%CI 0.56-0.90, p=0.023)., Conclusions: Calprotectin represents disease activity, even in patients who are clinical and ultrasonographical active but have normal CRP levels., (© 2021 The Mediterranean Journal of Rheumatology (MJR).)

Aims: Long-term data on TNFi treatment in patients with axSpA is scarce. The objective of this analysis was to assess long-term clinical efficacy of etanercept in early axSpA [including both non-radiographic and radiographic axSpA forms], who participated in the long-term (until year 10) extension of the ESTHER-trial., Methods: In the previously reported ESTHER-trial, patients with early active axSpA were randomized to treatment with etanercept ( n  = 40) or sulfasalazine ( n  = 36) during the first year. Patients in remission discontinued their therapy and were followed up until the end of year 2; in case of remission-loss, etanercept was (re)-introduced and continued until the end of year 10. If remission was not achieved at year 1, patients continued receiving (or were switched to) etanercept for up to 10 years., Results: A total of 19 patients (12 with r-axSpA and 7 with nr-axSpA at baseline) out of the initial 76 patients (= 25%) completed year 10 of the study. In the entire group, a sustained clinical response was seen over 10 years of follow up in the as-observed analysis. Completers were significantly more often male and showed lower values of patient and physician global assessments of disease activity, Ankylosing Spondylitis Disease Activity Score (ASDAS), and Ankylosing Spondylitis Quality of Life questionnaire (ASQoL) scores at baseline as compared with non-completers. When analyzing clinical data of the completers, mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) values were constantly below 2 and mean ASDAS below 2.1 during follow up with no statistically significant differences between the r-axSpA and nr-axSpA subgroups. A total of 39 serious adverse events were documented over the 10 years, while six of them were seen as possibly associated with the etanercept treatment, which led in five patients to treatment discontinuation., Conclusion: A sustained clinical response was observed over the 10 years of the study with comparable response and drop-out rates between r-axSpA and nr-axSpA. Etanercept was well tolerated across the entire treatment period and showed a good safety profile with no new safety signals., Competing Interests: Conflict of interest statement: FP: research grants from Novartis; speaker and consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, and UCB Pharma. AW: has nothing to disclose. MT: has nothing to disclose. MP: speaker and consulting fees from AbbVie and Novartis. VRR: speaker and consulting fees from AbbVie and Novartis. HH: speaker and consulting fees from Janssen, MSD, Novartis, Pfizer, and Roche. OB: employee of Pfizer. JS: research grants from AbbVie, Janssen, MSD, Pfizer, Roche; speaker and consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, and UCB Pharma. DP: research grants from AbbVie, MSD, Novartis, and Pfizer; speaker and/or consulting fees from AbbVie, Biocad, Bristol-Myers Squibb, Gilead, Eli Lilly and Company, GlaxoSmithKline, MSD, Novartis, Pfizer, Roche, and UCB Pharma., (© The Author(s), 2021.)

Background/aims: Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are the 3 main autoimmune liver diseases (AILDs). The epidemiology of AILD in Turkey is not known. To determine the scientific status, we performed a scientometric analysis of AILD-related original articles that originated from Turkey., Materials and Methods: We searched the Web of Science database, the Science Citation Index Expanded (SCI-E), and the Social Sciences Citation Index (SSCI) by using the keywords "autoimmune hepatitis," "primary biliary cholangitis/primary biliary cirrhosis," and "primary sclerosing cholangitis" in conjunction with "Turkey." A scientometric analysis was done on the search results., Results: We identified 117 AILD-related papers that were published in Turkey from 1997 to 2019. Among these, 70 case reports, letters, and reviews and 2 original articles that were not cited in SCI-E/SSCI were excluded. The remaining 45 original articles were further analyzed. These studies were related to AIH (n=22), PBC (n=7), PSC (n=9), PBC-AIH overlap (n=5), and others (n=2). Four of the publications originated in pediatric settings; 9 of 45 papers were published from 1997 to 2008 and 36 papers were published from 2009 to 2019. Most papers (75%) were reported from 5 centers; 9 papers (20%) were published in journals with an impact factor of 3 or higher., Conclusion: The overall number and quality of AILD-related papers in Turkey are unexpectedly low, although a number of papers have received considerable international recognition. More epidemiologic, prospective, and multicenter research projects are warranted to advance AILD knowledge and to produce high-quality research from Turkey.

Objectives: The diagnostic delay in axial spondyloarthritis (axial SpA) remains unacceptably high, with one of the reasons being a late referral. Structured physician-based referral programs are able to improve early diagnosis, but lack of implementation is still an issue. The objective of this study was to evaluate an online self-referral (OSR) tool for patients with back pain and to compare it to an established physician-based referral tool., Methods: Patients with back pain were included if they either fulfilled the requirements of the OSR tool or were referred by a physician using the Berlin referral tool. Rheumatologists in the specialized center performed a structured assessment in all patients that resulted in the final diagnosis of axial SpA / no axial SpA. Furthermore, we attempted to optimize the OSR tool in terms of maximizing the specificity constrained by a sensitivity of at least 90% of the original strategy., Results: 361 consecutive patients (180 via the OSR and 181 via the Berlin referral tool) were included in the study. A total of 35 patients (19.4%) in the self-referral group and 71 patients (39.2%) in the physician-referral group were finally diagnosed with axial SpA. Axial SpA patients from the OSR group were more often HLA-B27 negative, females, and were more frequently at a non-radiographic stage as compared to axial SpA patients who came via the physician-based tool. Both groups had, however, a similar disease burden. According to the pre-defined selection criterion we identified an optimized combination of ≥2 IBP parameters and ≥1 other SpA parameters (in addition to both stem parameters)., Conclusions: Despite the better performance of the physician-based referral strategy, the proportion of axial SpA among self-referred patients (19.4%) was clearly higher than the assumed 5% prevalence of axial SpA in patients with chronic back pain. Based on our data driven approach the performance of the OSR strategy could be further improved if at least two IBP parameters plus one additional SpA parameter had to be present in addition to the stem parameters. The OSR tool can be used in specialized centers in addition to a physician-based referral strategy to improve early diagnosis and to increase awareness of axial SpA., Competing Interests: Declaration of Competing Interest Authors declare no conflicts of interest in relation to the content of the present work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction/objectives: Primary Sjögren syndrome (pSS) is usually encountered between the fourth and sixth decades. It is known that the age of onset in autoimmune diseases may affect the clinical features. In this study, we aimed to investigate the clinical and laboratory characteristics of early onset pSS patients., Method: The data of 352 pSS patients were analyzed retrospectively. The patients were divided into two groups as those with the onset age of 35 or younger (early-onset) and those with the onset age of older than 35. The clinical, laboratory, and serological characteristics of the two groups were compared. p < 0.05 was considered statistically significant., Results: Forty patients in the group with an onset age of 35 or younger (11.4%) and 312 patients with an onset age of older than 35 (88.6%) were analyzed. The frequency of skin (22.5% vs 1.9%, p < 0.001) and renal involvement (10% vs 2.2%, p = 0.026) was significantly higher in the early-onset group than the late-onset group. There was no significant difference between the two groups in terms of xerostomia, eye dryness, arthritis, and other systemic involvement. Anti-Ro52 positivity (p = 0.04), elevated serum IgG levels (p = 0.004), and low C4 (p = 0.002) presence were more frequent in the early-onset group., Conclusions: Consequently, it is seen that the clinical phenotype of early-onset pSS patients may be different to those with later onset. Especially the more frequent observation of poor prognostic factors at early-onset ages shows the necessity to monitor these patients more regularly., Key Points: • The clinical and laboratory features of patients with early-onset primary Sjogren syndrome may differ from late-onset patients.

Background/objective: Interleukin (IL) 35 is a member of the IL-12 family. Studies show that IL-35 is an important anti-inflammatory cytokine and suppresses effector T-cell activity. In this study, we aimed to evaluate serum IL-35 levels in systemic sclerosis (SSc) patients and its potential relation with clinical findings., Methods: We conducted a cross-sectional analysis of 70 SSc patients and 29 healthy volunteers in a single center in 5 months' period. Extension of skin fibrosis was evaluated by using modified Rodnan skin score. Disease severity was assessed by Medsger disease severity scores. Serum IL-35 was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Cloud-Clone Corp, Wuhan, China). The relationship between IL-35 levels and clinical and laboratory parameters was investigated. Mann-Whitney U test was used to compare parameters among the groups. Correlation was tested by Spearsman correlation coefficient., Results: Serum IL-35 levels was significantly higher in SSc patients (8.69 [interquartile range, 29.33] pg/mL) than in healthy controls (7.11 [interquartile range 7.53] pg/mL; p < 0.001). There was no significant relationship between serum IL-35 levels and organ involvement. There was a negative correlation between serum IL-35 levels and Medsger disease severity score (Rho, -0.333; p = 0.006), modified Rodnan skin score (Rho, -0.307; p = 0.010), and C-reactive protein (Rho, -0.294; p = 0.015). There was no relationship between IL-35 and disease duration and erythrocyte sedimentation rate., Conclusions: Our study revealed that IL-35 levels were higher in SSc patients, and in contrast to previous studies, it was the first study that showed that IL-35 levels did not increase in SSc patients with pulmonary fibrosis.

Introduction/objectives: Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), mean platelet volume (MPV), and red cell distribution width (RDW) may potentially reflect inflammatory status in systemic autoimmune diseases. The aim of this study is to investigate the association between these proposed markers and disease manifestations, activity, and severity in systemic sclerosis (SSc)., Method: We conducted a cross-sectional study of 69 systemic sclerosis (SSc) patients and 50 healthy volunteers in a single center. Adult patients with SSc and healthy controls were compared in terms of NLR, MLR, MPV, RDW, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Venous blood samples were drawn after at least 8 h of fasting in the morning. Extension of skin fibrosis was evaluated by using modified Rodnan skin score (mRSS). Disease severity and activity were assessed by Medsger disease severity and European Scleroderma Trials and Research Group (EUSTAR) disease activity scores, respectively. Associations of disease manifestations, clinical, laboratory, and capillaroscopic findings, mRSS, and the disease activity and severity scores with the proposed hematological markers were evaluated. Multiple regression models were generated for significant associations., Results: The neutrophil number was higher (p = 0.004) and lymphocyte number was lower (p < 0.001) in SSc group compared to controls. SSc group also had higher NLR, MLR, and RDW. In multiple logistic regression, only the NLR (regression coefficient = 3.49, p = 0.031) and CRP (regression coefficient = 0.17, p = 0.037) remained significantly different between SSc and healthy control groups (Cox and Snell R 2  = 0.243, Nagelkerke R 2  = 0.337, p < 0.001). NLR and MLR positively correlated with mRSS, EUSTAR score, and CRP. MLR also positively correlated with Medsger score. Higher monocyte counts independently predicted higher EUSTAR and Medsger scores in multiple linear regressions. Patients with digital ulcers had higher NLR and MLR. We did not find any difference in MPV values between SSc and healthy control groups., Conclusions: Globally available and inexpensive hematological tests, particularly the NLR and MLR, may be associated with vascular and cutaneous manifestations as well as disease activity and severity in SSc.Key Points• Monocyte count itself independently predicted higher activity and severity scores in SSc.• Globally available and inexpensive hematological markers, particularly the NLR and MLR, may have an association with vascular and cutaneous manifestations as well as disease activity and severity in patients with SSc.

Introduction: Interleukin (IL)-17 is a proinflammatory cytokine considered to play a significant role in the immunopathogenesis of ankylosing spondylitis (AS)/axial spondyloarthritis (axSpA) as well as of other spondyloarthritides. There is a number of substances targeting IL-17, which are at different stages of development in the axSpA indication., Areas Covered: This review summarizes the current evidence on the role of IL-17 in the pathophysiology of axSpA and provided a comprehensive review of clinical and radiographic outcomes as well as of safety data from studies with IL-17A inhibitors secukinumab and ixekizumab. Ongoing studies on other IL-17 inhibitors (bimekizumab, brodalumab and BCD-085) that are being developed are also summarized., Expert Opinion: The development of the IL-17 inhibitors has expanded AS treatment with effective options and confirmed the pathophysiological role of IL-17 in axSpA. IL-17 inhibition showed sufficient efficacy against signs and symptoms of the disease even after the failure of tumor necrosis factor inhibitors, being at the same time reasonably safe.

Interleukin-6 (IL-6), IL-15, and heat shock protein 72 (Hsp72) are molecules that have significant metabolic effects on glucose and fat metabolism and a cell's stress response. The aim of this study is to determine serum levels of these molecules in runners after a long-distance trail run. Serum IL-15 levels after such endurance events have not been investigated yet. Blood samples were collected from 37 athletes (11 female, 26 male) before and after a 35-km trail run, with a total climb of 940 m. Serum was obtained from the samples, and IL-6, IL-15, and Hsp72 levels were measured from using the sandwich ELISA method. The athletes completed the race in 308.3 ± 37.4 min on average. After the race, the mean serum IL-6, IL-15, and Hsp72 concentrations increased 13.2-fold, 2.22-fold, and 1.6-fold, respectively ( p < 0.001, p < 0.001, and p = 0.039, respectively). This is the first study to demonstrate the increase in serum IL-15 levels following an acute endurance exercise. In addition to IL-15, we report that IL-6 and soluble Hsp72 levels also increased significantly following a 35-km trail run. Since these molecules are involved in regulating glucose and fat metabolism, significant increases of IL-6, IL-15, and soluble Hsp72 may have health benefits that may be associated with long-distance trail runs, which are becoming more popular worldwide.

Introduction: Gastric cancer is ranked fourth among all cancers in the world and second in cancer-related deaths. Gastritis leads to the activation of neutrophils, lymphocytes, macrophages, and platelets. Long-term inflammation leads to multistage histopathologic changes called Correa tract, which includes gastritis, atrophy, intestinal metaplasia (IM), dysplasia, and cancer stages., Aim: To determine if there is any difference in haematological parameters between gastric cancer (GC) patients, patients with IM, and healthy controls (HC)., Material and Methods: Seventy-three GC patients, 79 patients with IM, and 70 HCs were included in the study. Demographics and laboratory parameters of complete blood count were extracted from the hospital medical database records., Results: The mean Hb levels were statistically significant between all three groups. Mean red cell distribution width (RDW), white blood cells (WBC), mean platelet volume (MPV), platelet distribution width (PDW), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and monocyte-to-lymphocyte (MLR) levels were statistically significantly different between gastric cancer and healthy controls. Mean RDW, MPV, and PDW levels were statistically significantly different between the IM and healthy control groups. Mean WBC, NLR, PLR, and MLR levels were statistically significantly different between the gastric cancer and IM groups., Conclusions: RDW, platelet count, NLR, MLR, and PLR have diagnostic value and can help to distinguish patients with GC from those with IM. These parameters are accessible easily, the cost is not high, and it may help patients not to delay endoscopic screening., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2019 Termedia Sp. z o. o.)

Background: Post-operative hypoparathyroidism is a complication in patients who undergo thyroid surgery. Our study aimed to evaluate the incidence and causes of post-operative transient and permanent hypoparathyroidism in patients undergoing thyroid surgery., Materials and Methods: The data of 933 consecutive patients who underwent total thyroidectomy in a single center were retrospectively evaluated. The rate of post-operative hypoparathyroidism, clinicopathological features, and laboratory parameters during the post-operative first day, first month, and first year of patients with and without hypoparathyroidism were analyzed. Patients with hypoparathyroidism were classified as transient or permanent cases., Results: The incidence of post-operative hypoparathyroidism was 22.7%, including transient (20.6%) and permanent (2.1%). In multivariable analysis, independent predictors of permanent hypoparathyroidism were as follows: surgery due to malignant thyroid disease, tumor multifocality, and pre-operative vitamin-D deficiency (VDD) (p<0.001, 0.047, and 0.002, respectively). During the post-operative first month, the mean serum PTH levels were found to be 7.58 pg/mL, and they remained low on the post-operative first year in patients with permanent hypoparathyroidism., Conclusion: Surgery due to thyroid malignancy and VDD should be considered risk factors for permanent hypoparathyroidism in patients who undergo thyroid surgery. The post-operative first month is important in the prediction of permanent hypoparathyroidism., Key Words: Hypoparathyroidism, Permanent, Transient.

Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare, multisystemic, autosomal recessive condition typically presenting with digital clubbing, osteoarthropathy, and various skin manifestations. Radiographs show distinctive periosteal reaction and thickening along the long bones. PHO is caused by homozygous mutations in the HPGD gene in chromosome 4q34.1 or the SLCO2A1 gene in 3q22.1q22.2. Here, we report on a 20-year-old male with enlarged and swollen joints with arthralgia, palmoplantar hyperhidrosis, and large hands and feet with marked digital clubbing. We also present radiographic, MRI, and ultrasonographic features of the case. These clinical and imaging findings were compatible with the diagnosis of PHO, and a novel homozygous mutation, c.576C>G, p.Ile192Met, was found in SLCO2A1., (© 2019 S. Karger AG, Basel.)

Background: Increased angiogenetic activity in inflammatory bowel disease (IBD) has been shown in previous studies. The aim of this study was to evaluate the relationship of serum vascular endothelial growth factor (VEGF) and endostatin levels with clinical features and mucosal expression in patients with ulcerative colitis (UC)., Design and Setting: Cross-sectional analytical study conducted in a tertiary-level public hospital., Methods: Serum VEGF and endostatin levels were determined in 82 individuals: 39 with UC, 28 with irritable bowel syndrome (IBS) and 15 healthy controls (HCs), using enzyme-linked immunosorbent assays (ELISA). VEGF and endostatin expressions were studied using immunohistochemistry (IHC)., Results: Mean serum VEGF and endostatin levels were significantly higher in patients with UC than in patients with IBS and in HCs (511.9 ± 377.5 pg/ml, 305.0 ± 121.42 pg/ml and 36.1 ± 40.6 pg/ml; P = 0.001 for VEGF; and 155.50 ± 59.8 ng/ml, 116.9 ± 23.8 ng/ml and 102.2 ± 22.4 ng/ml; P < 0.001 for endostatin, respectively). There was a positive correlation between serum VEGF and endostatin levels (r = 0.422; P < 0.01). Mean H-scores for VEGF expression were higher in the active UC group than in the inactive UC and IBS groups, in the stroma, endothelium and epithelium. Mean H-scores for endostatin expression were higher in the active UC group than in the inactive UC and IBS groups, in the stroma and endothelium. There was no endostatin expression in the epithelium., Conclusion: Increased endostatin appears to be a defensive reaction to increased VEGF in patients with UC.

Background: The role of villous atrophy in apoptosis, a distinctive feature of celiac disease, is a matter of controversy. The aim of this study was to determine the apoptosis rate through immunohistochemical staining for M30 and M65 in celiac disease cases., Design and Setting: Analytical cross-sectional study in a tertiary-level center., Methods: Duodenal biopsies from 28 treatment-naive patients with celiac disease, 16 patients with potential celiac disease, 10 patients with a gluten-free diet and 8 controls were subjected to immunohistochemical staining for the end-apoptotic marker M30 and the total cell death marker M65. H-scores were compared. Several laboratory parameters were recorded concomitantly, and at the one-year follow-up for celiac disease and potential celiac disease patients., Results: There was a significant difference in H-score for M30 expression between the celiac disease, potential celiac disease and gluten-free diet groups (P = 0.009). There was no significant difference in H-score for M65 expression. There was a positive correlation between the H-score for M30 expression and the anti-tissue transglutaminase immunoglobulin A (anti-tTgIgA) and anti-tissue transglutaminase immunoglobulin G (anti-tTgIgG) levels (R = 0.285, P = 0.036; and R = 0.307, P = 0.024, respectively); and between the H-score for M65 expression and the anti-tTgIgA and anti-tTgIgG levels (R = 0.265, P = 0.053; and R=0.314, P = 0.021, respectively). There was no difference between celiac disease and potential celiac disease patients regarding the laboratory parameters selected., Conclusion: The rates of apoptosis and nutritional deficiencies in patients with potential celiac disease were similar to those in patients with celiac disease.

The management of spondyloarthritis (SpA) has substantially changed as a consequence of the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs). However, the treatment options in patients with axial SpA (axSpA) not responding to nonsteroidal anti-inflammatory drugs (NSAIDs) had been restricted to tumor necrosis factor alpha (TNFα) inhibitors for almost 15 years. With the approval of secukinumab, an interleukin (IL)-17A inhibitor, there is a new alternative in the treatment of axial SpA. In patients with psoriatic arthritis (PsA) not responding to conventional therapy with NSAIDs and conventional synthetic DMARDs, therapeutic options are more diverse. In addition to TNFα inhibitors and secukinumab, another IL-17A inhibitor ixekizumab, IL-12/23 blocker ustekinumab, phosphodiesterase-4 inhibitor apremilast, T-cell-mediated pathway inhibitor abatacept, and Janus kinase (JAK) inhibitor tofacitinib are the approved treatment. Nevertheless, there is still an unmet need for further treatment options in both axSpA and PsA. Further therapeutics, such as the dual IL-17A and F inhibitor bimekizumab, IL-17 receptor blocker brodalumab, and JAK inhibitors baricitinib, filgotinib and upadacitinib are in development for these indications. IL-23 inhibitors risankizumab, tildrakizumab, and guselkumab are further emerging drugs for PsA. Thus, the number of treatment options in SpA is likely to be increased over the next few years that make identification of optimal treatment strategies essential., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the relationship between serum adenosine deaminase (ADA) levels and histological features in patients with autoimmune hepatitis (AIH)., Methods: A total of 80 subjects (52 AIH cases and 28 healthy controls) were included in the study. Patients were diagnosed according to the simplified criteria suggested by the International Autoimmune Hepatitis Group. All of the cases had been diagnosed with AIH between 2010-2015 at Hacettepe University, Department of Gastroenterology. Serum blood samples were collected and stored at -80 °C until the biochemical estimation of ADA activity. The diagnosis of patients was confirmed by liver biopsy. Serum ADA > 20 U/L was considered to be high level., Results: Mean serum ADA levels were significantly higher in AIH patients than those in healthy controls (25.4 ± 9.6 U/L vs 12.8 ± 2.2 U/L, P < 0.001). Serum ADA levels > 20 U/L were found in 63.5% AIH patients and in 0% healthy controls ( P < 0.001). Mean serum ADA levels were significantly increased in each stage of histological activity: 15.2 ± 3.5 U/L for patients with mild interface hepatitis, 23.1 ± 10.0 U/L for patients with moderate interface hepatitis and 30.9 ± 7.0 U/L for patients with severe interface hepatitis ( P < 0.001). Correlation analysis showed that there was a positive association between serum ADA levels and histological activity ( r = 0.71, P < 0.001). Receiver operating characteristic analysis suggested that 24.5 U/L was the optimum cut-off point of ADA level for severe interface hepatitis (sensitivity 88%, specificity 85.2%, area under the curve: 0.88)., Conclusion: Because of the positive correlation with inflammatory activity, serum ADA level may be a potential biomarker for predicting or monitoring histological activity in patients with AIH., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose.

Background and Aim: 25-Hydroxyvitamin D [25(OH)D] has an important role in fibrosis progression and inflammatory response in patients with various etiologies of chronic liver disease. However, its influence on autoimmune hepatitis (AIH) has not been investigated. We evaluated the association of serum 25(OH)D levels with clinical, biochemical and histological features and response to therapy in AIH., Materials and Methods: Serum 25(OH)D levels were quantified in 68 therapy naïve AIH patients and 34 healthy controls., Results: Mean serum 25(OH)D levels were significantly lower in AIH compared to healthy controls (16.8 ± 9.2 vs. 35.7 ± 13.6, p < 0.0001). Low levels of 25(OH)D (<30 µg/L) were independently associated with advance fibrosis and severe interface hepatitis in AIH patients [p = 0.014; odds ratio (OR) 0.12, 95% confidence interval (CI) 0.02-0.65 and p = 0.020; OR 0.17, 95% CI 0.04-0.76, respectively]. Severe 25(OH)D deficiency (<10 µg/L) was associated with advance fibrosis, severe interface hepatitis, low platelet counts and sampling time in a univariate analysis. Only interface hepatitis and fibrosis scores were independently associated with 25(OH)D deficiency in a multiple regression analysis (p = 0.005; OR 0.12, 95% CI 0.03-0.53 and p = 0.022; OR 0.15, 95% CI 0.03-0.75, respectively). Mean serum 25(OH)D levels were lower in non-responders compared to responders (9.2 ± 4.8 vs. 17.1 ± 9.4, p = 0.015), and 25(OH)D deficiency was more commonly observed in non-responders than the responders (80 vs. 43%, p = 0.036)., Conclusions: Low 25(OH)D levels are associated with advance fibrosis and severe inflammation in AIH. Our study suggests that vitamin D may be a potential biomarker that predicts response to therapy and histological features in AIH.

Background: Primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome is used to describe the coexistence of both diseases, with either a sequential or a simultaneous presentation in the same patient. Available studies have focused on the simultaneous form, whereas there is limited information on sequential PBC-AIH. We carried out a retrospective study of patients who sequentially developed PBC-AIH overlap syndrome., Methods: The medical data of 1065 patients diagnosed with PBC (n=483) and AIH (n=582) were retrospectively analyzed., Results: A sequential development of PBC-AIH was observed in 19 (1.8%) patients after a mean of 6.5 (1-14) years of follow-up. AIH developed in 12 (2.5%) PBC patients, whereas PBC occurred in seven (1.2%) patients with AIH. The baseline serologic and histological findings of patients who developed PBC-AIH were similar to those of patients with typical PBC or AIH. Eighteen patients were treated with a combination of ursodeoxycholic acid (UDCA) and immunosuppression after the diagnosis of PBC-AIH was established. One patient showed a spontaneous resolution of hepatitic flare under UDCA therapy. Biochemical remission was achieved in 16 patients, whereas three progressed to decompensated cirrhosis and required liver transplantation., Conclusion: The sequential overlap of PBC-AIH can occur during the follow-up of patients with pure PBC or AIH. In our cohort, we could not identify any factors that predicted the development of this rare condition. The combination of UDCA and immunosuppression seems to be an appropriate therapy in the setting of PBC-AIH.