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Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and represent an important tool for the serological diagnosis of RA. In this study, we describe ACPA reactivity to overlapping citrullinated Epstein-Barr virus nuclear antigen-1 (EBNA-1)-derived peptides and analyze their potential as substrates for ACPA detection by streptavidin capture enzyme-linked immunosorbent assay. Using systematically overlapping peptides, containing a 10 amino acid overlap, labelled with biotin C -terminally or N -terminally, sera from 160 individuals (RA sera ( n = 60), healthy controls ( n = 40), systemic lupus erythematosus ( n = 20), Sjögren’s syndrome ( n = 40)) were screened for antibody reactivity. Antibodies to a panel of five citrullinated EBNA-1 peptides were found in 67% of RA sera, exclusively of the IgG isotype, while 53% of the patient sera reacted with a single peptide, ARGGSRERARGRGRG-Cit-GEKR, accounting for more than half of the ACPA reactivity alone. Moreover, these antibodies were detected in 10% of CCP2-negative RA sera. In addition, 47% of the RA sera reacted with two or three citrullinated EBNA-1 peptides from the selected peptide panel. Furthermore, a negative correlation between the biotin attachment site and the location of citrulline in the peptides was found, i.e. the closer the citrulline was located to biotin, the lower the antibody reactivity. Our data suggest that citrullinated EBNA-1 peptides may be considered a substrate for the detection of ACPAs and that the presence of Epstein-Barr virus may play a role in the induction of these autoantibodies. [ABSTRACT FROM AUTHOR]

Objective To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care. Methods We conducted an observational cohort study based on the Danish nationwide DANBIO registry. Treatment outcomes were evaluated using the American College of Rheumatology criteria for 20% improvement (ACR20)/ACR50/ACR70, European League Against Rheumatism (EULAR) response criteria for good response, and the 28-joint count Disease Activity Score (DAS28) (remission). Kaplan-Meier and regression analyses were used for drug survival analyses and to identify predictors of outcome after treatment switching. Results Of 1,422 patients starting TNFi agents, 548 patients (39%) switched to a second biologic drug during up to 10 years of followup. Median followup was 2.3 years (interquartile range [IQR] 1.0-4.3 years). Switchers were more frequently women (56% versus 45%), had a shorter disease duration (3 versus 4 years), a higher median Health Assessment Questionnaire (HAQ) score (1.1 [IQR 0.6-1.6] versus 0.9 [IQR 0.5-1.4]), DAS28 (4.8 [4.0-5.7] versus 4.4 [3.6-5.2]), pain score on a visual analog scale (VAS) (65 mm [46-77] versus 62 mm [40-75]), and fatigue score on a VAS (69 mm [50-83] versus 64 mm [42-80] mm) (all P < 0.05 at start of first TNFi). During the first and second treatment, HAQ, DAS28, and VAS scores and C-reactive protein levels had decreased after 6 months (all P < 0.05), and median drug survival was 2.2 versus 1.3 years ( P < 0.001). Lower fatigue score increased survival of the second TNFi. After switching, the proportions of patients achieving a sustained ACR20, ACR50, ACR70, EULAR good response, and DAS28 remission after 3-6 months were 22% (number needed to treat [NNT] 4.5), 13% (NNT 7.9), 5% (NNT 20), 19% (NNT 5.3), and 34% (NNT 2.9), respectively. Response rates were lower during the second treatment (all P < 0.01 versus first TNFi). At the 2-year visit, 47% of switchers had achieved an ACR20 response. No differences between drug-drug combinations were found. Conclusion Thirty-nine percent of the patients with PsA switched TNFi agents. Response rates and drug survival were lower after switching; however, half of the switchers had an ACR20 response 2 years after starting the first TNFi. [ABSTRACT FROM AUTHOR]

Background: Quality improvement is important to facilitate valid patient outcomes. Standardized examination procedures may improve the validity of US. The aim of this study was to investigate the learning progress for rheumatologists during training of US examination of the hand in patients with rheumatoid arthritis (RA). Methods: Rheumatologists with varying degrees of experience in US were instructed by skilled tutors. The program consisted of two days with hands-on training followed by personal US examinations performed in their individual clinics. Examinations were sent to the tutors for quality control. The US examinations were evaluated according to a scoring sheet containing 144 items. An acceptable examination was defined as > 80% correct scores. Results: Thirteen rheumatologists participated in the study. They included a total of 104 patients with RA. Only few of the initial examinations were scored below 80%, and as experience increased, the scores improved (p = 0.0004). A few participants displayed decreasing scores. The mean time spent performing the standardized examination procedure decreased from 34 min to less than 10 minutes (p = 0.0001). Conclusion: With systematic hands-on training, a rheumatologist can achieve a high level of proficiency in the conduction of US examinations of the joints of the hand in patients with RA. With experience, examination time decreases, while the level of correctness is maintained. The results indicate that US may be applied as a valid measurement tool suitable for clinical practice and in both single- and multi-centre trials. [ABSTRACT FROM AUTHOR]

Objective To study magnetic resonance imaging (MRI) as a tool for early diagnosis of rheumatoid arthritis (RA) in patients with early undifferentiated arthritis (UA). Methods Patients (n = 116) without a specific rheumatologic diagnosis, but with ≥2 tender joints and/or ≥2 swollen joints among the metacarpophalangeal, proximal interphalangeal, wrist, or metatarsophalangeal (MTP) joints for >6 weeks but <24 months, underwent clinical, biochemical, conventional radiographic, and MRI examinations and were followed up for >12 months for the final diagnosis of RA or non-RA. Based on univariate analyses, clinical, biochemical, and imaging parameters were selected for inclusion as explanatory variables in multiple logistic regression analysis, with development of RA as the dependent variable. A prediction model was developed, and its performance was tested and compared with that of a previous model developed by van der Helm-van Mil et al (the vdHvM model). Results Of the 116 patients with early UA, 27 (23.3%) developed RA. When the prediction model was applied, which included as explanatory variables presence of hand arthritis, positivity for rheumatoid factor (RF), morning stiffness lasting >1 hour, and the Outcome Measures in Rheumatology Clinical Trials MRI summary score for bone edema in the MTP and wrist joints, the outcome of RA or non-RA was correctly identified in 82% of the patients (sensitivity 81%, specificity 82%). Another cutoff value for the prediction index in the model would allow a higher specificity (98%) and higher accuracy (83%), but lower sensitivity (36%). With the vdHvM model, RA/non-RA was predicted in 60.2% of the population. Conclusion MRI evidence of bone edema in the MTP and wrist joints is an independent predictor of future RA in patients with early UA. A prediction model that includes the variables clinical hand arthritis, morning stiffness, positivity for RF, and bone edema on MRI in the MTP and wrist joints correctly identified the development or lack of development of RA in 82% of patients. [ABSTRACT FROM AUTHOR]

The article discusses a study which compared the treatment responses, remission rates and adherence of patients with rheumatoid arthritis (RA) to tumor necrosis factor α inhibitors, adalimumab, etanercept and infliximab. The study included 2,326 RA patients who received either adalimumab, etanercept or infliximab. It found that older age, low functional status and concomitant prednisolone administration are negative predictors of clinical response and remission.

In human autoimmune diseases, low plasma levels of complement factors C3 and C4 are commonly used as a proxy for complement activation. The measurements of C3 and C4 concentrations (the result of synthesis and consumption) however, show low sensitivity in patient follow-up. We find that the estimation of the C3dg fragment released during complement activation is a better parameter for complement activation. Available techniques for measuring the activation fragment C3dg, e.g. immune-electrophoresis or involving PEG-precipitation, are time-consuming and difficult to standardize. Here we examine the specificity and use of an antibody with mono-specificity for a neoepitope at the N-terminus of C3dg, which is only exposed after cleavage of C3. We present a stable, reproducible, and easy-to-use, time-resolved immunoassay with specificity for C3dg that can be used to directly evaluate ongoing complement activation. We demonstrate that the assay can be applied to clinical samples with a high specificity (95%) and a positive likelihood ratio of 10. It can also differentiate the complement related disease Systemic Lupus Erythematosus from controls and other immune-mediatedimmune mediated diseases like Rheumatoid Arthritis (86% specificity) and Spondyloarthritis (91% specificity). Further, we establish how the assay may also be used for experimental research in in vivo mouse models. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether a 2-year MRI treat-to-target strategy targeting the absence of osteitis combined with clinical remission, compared with a conventional treat-to-target strategy targeting clinical remission only (IMAGINE-rheumatoid arthritis (RA) trial) improves clinical and radiographic outcomes over 5 years in patients with RA in clinical remission., Methods: IMAGINE-more was an observational extension study of the original 2-year IMAGINE-RA randomised trial (NCT01656278). Clinical examinations and radiographs (hands and feet) were obtained yearly. Prespecified coprimary outcomes at year 5 were Disease Activity Score in 28 joints C reactive protein (DAS28-CRP) remission rate (DAS28-CRP<2.6) and no radiographic progression (van der Heijde-modified Sharp score (vdHSS) ≤0) from baseline. Secondary outcomes included 5-year changes in radiographic, MRI and clinical measures of disease activity and physical function., Results: In total 131 patients, 86 women (67%), mean age 61.2, disease duration 9.5 years, median baseline DAS28-CRP 1.9 (IQR 1.6-2.2) and vdHSS 16.0 (IQR 7.0-36.0) were included in the study; 59 (59%) patients from the original MRI treat-to-target group and 72 (72%) from the conventional group. At year 5, 47 patients (80%) in the MRI treat-to-target group vs 54 patients (75%) in the conventional treat-to-target group were in DAS28-CRP remission (OR 2.00 (95% CI 0.76 to 5.28); p=0.16) while 14 patients (24%) vs 19 patients (26%) had no radiographic progression (OR 0.70, (95% CI 0.28 to 1.71); p=0.43)., Conclusion: A 2-year combined MRI and clinical treat-to-target strategy, compared with a conventional clinical treat-to-target strategy alone, had no effect on the long-term probability of achieving DAS28-CRP remission and of avoiding radiographic progression., Competing Interests: Competing interests: SMB has received research support from AbbVie and support for attending meetings and/or travl from Medac and Novartis. KHP has received research support from AbbVie. LMØ has received research grant from Novartis. MLH has received research grant from AbbVie, Biogen, BMS, Celltrion, Eli Lilly, Janssen Biologics B.V, Lundbeck Foundation, MSD, Pfizer, Roche, Samsung Biopies, Sandoz, Novartis, Nordforsk and speaking fees and/or honoraria from Pfizer, Medac, Sandoz paid to institution and has chaired the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies. MLH co-chairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondylorthritis based on secondary data and is partly funded by Novartis. DG has received consulting fees from Janssen and speaking fees from Eli Lilly and Advisory board activity for AbbVie and Eli Lilly. MB has received research support from AbbVie and speaking fees from AbbVie, UCB, Eli Lilly, Image Analysis Group, Esaote. EMH has received research grants from Independent Research Fund Denmark, Novo Nordic Foundation, Danish Rheumatism Association, Aarhus University, Danish Regions Medicine Grants, Galapagos, AbbVie, Roche, Novartis, consulting fees from Novo Nordic, Novartis, AbbVie, Sanofi, Sobi, MSD, UCB, spekin fees from Novo Nordic, Novartis, AbbVie, Sanofi, Sobi, MSD, UCB, support for attending meetings and/or travl from Pfizer Sobi, AbbVie, Celgene, MSD, Roche, advisory board SynACT Pharma and principal trial investigator/site investigator for trials supported by AbbVie, Novartis, Novo Nordic, Sanofi, SynACT Pharma. OH has received speaking fees from Abbvie, Pfizer, Novartis, Eli-Lilly and support for attending meetings and/or travl from Pfizer, Abbvie. NSK has received grants from ScandRA and EuroStar. MØ has received research support 15 from AbbVie and grants from Amgen, BMS, Merck, Celgene and Novartis, Galapagos, Gilead, Hospira, Janssen, Merck, Novartis, Pfizer, UCB and consulting fees from Abbvie, BMS, Eli-Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, UCB, speaking fees from Abbvie, BMS, EliLilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, UCB. BE, JM, SMN, KSP, ORM, BJ, JAV, HL, AGJ, HST, RC, have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action., Methods: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025)., Results: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%., Conclusions: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments., Trial Registration Number: NCT01491815., Competing Interests: Competing interests: MØ received the study drug from BMS and UCB; research grants from Abbvie, BMS, Merck, Novartis and UCB; speaker fees from Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, MEDAC, Merck, Novartis, Pfizer, Sandoz, and UCB; and consultancy fees from Abbvie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, MEDAC, Merck, Novartis, Pfizer, Sandoz and UCB. RFvV received the study drug from BMS and UCB; research grants from BMS, GSK, UCB and AstraZeneca; consulting fees from AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer and UCB; expert fees from AbbVie, Galapagos, GSK, Janssen, Pfizer, R-Pharma and UCB; and advisory board fees from AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer and UCB. MLH received research grants from AbbVie, Biogen, BMS, Celtrion, Eli Lily, Janssen Biologics B.V., Lundbeck Foundation, MSD, Pfizer, Roche, Samsung Biopies, Sandoz and Novartis; and institution pay from Pfizer, Medac, AbbVie and Sandoz; chaired the steering committee of the Danish Rheumatology Quality Registry (DANBIO), which receives public funding from the hospital owners and funding from pharmaceutical companies; cochairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondylorthritis based on secondary data and is partly funded by Novartis. DCN received consulting fees from AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB' meeting support from Pfizer; advisory board participation fee from Novartis; and other service fee by BMS. MTN received research grants from AbbVie, BMS, Pfizer, Galapagos, Amgen and Eli Lily. BG received consulting fee from Novartis and honorary lecture payment from Novartis and Nordic-Pharma. IG received royalty fee for book authorship and support for attending meetings by EULAR. DG received advisory board fee from Eli Lily and AbbVie and speakers fee from Eli Lily. A-BA received speakers fee from AbbVie, Eli Lily, Novartis and Pfizer. CG received the study drug from BMS and UCB. MKL received advisory board fee from AbbVie. AS received advisory board fee from GSK (institution pay). LU received speakers fee from Janssen and support for meeting/travel from AbbVie and Eli Lily. DJS received honorarium fee from UCB (not a part of this, unrelated medication). GB received consultancy fee from UCB. ICO received research grants from EU Horizon 2020 and EU Horizon Europe, advisory board participation from IMPRESS-Norway, ALPHA2PREVENT, FLECAPRO and EVOLVD, and meeting/travel support from European Clinical Research Infrastructure Network. The remaining authors declared no disclosures., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Eosinophilic granulocytes are normally present in low numbers in the bloodstream. Patients with an increased number of eosinophilic granulocytes in the differential count (eosinophilia) are common and can pose a clinical challenge because conditions with eosinophilia occur in all medical specialties. The diagnostic approach must be guided by a thorough medical history, supported by specific tests to guide individualized treatment. Neoplastic (primary) eosinophilia is identified by one of several unique acquired genetic causes. In contrast, reactive (secondary) eosinophilia is associated with a cytokine stimulus in a specific disease, while idiopathic eosinophilia is a diagnosis by exclusion. Rational treatment is disease-directed in secondary cases and has paved the way for targeted treatment against the driver in primary eosinophilia, whereas idiopathic cases are treated as needed by principles in eosinophilia originating from clonal drivers. The vast majority of patients are diagnosed with secondary eosinophilia and are managed by the relevant specialty-e.g., rheumatology, allergy, dermatology, gastroenterology, pulmonary medicine, hematology, or infectious disease. The overlap in symptoms and the risk of irreversible organ involvement in eosinophilia, irrespective of the cause, warrants that patients without a diagnostic clarification or who do not respond to adequate treatment should be referred to a multidisciplinary function anchored in a hematology department for evaluation. This review presents the pathophysiology, manifestations, differential diagnosis, diagnostic workup, and management of (adult) patients with eosinophilia. The purpose is to place eosinophilia in a clinical context, and therefore justify and inspire the establishment of a multidisciplinary team of experts from diagnostic and clinical specialties at the regional level to support the second opinion. The target patient population requires highly specialized laboratory analysis and therapy and occasionally has severe eosinophil-induced organ dysfunction. An added value of a centralized, clinical function is to serve as a platform for education and research to further improve the management of patients with eosinophilia. Primary and idiopathic eosinophilia are key topics in the review, which also address current research and discusses outstanding issues in the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Thomsen, Christoffersen, Lindegaard, Davidsen, Hartmeyer, Assing, Mortz, Martin-Iguacel, Møller, Kjeldsen, Havelund, El Fassi, Broesby-Olsen, Maiborg, Johansson, Andersen, Vestergaard and Bjerrum.)

Background: The Arthritis Ultrasound Robot (ARTHUR) is an automated system for ultrasound scanning of the joints of both hands and wrists, with subsequent disease activity scoring using artificial intelligence. The objective was to describe the patient's perspective of being examined by ARTHUR, compared to an ultrasound examination by a rheumatologist. Further, to register any safety issues with the use of ARTHUR., Methods: Twenty-five patients with rheumatoid arthritis (RA) had both hands and wrists examined by ultrasound, first by a rheumatologist and subsequently by ARTHUR. Patient-reported outcomes (PROs) were obtained after the examination by the rheumatologist and by ARTHUR. PROs regarding pain, discomfort and overall experience were collected, including willingness to be examined again by ARTHUR as part of future clinical follow-up. All ARTHUR examinations were observed for safety issues., Results: There was no difference in pain or discomfort between the examination by a rheumatologist and by ARTHUR (p = 0.29 and p = 0.20, respectively). The overall experience of ARTHUR was described as very good or good by 92% (n = 23), with no difference compared to the examination by the rheumatologist (p = 0.50). All (n = 25) patients were willing to be examined by ARTHUR again, and 92% (n = 23) would accept ARTHUR as a regular part of their RA clinical follow up. No safety issues were registered., Conclusions: Joint ultrasound examination by ARTHUR was safe and well-received, with no difference in PRO components compared to ultrasound examination by a rheumatologist. Fully automated systems for RA disease activity assessment could be important in future strategies for managing RA patients., Trial Registration: The study was evaluated by the regional ethics committee (ID: S-20200145), which ruled it was not a clinical trial necessary for their approval. It was a quality assessment project, as there was no intervention to the patient. The study was hereafter submitted and registered to Odense University Hospital, Region of Southern Denmark as a quality assessment project and approved (ID: 20/55294)., (© 2022. The Author(s).)

Introduction: Patients with eosinophilia (an increased number of eosinophilic granulocytes > 0.5 × 10⁸/l in the blood) are encountered in all medical specialties and frequently need thorough workup to identify the eliciting causes and decide whether treatment is indicated. In Denmark, highly specialised centres for eosinophilic diseases or conditions have been established to provide a foundation for the management of complicated cases. Here, we present experiences from such a multidisciplinary centre., Methods: This was a retrospective study of all patients seen in our tertiary centre for eosinophilia in the 2016-2019 period., Results: Referrals mainly derived from specialised secondary care and to a lesser degree from primary care physicians. Patients were either asymptomatic or exhibited symptoms from up to three organ systems and presented a median eosinophil count of 1.7 × 10⁸/l. Up to eight new clonality analyses or imaging studies per patient were performed after referral. One of these, T-cell receptor analysis, was performed frequently but provided limited information, whereas, e.g., flow cytometry proved more clinically applicable owing to its broader diagnostic range. In total, 51 patients were evaluated and classified as secondary (59%), myeloid neoplasm with PDGFRA rearrangement (2%), idiopathic hypereosinophilic syndrome (31%) and idiopathic hypereosinophilia (8%)., Conclusion: The value of a multidisciplinary and versatile approach in a highly specialised centre has a positive impact on diagnostic processes as well as on the evaluation of treatment need., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Objectives: To correlate the level of fibrocytes in peripheral blood, synovial tissue and in vitro culture in rheumatoid arthritis (RA) with changes in disease activity, imaging and pulmonary function., Methods: Twenty patients with early RA (ERA) and 20 patients with long-standing RA (LRA) were enrolled in a 6-month prospective study. Sixteen patients undergoing wrist arthroscopy were healthy controls. Patients with RA underwent pulmonary function tests, ultrasound and synovial ultrasound-guided needle biopsy of the same wrist at baseline and 6 months. Wrist MRI was performed at baseline (all) and 6 months (ERA). Circulating fibrocytes were measured by flow cytometry, in vitro by the number of monocytes that were differentiated to fibrocytes and in synovial biopsies by counting in histological sections., Results: Fibrocytes were primarily located around vessels and in the subintimal area in the synovium. Fibrocyte levels did not decline during the trial despite effective RA treatment. In the ERA group, increased synovitis assessed by ultrasound was moderate and strongly correlated with an increase in circulating and synovial fibrocyte levels, respectively. Increased synovitis assessed by MRI during the trial in the ERA group was moderately correlated with both increased numbers of circulating and cultured fibrocytes. Absolute diffusion capacity level was overall weakly negatively correlated with the level of circulating and synovial fibrocytes. The decline in diffusion capacity during the trial was moderately correlated with increased levels of synovial fibrocytes., Conclusion: Our findings suggest that fibrocytes are involved in RA pathogenesis, both in the synovium and the reduction in lung function seen in a part of patients with RA., Trial Registration Number: NCT02652299., Competing Interests: Competing interests: None declared., (© 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.)

Introduction: In this retrospective, register-based population study, we evaluated if anti-citrullinated protein antibodies (ACPA) is a better choice than immunoglobulin M rheumatoid factor (IgM RF) in primary care when rheumatoid arthritis (RA) is suspected, as it determines predictive values in real-life settings. Furthermore, the study described ordering patterns to investigate the benefit of repeated testing., Methods: Test result, requisitioning unit, test date and the patient's social security number were collected from the Department of Clinical Immunology at Odense University Hospital in 2007-2016 and merged with patient diagnoses from the Danish National Patient Registry., Results: Overall, 5% were diagnosed with RA. IgM RF remained the preferred test during the entire period. Test sensitivity was 61% for IgM RF and 54% for ACPA. The test specificity was 88% for IgM RF and 96% for ACPA. Positive predictive value (PPV) was higher for ACPA than for IgM RF (30% versus 12%) and negative predictive value (NPV) was equal (99%) in primary care. Few individuals seroconverted from negative to positive (ACPA 2% and IgM RF 5%) and positive to negative (ACPA 3% and IgM RF 6%)., Conclusions: ACPA has a higher PPV for RA than IgM RF, whereas their NPV is identical. ACPA is the better choice when testing for RA in primary care. Seroconversion is rare, and it is only rarely relevant to retest., Funding: The Department of Clinical immunology at Odense University Hospital funded the study., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Objectives: To study circulating MFAP4 in rheumatoid arthritis (RA) and its associations with clinical phenotype., Methods: Early RA (ERA): 47 patients with newly diagnosed, treatment naïve RA were included. Serum MFAP4, clinical and laboratory disease variables were recorded serially during 12 months of intensive synovitis suppressive treatment. Long-standing RA (LRA): 317 patients participated, all receiving DMARD treatment. Disease activity, autoantibody status, extra-articular manifestations and cardiovascular morbidity were recorded. Paired serum and synovial fluid samples were obtained from 13 untreated ERA patients. Healthy blood donors served as reference points. MFAP4 was quantified by AlphaLISA immunoassay. Univariate, multivariate and mixed effects regression models were applied in the statistical analysis., Results: ERA: MFAP4 increased from baseline and was significantly elevated at the 12-month follow-up, 17.8 U/l [12.6;24.1] vs. healthy controls, 12.7 U/l [9.5;15.6], p<0.001. MFAP4 did not correlate with joint counts or C-reactive protein. LRA: MFAP4 was increased, 25.9 U/l [20.4;33.7] vs. healthy controls, 17.6 U/l [13.7;21.2], p<0.0001, but did not correlate with disease activity measures or presence of extra-articular manifestations. Notably, MFAP4 correlated inversely with smoking (p<0.0001) and presence of antibodies against cyclic citrullinated peptides (anti-CCP), p=0.005. There was a positive association with systolic blood pressure, p=0.001 and co-occurrence of three cardiovascular events and/or risk factors, p<0.0001. The serum:synovial fluid MFAP4 ratio was 2:1., Conclusions: MFAP4 increases from diagnostic baseline despite intensive treatment but does not associate with synovitis at early or late stages of RA. Correlation patterns indicate that increased MFAP4 may reflect enhanced RA-related vascular remodelling.

Introduction: Standardised scoring systems for rheumatoid arthritis (RA) joint disease activity include Larsen score for radiographs, rheumatoid arthritis magnetic resonance imaging score (RAMRIS) for MRI and using the European League Against Rheumatisms-Outcome Measures in Rheumatology (EULAR-OMERACT) score for ultrasound (US) images. The aim of this prospective study was to investigate the relationship between histological synovitis and radiological synovitis, assessed by conventional X-ray, US and MRI of the wrist radiocarpal joint., Methods: 20 patients with treatment naive early RA (ERA) and 20 with long-standing RA (LRA) were enrolled in a 6-month prospective study. Patients with RA underwent US-guided synovial biopsy, X-ray and US of the wrist at enrolment and 6 months. MRI at baseline and also at 6 months for the ERA group, and scored with the RAMRIS system. X-ray was scored by Larsen score and US by the EULAR-OMERACT system. Synovial biopsy inflammation was determined by the Krenn score., Results: In the ERA group at baseline, Krenn score was correlated strongly with both US combined score (r = 0.77 p < 0.001) and MRI synovitis score (r = 0.85 p < 0.001), while uncorrelated at 6 months. In the LRA group at baseline, these scores correlated strongly (r = 0.83, p < 0.001) to moderately (r = 0.61, p = 0.002), and persisted at 6 months for US score (r = 0.81 p < 0.001). For all patients with RA, change in Krenn score between baseline and 6 months was correlated with both change in US combined score (r = 0.65, p < 0.001) and change in MRI synovitis score (r = 0.50, p = 0.03)., Conclusion: The MRI RAMRIS synovitis score and EULAR-OMERACT US scoring system are sensitive measures of histological synovitis in LRA and ERA. After 6 months, this correlation persists in the established RA group, but not in the ERA group. Overall, decreases in MRI/US synovitis are associated with reductions in histological synovitis. The study validates the use of MRI RAMRIS and EULAR-OMERACT US scores as surrogate markers of histological synovitis in established RA and early untreated RA., Competing Interests: Competing interests: None declared.

Objectives: Real-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised., Methods: Observational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted)., Results: 1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months' preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers' clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective., Conclusion: Seventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects., Competing Interests: Competing interests: BG: AbbVie, Biogen, Pfizer, MSD. MLH: Orion, BMS, AbbVie, Biogen, Pfizer, MSD, Celltrion. IMJH: Roche. AGL: AbbVie, MSD, Novartis, Pfizer, Roche, UCB OH: AbbVie, Roche, Novartis. HN: AbbVie, Novartis, Medac. LSA: Pfizer. The remaining authors: none declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We present a European multicenter study, comparing safety data and patient-reported outcomes (PRO) from patients undergoing synovial biopsy using ultrasound-guided needle biopsy (US-NB), ultrasound-guided portal and forceps (US-P&F) or arthroscopic-guided (AG) procedures., Objectives: To describe safety and PRO data on joint indices of pain, stiffness and swelling before and after biopsy, procedural discomfort, joint status compared with before biopsy and willingness to undergo a second biopsy for each technique and compare the three techniques. To evaluate the impact on PRO and safety data of corticosteroid therapy as part of the biopsy procedure and sequential biopsy procedures., Methods: Data were collected on the day of biopsy and 7-14 days postprocedure. Joint pain, swelling and stiffness indices were recorded as 0-100  mm Visual Analogue Scale; qualitative outcome variables on five-point Likert scales. Groups were compared with linear regression, adjusting for disease activity, corticosteroid therapy and prebiopsy PRO value and accounting for repeated measurements., Results: A total of 524 synovial biopsy procedures were documented (402 US-NB, 65 US-P&F and 57 AGSB). There were eight adverse events (1.5%) with no difference between biopsy methods (p=0.55). All PROs were improved 2  weeks postprocedure, and there were no differences in postbiopsy change in PROs between biopsy methods. Corticosteroid administration, whether intramuscular (n=62) or intra-articular (n=38), did not result in more adverse events (p=0.81) and was associated with reduction in postbiopsy swelling (p<0.01). Sequential biopsy procedures (n=103 patients) did not result in more adverse events (p=0.61) or worsening in PRO data., Conclusion: Overall, our results do not suggest a significant difference in safety or patient tolerability between US-NB, US-P&F and AGSB sampling. Further, corticosteroid therapy as part of the biopsy procedure and sequential biopsies is safe and well tolerated in patients., Competing Interests: Competing interests: None declared.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Anti-citrullinated protein antibodies (ACPA) are crucial for the serological diagnosis of RA, where Epstein-Barr virus (EBV) has been suggested to be an environmental agent in triggering the onset of the disease. This study aimed to analyse antibody reactivity to citrullinated EBV nuclear antigen-2 (EBNA-2) peptides from three different EBV strains (B95-8, GD1 and AG876) using streptavidin capture enzyme-linked immunosorbent assay. One peptide, only found in a single strain (AG876), obtained a sensitivity and specificity of 77% and 95%, respectively and showed high sequence similarity to the filaggrin peptide originally used for ACPA detection. Comparison of antibody reactivity to commercial assays found that the citrullinated peptide was as effective in detecting ACPA as highly sensitive and specific commercial assays. The data presented demonstrate that the citrullinated EBNA-2 peptide indeed is recognised specifically by RA sera and that the single peptide is able to compete with assays containing multiple peptides. Furthermore, it could be hypothesized that RA may be caused by (a) specific strain(s) of EBV.

Objectives: To investigate predictors of 10-year risk of revision and 1-year risk of prosthetic joint infection (PJI) and death following total hip/total knee arthroplasty (THA/TKA) in (1) patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis (OA); and (2) patients with RA treated with biological disease-modifying antirheumatic drugs (bDMARD) within 90 days preceding surgery compared with non-treated., Methods: Register-based cohort study using the Danish National Patient Register, the DANBIO rheumatology register (RA-specific confounders and treatment episodes) and the Danish Hip and Knee Arthroplasty Registers. Survival analyses were used to calculate confounder-adjusted sub-HRs (SHR) and HRs., Results: In total, 3913 patients with RA with THA/TKA were compared with 120 499 patients with OA. Patients with RA had decreased risk of revision (SHR 0.71 (0.57-0.89)), but increased risk of PJI (SHR=1.46 (1.13-1.88)) and death (HR=1.25 (1.01-1.55)). In DANBIO, 345 of 1946 patients with RA with THA/TKA had received bDMARD treatment within 90 days preceding surgery. bDMARD-treated patients did not have a statistically significant increased risk of revision (SHR=1.49 (0.65-3.40)), PJI (SHR=1.61 (0.70-3.69)) nor death (HR=0.75 (0.24-2.33)) compared with non-treated. Glucocorticoid exposure (HR=2.87 (1.12-7.34)) and increasing DAS28 (HR=1.49 (1.01-2.20)) were risk factors for mortality., Conclusion: Patients with RA had a decreased 10-year risk of revision while the risk of death and PJI was increased compared with patients with OA following THA/TKA. bDMARD exposure was not associated with statistically significant increased risk of neither PJI nor death in this study. Glucocorticoid exposure and increased disease activity were associated with an increased risk of death., Competing Interests: Competing interests: PH has received speaking fees from Celgene and UCB outside the present work. LEK has received fees for speaking and/or consultancy from Pfizer, AbbVie, Amgen, UCB, Celgene, BMS, Biogen, Sanofi, MSD, Novartis, Eli Lilly and Janssen Pharmaceuticals. LD has received speaking fees from MSD and UCB outside the present work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs)., Methods: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests., Results: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs., Conclusions: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand., Trial Registration Number: NCT00660647., Competing Interests: Competing interests: MLH: research support and grants from: BMS, AbbVie, Pfizer, UCB-Nordic, MSD and Biogen; consultation fees from: Orion, KH-P: consultation fees from: AbbVie and UCB, MBA: research support and grants from: AbbVie, MØ: consultation fees from: AbbVie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, Wyeth; research support and grants from: AbbVie, BMS, Janssen and Merck., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: According to guidelines, a nationwide non-medical switch from originator (INX, Remicade) to biosimilar infliximab (Remsima, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry., Methods: Disease activities 3 months before and after switch and changes over time were calculated. Flare was defined as change in 28 Joint Disease Activity Score (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude and adjusted retention rates were compared with a historic cohort of INX-treated patients., Results: Eight hundred and two patients switched (403 RA/120 PsA/279 AxSpA; 51% women, age (median (IQR): 55 (44-66)) years). Follow-up was 413 (339-442) days. Prior INX treatment duration was 6.8 (4.3-9.5) years. Disease activities were similar 3 months before/after switch. Crude 1-year CT-P13 retention rate (84.1 (95% CI 81.3 to 86.5)) was similar to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), p=0.22). The adjusted absolute retention rates were 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 to 88.8), respectively (p=0.03). In total 132 patients withdrew (lack of effect: 71/132=54%, adverse events: 37/132=28%). Patients with previous INX treatment duration >5 years had longer CT-P13 retention., Conclusion: In 802 arthritis patients treated with INX for median >6 years, a nationwide non-medical switch to CT-P13 had no negative impact on disease activity. Adjusted 1-year CT-P13 retention rate was slightly lower than for INX in a historic cohort., Competing Interests: Competing interests: BG: AbbVie; IMJH: Roche; AGL, MLH: AbbVie, BMS, MSD, Pfizer, Roche and UCB; the remaining authors: none declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD)., Method: CD45 + CD34 + CD11b + (7-AAD - CD3 - CD19 - CD294 - ) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted., Results: 90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCO c ) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCO c (r = -0.61 an r = -0.58 both p < 0.05)., Conclusions: We presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCO c was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies., Trial Registration: ClinicalTrials.gov : NCT02711657 , registered 13/3-2016, retrospectively registered.

Background: Undifferentiated arthritis (UA) is a label applied to patients with joint complaints which cannot be classified according to current criteria, which implies a need for precision diagnostic technologies. We studied serum galectin-3, a proinflammatory mediator, and seromarkers of structural joint elements in patients with early, UA and their associations with disease profile and biochemical and imaging findings., Methods: One hundred and eleven UA patients were followed-up for at least 12 months and reclassified according to appropriate criteria (TUDAR). At baseline, demographics and laboratory and clinical disease measures, as well as wrist magnetic resonance imaging (MRI) synovitis, erosion, and bone marrow edema scorings, were recorded. Galectin-3, the type IIA collagen N-terminal propeptide (PIIANP), which is a marker of regenerative cartilage formation, and hyaluronan (HYA), which is prevalent in synovial tissue swellings, were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) curve analysis was carried out to assess the discriminant capacity of galectin-3 against arthritis subsets., Results: Galectin-3 was increased in pre-rheumatoid arthritis (RA) (4.6 μg/l, interquartile range (IQR) 3.8-5.5) versus non-RA (4.0 μg/l, IQR 3.1-4.9; p = 0.03) and controls (3.8 μg/l, IQR 3.0-4.8; p = 0.009). PIIANP was equally depressed in either subset (p < 0.01). Galectin-3 in non-RA and HYA in UA did not differ from healthy controls. In the entire UA cohort, galectin-3 correlated with the MRI bone marrow edema score, while PIIANP correlated with the MRI erosion score, and HYA with the synovitis and erosion scores. ROC curve analysis showed that baseline galectin-3 discriminated well between pre-RA and non-RA with univariate area under the curve (AUC) of 0.64 (95% confidence interval (CI) 0.53-0.76) while AUC for galectin-3 + anti-CCP increased to 0.71 (95% CI 0.59-0.83)., Conclusions: Galectin-3 in serum was increased in patients with early UA of pre-RA origin. Cartilage remodeling assessed by PIIANP was diminished in UA irrespective of subsequent clinical differentiation, while HYA did not differ from controls. ROC analysis showed a potential for galectin-3 to discriminate between pre-RA and non-RA., Trial Registration: KF 11 315829. Registered 25 July 2006.

To clarify if musculoskeletal ultrasound (MSUS) improves early diagnosis of RA when added to the clinical examination of patients with possible arthritis. We performed a systematic literature review of original studies dealing with the value of MSUS in the early diagnosis of RA. Studies were identified using the databases of PubMed, EMBASE and Cochrane library. Only studies in English investigating populations with non-classified arthritis or arthralgia were included. Fifteen original studies investigating the added value of MSUS in diagnosing RA were identified. They differed in sample size, study population, serology status, number of joints investigated and regarding the ultrasound machines and probes used. Thirteen out of 15 studies concluded that use of MSUS had an added value compared to clinical examination and laboratory evaluation alone for diagnosing RA. One study found that MSUS did not add substantial discriminatory value for predicting RA in an early arthritis cohort when added to routine assessment. However, in this study only 16 joints were examined (wrists and MTP 3-5 were not included). One study investigated only seropositive patients and found no significant advantage of MSUS on patient level although a trend was noted. Accordingly, two other studies found MSUS to be useful especially in seronegative patients. The use of MSUS adds value in diagnosing early RA, especially in seronegative arthritis. However, no study to date has documented any effect of DMARD initiation based on MSUS findings (subclinical arthritis) alone. More studies investigating this matter are warranted.

Background: Rheumatoid arthritis is characterised by progressive joint destruction and loss of periarticular bone mass. Hand bone loss (HBL) has therefore been proposed as an outcome measure for treatment efficacy. A definition of increased HBL adjusted for age- and sex-related bone loss is lacking. In this study, we aimed to: 1) establish reference values for normal hand bone mass (bone mineral density measured by digital x-ray radiogrammetry (DXR-BMD)); and 2) examine whether HBL is normalised in rheumatoid arthritis patients during treatment with tumour necrosis factor alpha inhibitors (TNFI)., Methods: DXR-BMD was measured from hand x-rays in a reference cohort (1485 men/2541 women) without arthritis randomly selected from an urban Danish population. Sex- and age-related HBL/year was estimated. DXR-BMD was measured in rheumatoid arthritis patients (n = 350: at start of TNFI, and ~2 years after TNFI start), of which 135 patients had three x-rays (~2 years prior to TNFI, at start of TNFI, and ~2 years after TNFI start). Individual HBL/year prior to and during TNFI was calculated and compared to reference values., Results: Estimated HBL/year varied strongly with age and sex. Compared to the reference values, 75 % of 135 patients had increased HBL prior to TNFI treatment and 59 % had increased HBL during TNFI treatment (p = 0.17, Chi-squared). In 38 % (38/101) of patients with increased HBL, HBL was normalised during TNFI treatment, whereas 47 % (16/34) of patients with normal HBL prior to TNFI had increased HBL during TNFI treatment. In the 350 patients, increased HBL during TNFI was associated with time-averaged 28-joint disease activity score (odds ratio 1.69 (95 % Confidence Interval 1.34-2.15)/unit increase, p < 0.001), and patients in time-averaged remission had lower HBL than patients without remission (0.0032 vs. 0.0058 g/cm(2)/year; p < 0.001, Mann-Whitney)., Conclusions: We established age- and sex-specific reference values for DXR-BMD in a large cohort without arthritis. HBL was increased in the majority of rheumatoid arthritis patients initiating TNFI in clinical practice, and only normalised in a minority during TNFI.

Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte antigens is reported for multiple sclerosis. We speculate the possibility that recombinants or mixed viral particles are formed and that the resulting viruses stimulate the innate immune system, thereby initiating the autoimmune response.

Objectives: To estimate the prevalence of Danish RA patients currently on biologic monotherapy and compare the effectiveness and drug adherence of biologic therapies applied as monotherapy., Methods: All RA patients registered in the Danish biologics database (DANBIO) as receiving biologic DMARD (bDMARD) treatment as monotherapy without concomitant conventional synthetic DMARDs (csDMARDs) during the study period 1 May, 2011 through 30 April 2013 were eligible for inclusion. All patient files were checked to ensure that they were in accordance with the treatment registration in DANBIO. Descriptive statistics for prevalence, effectiveness and drug adherence of bDMARD monotherapy were calculated., Results: Of the 775 patients on bDMARD monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent biologic agents administered. At the 6-month follow-up, the overall crude clinical disease activity index remission rate in patients still on a biologic drug was 22%, the 28-joint DAS remission rate was 41% and the response rate of those with a 50% improvement in ACR criteria was 28%. At the 6-month follow-up, the drug adherence rates were similar for the different bDMARDs, with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001). The overall drug adherence (except for infliximab) was approximately 70% after 2 years., Conclusion: Nearly one in five (19%) biologic treatments for RA was prescribed in Denmark as monotherapy, of which 70% were on monotherapy from bio-initiation and 30% were on monotherapy after cessation of a concomitant csDMARD. Acceptable drug adherence and remission rates were achieved with bDMARDs. With the exception of infliximab, no statistically significant differences were observed between anti-TNFs and biologics with other modes of action., (© The Author 2015. 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: To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect., Methods: In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients., Results: Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months' follow-up, with mean change scores of -3.7 (median -3.0), -2.2 (-1) and -5.3 (-4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann-Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months' follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001-0.002 and p=0.062-0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up., Conclusions: A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months., Methods: In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6-9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward., Results: Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7-5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7-4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008

Background. Eosinophilia may represent an early paraclinical sign of malignant disease and a host anti-tumor effect. The association between eosinophilia and the development of solid tumors has never before been examined in an epidemiological setting. The aim of the present study was to investigate eosinophilia in routine blood samples as a potential biomarker of solid tumor development in a prospective design. Material and methods. From the Copenhagen Primary Care Differential Count (CopDiff) Database, we identified 356 196 individuals with at least one differential cell count (DIFF) encompassing the eosinophil count during 2000-2007. From these, one DIFF was randomly chosen and categorized according to no (< 0.5 × 10(9)/l), mild (≥ 0.5-1.0 × 10(9)/l) or severe (≥ 1.0 × 10(9)/l) eosinophilia. From the Danish Cancer Registry we ascertained solid tumors within the first three years following the DIFF. Using multivariable logistic regression, odds ratios (OR) were calculated and adjusted for previous eosinophilia, sex, age, year, month, C-reactive protein, previous cancer and Charlson's comorbidity index. Results. The risk for breast cancer was significantly lower in individuals exhibiting mild eosinophilia than in individuals with normal eosinophil counts [OR (95% confidence intervals) = 0.51 (0.35-0.76), p = 0.0005]. The risk of bladder cancer, however, increased with severity of eosinophilia [2.27 (1.53-3.39), p < 0.0001 and 2.62 (0.96-7.14), p = 0.0592 for mild and severe eosinophilia, respectively]. No associations with eosinophilia were observed for remaining solid cancers. Conclusion. We demonstrate that eosinophilia in routine blood samples associate with a decreased risk of breast cancer and an increased risk of bladder cancer. Our data emphasize that additional preclinical studies are needed in order to shed further light on the role of eosinophils in carcinogenesis, where it is still unknown whether the cells contribute to tumor immune surveillance or neoplastic evolution.

Eosinophilia may represent an early paraclinical sign of hematological malignant disease, but no reports exist on its predictive value for hematological malignancies. From the Copenhagen Primary Care Differential Count (CopDiff) Database, we identified 356,196 individuals with at least one differential cell count (DIFF) encompassing the eosinophil count during 2000-2007. From these, one DIFF was randomly chosen and categorized according to no (<0.5 × 10(9) /L), mild (≥ 0.5-1.0 × 10(9) /L) or severe (≥ 1.0 × 10(9) /L) eosinophilia. From the Danish Cancer Registry and the Danish Civil Registration System, we ascertained hematological malignancies and death within 3 years following the DIFF. Using multivariable logistic regression odds ratios (ORs) were calculated and adjusted for previous eosinophilia in a DIFF, sex, age, year, month, C-reactive protein, previous cancer, and comorbidity. ORs for developing Hodgkin's lymphoma (HL) was significantly increased in individuals exhibiting severe eosinophilia, OR = 9.09 (C.I. 2.77-29.84), P = 0.0003. The association with classical myeloproliferative neoplasms (cMPNs) showed an increasing risk with OR = 1.65 (1.04-2.61) P = 0.0322 and OR = 3.87 (1.67-8.96) P = 0.0016 for mild and severe eosinophilia. Eosinophilia was in a similar fashion associated with chronic lymphatic leukemia (CLL), OR = 2.57 (1.50-4.43), P = 0.0006 and OR = 5.00 (1.57-15.94), P = 0.0065, and all-cause death, OR of 1.16 (1.09-1.24), P < 0.0001 and 1.60 (1.35-1.91), P < 0.0001. We confirm associations between eosinophilia and HL and cMPNs, and in addition for the first time demonstrate a dose-dependent association between eosinophilia and CLL as well as death. Unexplained eosinophilia should prompt clinicians to consider conditions where early diagnosis may improve prognosis., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: To investigate frequencies and reasons for switching, treatment responses and drug survival in patients with ankylosing spondylitis (AS) switching tumour-necrosis-factor-α inhibitor (TNFi) treatment in routine clinical care., Methods: AS patients were identified in the Danish nationwide DANBIO registry. Disease activity, treatment responses (50% or 20 mm reduction in Bath AS Disease Activity Index (BASDAI)), duration and rates of drug survival and predictors thereof were studied in patients receiving ≥2 different biological drugs., Results: Of 1436 AS patients starting TNFi treatment, 432 patients (30%) switched to a second and 137 (10%) to a third biological drug. Compared with non-switchers, switchers were more frequently women (33%/22%), had shorter disease duration (3 years/5 years) and higher BASDAI (62(52-76) mm/56(43-69) mm (median(interquartile-range))), Bath AS Functional Index (BASFI) (54(39-71) mm/47(31-65) mm) and visual-analogue-scale (VAS) global, pain and fatigue scores when they started the first TNFi (all p<0.01). Main reason for switching was lack of response (56%). During the first, second and third treatment BAS- and VAS scores had decreased after 6 months' treatment (all p<0.05). Median drug survivals were 3.1, 1.6 and 1.8 years respectively (p<0.001). After 2 years of treatment 52% of switchers and 63% of non-switchers had achieved response (number needed to treat 1.9 and 1.6, respectively, p=0.01). Drug survivals were similar regardless of the reason for switching. Male gender and low BASFI predicted drug survival of the second TNFi., Conclusions: Nearly one-third of AS patients in clinical practice switched biological treatment. Response rates and drug survivals were lower among switchers, however, half of switchers achieved treatment response.

Objectives: To compare radiographic progression during treatment with disease-modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor α inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice., Methods: Conventional radiographs (x-rays) of hands and wrists were obtained ∼2 years before start (prebaseline), at baseline and ∼2 years after start (follow-up) of TNF-I. Clinical data were obtained from the DANBIO registry and the patient files. x-Rays were scored blinded to chronology according to the Sharp/van der Heijde method. Annual radiographic progression rates during the DMARD (prebaseline to baseline x-ray) and TNF-I (baseline to follow-up x-ray) periods were calculated., Results: 517 RA patients (76% women, 80% IgM rheumatoid factor positive, 65% anticyclic citrullinated peptide positive, 40% current smokers, age 54 years (range 21-86), median disease duration 5 years (range 0-57)) were included. Patients were treated with infliximab (61%), etanercept (15%) or adalimumab (24%). During the DMARD period 85% of patients received methotrexate, 51% sulphasalazine and 78% prednisolone. The median DMARD period was 733 days (IQR 484-1002) and the median TNF-I period was 562 days (IQR 405-766). The median radiographic progression rate decreased from 0.7 (IQR 0-2.9) total Sharp score units/year (dTSS) in the DMARD period to 0 (0-0.9) units/year in the TNF-I period (p<0.0001, Wilcoxon). Corresponding mean dTSS values were 2.1 (SD 3.7) versus 0.7 (SD 2.3) units/year (p<0.0001, paired t test). 305 patients progressed (dTSS >0) in the DMARD period compared with 158 patients in the TNF-I period (p<0.0001, χ(2))., Conclusion: This nationwide observational study of RA patients documented significantly reduced radiographic progression during TNF-I treatment compared with the previous period of DMARD treatment.

Objectives: To investigate the incidence of cancer in arthritis patients treated with or without TNFα inhibitors (TNF-I)., Methods: Arthritis patients from the DANBIO database were followed-up for cancer in the Danish Cancer Registry during 2000-2008., Results: Hazard ratio for cancer overall was 1.02 (95% confidence interval (CI) 0.80-1.30) in 3347 TNF-I-treated RA patients compared to non-treated. Excess among TNF-I-treated was found for colon cancer (HR 3.52 (95%CI 1.11-11.15), whereas 6 and 0 ovarian cancer cases were observed in treated and non-treated patients, respectively. Compared to the general population, TNF-I-treated RA patients had increased risk for cancer overall, cancer in lymphatic-haematopoietic tissue and non-melanoma skin cancer, while non-RA patients had no increase in overall cancer risk., Conclusions: Our results suggest that TNF-I therapy in routine care is not associated with an overall excess of cancer in arthritis patients, but observed increased risks of colon and ovarian cancer need further investigation.

Objective: To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA)., Methods: During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan-Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested., Results: 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not., Conclusion: In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Introduction: Rheumatoid arthritis (RA) is a chronic disease with autoimmune traits of unknown aetiology which primarily affects synovial joints. Glucocorticoids (GCs) are still widely used in RA treatment despite the expanding use of targeted and very efficient agents. The objective of this study was to assess the impact of treatment with tumour necrosis factor-α inhibitors (TNFi) on GC utilization in real-life practice among Danish RA patients., Material and Methods: The DANBIO registry is a nationwide rheumatologic database which collects demographic and clinical data. This retrospective study included RA outpatients from a tertiary rheumatologic department recruited from the DANBIO registry who initiated their first TNFi treatment between January 2000 and February 2010 (n = 171). GC dosing during the year before and the year after TNFi initiation were compared. Patients acted as their own control., Results: The median daily prednisolone dose was significantly decreased after initiation of TNFi treatment (p < 0.01). At TNFi initiation, 78 patients (46%) received prednisolone compared with 53 (31%) by the end of follow-up. After TNFi initiation, 30 patients (38%) discontinued prednisolone and in 34 (44%) prednisolone dose was reduced. Similarly, the number of GC injections decreased significantly at 13, 26 and 52 weeks following TNFi initiation (p < 0.01)., Conclusion: GC utilization is significantly reduced after initiation of TNFi treatment. Among patients on prednisolone at TNFi onset, prednisolone was withdrawn in one third and the dose was reduced in nearly half. Furthermore, the need for GC injections decreased.

Objective: At 5 years' follow-up of early (<6 months) rheumatoid arthritis patients to (1) investigate whether initial combination therapy with methotrexate (MTX) and ciclosporin (CSA) (n=80) is superior to initial monotherapy with MTX (n=80) with respect to prevention of radiographic progression, (2) investigate whether the favourable clinical and radiographic response reported at 2 years in the CIMESTRA trial can be maintained and (3) identify predictors of radiographic outcome., Methods: 139 patients completed 5 years' follow-up with maintained double-blinding and a strict synovitis suppressive treatment strategy with intra-articular betamethasone injections (intra-articular glucocorticosteroid (GC)) and escalation of disease-modifying anti-rheumatic drug treatment. Disease activity, total Sharp-van der Heijde Score (TSS) of hands, wrists and forefeet were assessed at baseline and after 3, 4 and 5 years. MRI of the wrist and anti-cyclic citrullinated peptide (anti-CCP) were assessed at baseline., Results: At 5 years, TSS progression rate was <1 unit/year and 47% had not progressed radiographically since baseline. 78% were in Disease Activity Score remission, 56% in American College of Rheumatology remission and 17% withdrawn from treatment due to remission. There were no differences between initial treatment groups. MRI-bone marrow oedema, TSS and anti-CCP predicted radiographic progression at 5 years., Conclusion: Early and strict synovitis suppressive treatment with MTX and intra-articular GC lead to high remission rates and halting of erosive progression at 5 years. No additional effect of initial combination therapy with CSA was found. The results parallel those reported for tumour necrosis factor α antagonists. Baseline MRI-bone oedema, TSS and anti-CCP predicted radiographic progression.

A case of carotinaemia in a patient with excessive beta-carotene food-intake, diabetes mellitus and physiological amenorrhea is reported. The patient developed yellow discolouration in the palms and the soles of her feet. Blood samples showed a significantly increased lever of serum beta-carotene, but normal vitamine A value and liver enzymes. The patient reported an excessive intake of carrots (approximately 1 kg per day). The status of physiological amenorrhoea and dysregulated diabetes mellitus may have deteriorated the yellow discolouration of the skin.

Rheumatoid arthritis (RA) is a chronic disabling inflammatory joint disease of unknown aetiology. Genetic and environmental factors are implicated in its pathogenesis. We performed a literature search on MEDLINE, the Cochrane database and EMBASE on the interaction between smoking and RA. It is concluded that previous and current smoking constitute a risk factor for RA development. Smoking acts synergistically with other RA risk factors, including IgM-rheumatoid factor, anti-CCP and shared epitopes. The effect of smoking on the course of RA has not been described in sufficient detail.

Objective: To investigate the efficacy of switching to a second biological drug in rheumatoid arthritis (RA) patients., Methods: Since 2000, Danish RA patients (n = 1021) receiving biological therapy have been registered in the nationwide DANBIO database. The first and second treatment series of patients, who switched therapy before 2005 (n = 235), were analysed for their reasons for switching, Disease Activity Score 28 (DAS28), DAS28 improvement, European League against Rheumatology (EULAR) response and drug survival. Most patients switched from infliximab to etanercept or adalimumab., Results: Median survivals for switchers' first/second treatment were 37/92 weeks (all patients' first treatment 119 weeks). Reasons for switching were lack of efficacy (LOE; 109 patients), adverse events (AE; 72), other reasons (54). If patients experienced AE to the first drug, 15% had AE to the second. Median DAS28 improvements in first/second treatment at 3 months were: LOE switchers 1.1/1.6; AE switchers 1.5/0.8. In LOE switchers, a good/moderate EULAR response was more prevalent during the second treatment course than during the first (63% versus 54%, p = 0.02). AE switchers achieved similar EULAR responses to both treatments (59% versus 50%, p = 0.38)., Conclusion: LOE switchers had a better clinical response to the second treatment. AE switchers responded equally well to both treatments, with a low risk of discontinuing the second drug as a result of AE. Drug survival of the switchers' second biological therapy was higher than of the first, but lower than that of non-switchers. No difference between various sequences of drugs were found. Danish post-marketing data thus support that RA patients may benefit from switching biological therapy.

Objective: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect., Methods: Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg., Results: At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group., Conclusion: Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups.

Introduction: Our aim was to describe the referral pattern among patients admitted to early arthritis clinics (EAC) in the counties of Funen and South Jutland, Denmark., Materials and Methods: In order to accelerate the diagnostic workup of patients with suspected rheumatoid arthritis (RA), general practitioners, rheumatology specialists and neighbouring hospital departments were invited to refer to the EAC patients who had synovitis in at least one joint lasting more than 6 weeks but less than 12 months., Results: 226 patients were admitted. The median total lag time from onset of joint complaints to visiting the EAC was 89 days (IQ 57-154). The average lag time between receipt of the referral to the first visit to the EAC was 18 days (IQ 5-31). 91 (40%) of the patients had synovitis upon clinical examination. 51 (23%) of these fulfilled the ACR 1987 classification criteria for RA, and 40 (17%) had synovitis of other aetiologies than RA. Compared with non-RA patients, the RA subset was characterised by older age, female preponderance, higher joint counts and disability and a more pronounced acute phase response. Despite the short duration of the disease, 17% of the RA patients had X-ray erosions., Discussion: In spite of the rigid criteria for referral to the EAC, synovitis was demonstrated by clinical examination in only 40% of the patients. Half of these were classified as RA. The total median lag time of three months from the onset of joint symptoms to the first visit to the EAC accords with current recommendations. Standardised criteria for referral to EACs should be prepared and combined with educational efforts to improve joint assessment skills.