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Background: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis., Methods: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93)., Findings: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study., Interpretation: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase., Funding: Innovative Medicine Initiative., Competing Interests: Declaration of interests JR reports receiving an unrestricted research grant from Sobi and Novartis, and speakers' honoraria and consulting fees from Bristol-Myers Squibb, Novartis, and Sobi. KT reports receiving speakers' honoraria and consulting fees from Novartis and Union Chimique Belge, and travel support from Celltrion. MØ reports receiving grants from AbbVie, Bristol-Myers Squibb, Merck, Novartis, and Union Chimique Belge, consulting fees from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, MEDAC, Merck, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and Union Chimique Belge, and honoraria for lectures, presentations, and speakers' bureaus from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Medac, Merck, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and Union Chimique Belge. AK reports receiving honoraria for lectures and presentations, honoraria for participation on a data safety monitoring board (IIT TOLERA study), and honoraria for drug supply (IIT TOLERA study) from Bristol-Myers Squibb. BM reports receiving honoraria for lectures from Gilead, AbbVie, Janssen, and Pfizer. AJH reports receiving payment for a conditional grant from Galapagos and Novartis, consulting fees from AbbVie, Amgen, Galapagos, Janssen, Eli Lilly, Novartis, and Union Chimique Belge, and payment for lectures and presentations from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Eli Lilly, Medupdate, Novartis, Pfizer, Rheumaakademie, and Union Chimique Belge. XB reports receiving consulting fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Union Chimique Belge, honoraria for lectures and presentations from AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Union Chimique Belge, and payment for participation on a data safety monitoring board or an advisory board from AbbVie, Eli Lilly, Galapagos, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Union Chimique Belge. MFl reports receiving honoraria for presentations and lectures from AbbVie, Actelion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Janssen, Medac, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, Rheumaakademie, Roche, and Sobi. AR-R reports receiving consulting fees from Bristol-Myers Squibb, AbbVie, Pfizer, and Eli Lilly, payment for lectures and presentations from AbbVie, Bristol-Myers Squibb, Pfizer, Galapagos, Eli Lilly, Merck Sharp & Dohme, Union Chimique Belge, Sanofi, and Roche, payment for expert testimony from AbbVie and Galapagos, support for attending meetings or travel (or both) from Pfizer and Sanofi, participating on a data safety monitoring board for R-Pharm, and having a leadership or fiduciary role in the Swiss Rheumatology Society. RV reports receiving payment for lectures and presentations from AbbVie, AstraZeneca, Galapagos, GlaxoSmithKline, Novartis, Janssen–Cilag, and Pfizer, institutional support for attending meetings or travel (or both) from AbbVie, Galapagos, and Janssen–Cilag, institutional grants from Novartis and Pfizer, and participating on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Novartis, GlaxoSmithKline, and Union Chimique Belge. NV reports receiving honoraria for lectures and presentations and support for attending scientific meetings and congresses (congress fee and travel expenses) from Bristol-Myers Squibb. JT reports receiving an unrestricted research grant from Bristol-Myers Squibb, consulting fees from AbbVie, AstraZeneca, Novartis, GlaxoSmithKline, Eli Lilly, and Vifor, support for attending a meeting from Galapagos and Bristol-Myers Squibb, and participating on an advisory board for Novartis. EF reports receiving honoraria for lectures and presentations from AbbVie, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, and Sobi, support for attending meetings from Novartis, and institutional grants from Eli Lilly, Novartis, and Galapagos. KK reports receiving honoraria from Union Chimique Belge for participation in an advisory board and reports payment for presentations from AbbVie, Novartis, and Union Chimique Belge. JS reports receiving honoraria for lectures and presentations from AbbVie, Bristol-Myers Squibb, Union Chimique Belge, Pfizer, Novartis, and Amgen, support for attending meetings from Union Chimique Belge and Janssen, and participating on an advisory board from AbbVie, Novartis, and Union Chimique Belge. EN reports receiving institutional payment from Pfizer and Eli Lilly, and payment for lecturing from AbbVie, Pfizer, and Eli Lilly. GS reports receiving speakers' honoraria and consulting fees from Bristol-Myers Squibb, Cabaletta, Janssen, Kyverna, Miltenyi, and Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany., Methods: This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care., Results: A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost-benefit ratio compared with standard care., Discussion: Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach., Competing Interests: Competing interests: None declared., (© 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: Durable vaccine-mediated immunity relies on the generation of long-lived plasma cells and memory B cells (MBCs), differentiating upon germinal center (GC) reactions. SARS-CoV-2 mRNA vaccination induces a strong GC response in healthy volunteers (HC), but limited data is available about response longevity upon rituximab treatment., Methods: We evaluated humoral and cellular responses upon 3rd vaccination in seven patients with rheumatoid arthritis (RA) who initially mounted anti-spike SARS-CoV-2 IgG antibodies after primary 2x vaccination and got re-exposed to rituximab (RTX) 1-2 months after the second vaccination. Ten patients with RA on other therapies and ten HC represented the control groups. As control for known long-lived induced immunity, we analyzed humoral and cellular tetanus toxoid (TT) immune responses in steady-state., Results: After 3 rd vaccination, 5/7 seroconverted RTX patients revealed lower anti-SARS-CoV-2 IgG levels but similar neutralizing capacity compared with HC. Antibody levels after 3rd vaccination correlated with values after 2nd vaccination. Despite significant reduction of circulating total and antigen-specific B cells in RTX re-exposed patients, we observed the induction of IgG+ MBCs upon 3 rd vaccination. Notably, only RTX treated patients revealed a high amount of IgA+ MBCs before and IgA+ plasmablasts after 3 rd vaccination. IgA+ B cells were not part of the steady state TT+ B cell pool. TNF-secretion and generation of effector memory CD4 spike-specific T cells were significantly boosted upon 3 rd vaccination., Summary: On the basis of pre-existing affinity matured MBCs within primary immunisation, RTX re-exposed patients revealed a persistent but atypical GC immune response accompanied by boosted spike-specific memory CD4 T cells upon SARS-CoV-2 recall vaccination., 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 © 2022 Stefanski, Rincon-Arevalo, Schrezenmeier, Karberg, Szelinski, Ritter, Chen, Meisel, Jahrsdörfer, Ludwig, Schrezenmeier, Lino and Dörner.)

ObjectiveTo analyse the performance of the rheumatoid arthritis impact of disease (RAID) score in patients with ankylosing spondylitis, polymyalgia rheumatica, systemic lupus erythematosus, primary Sjögren's syndrome, idiopathic inflammatory myositis and systemic sclerosis, as compared with rheumatoid arthritis (RA). Methods A total of 12 398 patients from the German National Database were included. For each diagnosis, we calculated age-adjusted/sex-adjusted partial correlation coefficients between RAID and patient global (PtGl) health, PtGl disease activity, physician global (PhGl) disease activity, Well-Being Index (WHO-5) and EuroQoL-5 Dimensions (EQ-5D). As a measure of agreement, the mean differences between the RAID and other outcomes were compared with the respective differences for RA. The effect of each diagnosis on the difference between RAID and the other scores was assessed with linear regression, with RA as the reference. Results Across all diagnoses, RAID correlated strongly with PtGl health (0.71-0.83), moderately to strongly with PtGl disease activity (0.59-0.79), WHO-5 (0.65-0.81) and EQ-5D (0.68-0.73) and weakly with PhGl disease activity (0.23-0.38). Mean differences were calculated for RAID and PtGl disease activity (0 to -0.6), PtGl health (-0.4 to -0.9), WHO-5 (-0.7 to -1.3), EQ-5D (1.1 to 1.7) and PhGl disease activity (1.4 to 2.2). Discrepancies between other scores and RAID were comparable to RA. Linear regression revealed no clinically relevant effect of any of the diagnoses on the difference between RAID and the other outcomes. Conclusion The RAID score performs comparably across all diagnoses investigated. This supports the use of RAID for measuring the impact also of other rheumatic diseases., Competing Interests: Competing interests: KT, KA, AZ, MA, KK and UvH: None declared, SS: Speakers bureau: BMS, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Sanofi, UCB, Consultant of: Abbvie, Gilead, GSK, UCB, Novartis. JC: Paid instructor for Rheumatologische Fortbildungsakademie GmbH, Grant/research support from Abbvie, AstraZeneca, BMS, GALAPAGOS, GSK, Lilly, Medac, MSD, Pfizer, Sanofi, 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: Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy are at higher risk of poor COVID-19 outcomes and show substantially impaired humoral immune response to anti-SARS-CoV-2 vaccine. However, the complex relationship between antigen-specific B cells and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown., Methods: Antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 patients with rheumatoid arthritis (RA) or antineutrophil cytoplasmic antibody-associated vasculitis receiving RTX, 12 patients with RA receiving other therapies, and 30 healthy controls after SARS-CoV-2 vaccination with either messenger RNA or vector-based vaccines., Results: A minimum of 10 B cells per microliter (0.4% of lymphocytes) in the peripheral circulation appeared to be required for RTX-treated patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX-treated patients who lacked IgG seroconversion showed reduced receptor-binding domain-positive B cells (P = 0.0005), a lower frequency of Tfh-like cells (P = 0.0481), as well as fewer activated CD4 (P = 0.0036) and CD8 T cells (P = 0.0308) compared to RTX-treated patients who achieved IgG seroconversion. Functionally relevant B cell depletion resulted in impaired interferon-γ secretion by spike-specific CD4 T cells (P = 0.0112, r = 0.5342). In contrast, antigen-specific CD8 T cells were reduced in both RA patients and RTX-treated patients, independently of IgG formation., Conclusion: In RTX-treated patients, a minimum of 10 B cells per microliter in the peripheral circulation is a candidate biomarker for a high likelihood of an appropriate cellular and humoral response after SARS-CoV-2 vaccination. Mechanistically, the data emphasize the crucial role of costimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B cell and plasma cell differentiation., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Vaccination is considered as most efficient strategy in controlling SARS-CoV-2 pandemic spread. Nevertheless, patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) are at increased risk to fail humoral and cellular responses upon vaccination. The ability to predict vaccination responses is essential to guide adequate safety and optimal protection in these patients., Methods: B- and T- cell data before vaccination were evaluated for characteristics predicting vaccine responses in altogether 15 patients with autoimmune inflammatory rheumatic diseases receiving RTX. Eleven patients with rheumatoid arthritis (RA) on other therapies, 11 kidney transplant recipients (KTR) on regular immunosuppression and 15 healthy controls (HC) served as controls. A multidimensional analysis of B cell subsets via UMAP algorithm and a correlation matrix were performed in order to identify predictive markers of response in patients under RTX therapy., Results: Significant differences regarding absolute B cell counts and specific subset distribution pattern between the groups were identified at baseline. In this context, the majority of B cells from vaccination responders of the RTX group (RTX IgG+) were naïve and transitional B cells, whereas vaccination non-responders (RTX IgG-) carried preferentially plasmablasts and double negative (CD27-IgD-) B cells. Moreover, there was a positive correlation between neutralizing antibodies and B cells expressing HLA-DR and CXCR5 as well as an inverse correlation with CD95 expression and CD21low expression by B cells among vaccination responders., Summary: Substantial repopulation of the naïve B cell compartment after RTX therapy appeared to be essential for an adequate vaccination response, which seem to require the additional capability of antigen presentation and germinal center formation. Moreover, expression of exhaustion markers represent negative predictors of vaccination responses., 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 © 2022 Stefanski, Rincon-Arevalo, Schrezenmeier, Karberg, Szelinski, Ritter, Chen, Jahrsdörfer, Ludwig, Schrezenmeier, Lino and Dörner.)

Objectives: To capture comorbidity and medication of persons with Sjögren's syndrome (SS) in a population-based cohort in comparison to matched controls., Methods: Individuals with an outpatient diagnosis of M35.0 (ICD-10) in ≥2 quarters of a year or an inpatient diagnosis of M35.0 were identified in a German statutory health insurance fund covering 7.2 million people. Persons in rheumatologic care were grouped by incident or prevalent diagnosis and by co-existing autoimmune disease (sSS) or primary (p)SS and compared to age- and sex-matched controls regarding comorbidity (ICD-10), medical prescriptions, hospitalisation and inability to work in the previous year., Results: In 2018, 7,283 persons (0.10%) had incident and 54,273 persons (0.75%) prevalent SS diagnosis, and 5,961 (11%) were in rheumatologic care. Of these (90% female, mean age 66 years), 3,457 (58%) had further autoimmune disease (sSS), mostly rheumatoid arthritis (80%) and systemic lupus erythematosus (13%). Compared to controls, frequent comorbid conditions in SS were hypertension (controls: 52%, pSS: 55%, sSS: 63%), osteoarthritis (22%/40%/47%), osteoporosis (10%/26%/38%) and depression (21%/34%/36%). Systemic antirheumatic drugs were prescribed in 31% (pSS) and 66% (sSS) while < 5% received topical therapies. Glucocorticoids (8%/34%/59%), NSAIDs (28%/41%/45%), opioids (8%/15%/21%), analgesics (19%/30%/36%) and antidepressants (14%/21%/21%) were frequently prescribed. Compared to controls, hospitalisation (21%/32%/39%) and inability to work in persons <65 years (41%/48%/44%, median days 17/24/30) were more frequent in pSS and sSS than in controls., Conclusions: SS claims diagnosis is associated with substantial comorbidity and frequent prescription of anti-inflammatory drugs, analgesics and antidepressants. The individual and societal burden of SS shows that, in addition to effective treatment strategies, intensive attention to comorbidities is important in this disease.

Background: New strategies and options for the treatment of rheumatoid arthritis (RA) have evolved during the past decade. A study was undertaken to investigate to what extent this influenced daily rheumatological care and how this translates into clinical and patient-reported outcomes., Methods: Data from a total of 38 723 outpatients with RA enrolled in the National Database of the German Collaborative Arthritis Centres in the years 1997-2007 were analysed. The cross-sectional annual data were compared to detect time trends., Results: Between 1997 and 2007 the prescription of combinations of traditional disease-modifying antirheumatic drugs (DMARDs) increased from 8% of all patients to 23%; biological agents were prescribed to 16% of patients with RA in 2007. The mean disease activity (DAS28) fell from 4.5 to 3.4 (median 4.5-3.2). The percentage of patients with low disease activity (DAS28 <3.2) increased significantly from 23% to 49%. The proportion of patients with ≥6 swollen joints fell from 43.1% in 1997 to 8.1% in 2007 and, in those with ≥6 tender joints, from 46.3% to 15.8%. There was a large decrease in the total annual number of days of sick leave due to the rheumatic condition from 27.2 to 8.8 days per gainfully employed person. This reduction is far beyond the decline in the general population. There was also a tendency to higher participation in the work force, specifically in older patients, reflecting the trend seen in the general population., Conclusions: The intensity of drug treatment in patients with RA has increased during the past 7 years. This has been accompanied by not only a decrease in disease activity but also a considerable reduction of economic losses due to sick leave and permanent work disability.

Objective: Autoantibodies against citrullinated peptide antigens (ACPA) are routinely determined to diagnose rheumatoid arthritis (RA) and are predictive of a more severe course of the disease. We here set out to address an involvement of ACPA in the pathogenesis of RA and investigated the recognition pattern of antibodies against 2 citrullinated antigens in more detail., Methods: The sera of 77 patients fulfilling the American College of Rheumatology criteria for RA were analyzed for subclass titers of anti-mutated citrullinated vimentin (MCV) and anticyclic citrullinated peptide (CCP) antibodies by combining subclass specific detection antibodies with commercially available CCP and MCV ELISA plates. Cross-reactivities between anti-MCV and anti-CCP antibodies were detected using a sequential ELISA system., Results: IgG1, IgG3, and IgG4 titers among anti-MCV and anti-CCP antibodies correlated significantly. Cross-reactivity of MCV-specific antibodies against CCP could be detected in 8 of 16 patients' sera; however, cross-binding of MCV-specific IgG4 was weaker compared to total IgG., Conclusion: The inherent capacity of IgG4 to exchange F(ab) arms provides insight into the anti-MCV antibody diversity and suggests a classification of ACPA positive patients into broad and narrow responders.