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Real-world data are crucial to continuously improve the management of patients with rheumatic and musculoskeletal diseases (RMDs). The German RheumaDatenRhePort (RHADAR) registry encompasses a network of rheumatologists and researchers in Germany providing pseudonymized real-world patient data and allowing timely and continuous improvement in the care of RMD patients. The RHADAR modules allow automated anamnesis and adaptive coordination of appointments regarding individual urgency levels. Further modules focus on the collection and integration of electronic patient-reported outcomes in between consultations. The digital RHADAR modules ultimately allow a patient-centered adaptive approach to integrated medical care starting as early as possible in the disease course. Such a closed-loop system consisting of various modules along the whole patient pathway enables comprehensive and timely patient management in an unprecedented manner.

Objective: Treatment options with disease-modifying antirheumatic drugs (DMARDs) for psoriatic arthritis (PsA) have evolved over recent years. In addition to Janus kinase inhibitors (JAKi), four classes of biologic DMARDs (bDMARDs; interleukin [IL]-23 inhibitors [IL-23i], IL-12/23 inhibitors [IL-12/23i], tumor necrosis factor inhibitors [TNFi], and IL-17 inhibitors [IL-17i]) are currently approved for moderate to severe PsA treatment. There is minimal evidence of the persistence of these drugs among PsA outpatients in a real-world scenario during the period following the approval of JAKi. Therefore, we aimed to analyze the drug survival rates of biologic and JAKi therapies among German PsA outpatients during routine clinical care. Methods: We retrospectively analyzed PsA patients with a new prescription for a biologic or JAKi in the RHADAR database between January 2015 and October Results: 1352 new prescriptions with bDMARDs (IL-12/23i [n=50], IL-23i [n=31], TNFi [n=774], IL-17i [n=360]) or JAKi (n=137) were identified. The 5-year drug survival rate was 67.8% for IL-17i, 62.3% for TNFi, 53.3% for JAKi, and 46.0% for IL-12/23i. Discontinuation probabilities for JAKi and IL-12/23i were significantly higher compared with TNFi (JAKi hazard ratio [HR] 1.66, [95% CI 1.23-2.24], p=0.001; IL-12/23i HR 1.54, [95% CI 1.02-2.33], p=0.042) and IL-17i (JAKi HR 1.77, [95% CI 1.27-2.47], p=0.001; IL-12/23i HR 1.64, [95% CI 1.06-2.55], p=0.027). JAKi-treated patients had more severe disease and more osteoarthritis (OA) compared to TNFi and more OA compared to IL-17i. Conclusion: German PsA outpatients might persist longer with TNFi and IL-17i compared with IL-12/23i or JAKi. For TNFi, differences in subgroup characteristics and comorbidities (OA) may have affected drug survival rates. For IL-17i, the longer drug survival might not only be related to less OA compared to JAKi and, therefore, might be affected by other factors. [ABSTRACT FROM AUTHOR]

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

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 3rd 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 antigenspecific B cells in RTX re-exposed patients, we observed the induction of IgG+ MBCs upon 3rd vaccination. Notably, only RTX treated patients revealed a high amount of IgA+ MBCs before and IgA+ plasmablasts after 3rd 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 3rd 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: The objective of the study was to validate the Ankylosing Spondylitis Disease Activity Score (ASDAS) based on a quick quantitative C-reactive protein (qCRP) assay (ASDAS-Q) in a multicentre, prospective, cross-sectional study in patients with axial spondyloarthritis (axial SpA). Methods: Disease activity assessment was performed in prospectively recruited patients with axial SpA. Routine laboratory CRP was determined in the central laboratory of each study centre, while quick qCRP and erythrocyte sedimentation rate (ESR) were measured locally. Consequently, ASDAS-CRP, ASDAS-Q using the qCRP and ASDAS-ESR were calculated. The absolute agreement on the disease activity category ascertainment was analysed with cross-tabulations and weighted Cohen's kappa. Bland–Altman plots and intraclass correlation coefficients (ICCs) were used to analyse the criterion validity. Results: Overall, 251 axial SpA patients were included in the analysis. The mean qCRP value (6.34 ± 11.13 mg/l) was higher than that of routine laboratory CRP (5.26 ± 9.35 mg/l). The ICC for routine laboratory CRP versus qCRP was 0.985 [95% confidence interval (CI): 0.972–0.991]. Comparing ASDAS-Q with ASDAS-CRP, 242 of 251 (96.4%) patients were assigned to the same disease activity categories with a weighted Cohen's kappa of 0.966 (95% CI: 0.943–0.988) and ICC of 0.997 (95% CI: 0.994–0.999). Conclusions: ASDAS-Q showed an almost perfect agreement with ASDAS-CRP in the assignment to specific disease activity categories. Consequently, ASDAS-Q using the qCRP value can be applied as an accurate and quickly available alternative to ASDAS-CRP, thus facilitating the implementation of the treat-to-target concept in clinical trials and clinical routine. [ABSTRACT FROM AUTHOR]

Objective: Autoantibodies against CD74 (anti‐CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti‐CD74 and HLA–B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA). Methods: Patients ages 18–45 years with inflammatory back pain of ≤2 years' duration and a clinical suspicion of axSpA were recruited. HLA–B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty‐nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed. Results: One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti‐CD74 and IgG anti‐CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti‐CD74 and IgG anti‐CD74 was 95.3%. The sensitivity of HLA–B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti‐CD74), 3.6 (IgG anti‐CD74), and 8.1 (HLA–B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti‐CD74, 15.3% for IgG anti‐CD74, and 28.8% for HLA–B27. A combination of IgA anti‐CD74 and HLA–B27 results in a posttest probability of 80.2%. Conclusion: IgA anti‐CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation. [ABSTRACT FROM AUTHOR]

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.)

This longitudinal analysis compares the prevalence of depressive symptoms in patients with psoriatic arthritis in the context of the COVID-19 pandemic. Data from a national patient register in Germany were analyzed regarding the Patient Health Questionnaire 2 (PHQ-2) to identify cases suspicious for depression at two time points, i.e., before and during the COVID-19 pandemic. Only patients with complete concurrent information on the Disease Activity in Psoriatic Arthritis Score (DAPSA) were included in the analysis. The frequency of depressive symptoms in psoriatic arthritis patients during the COVID-19 pandemic did not differ from the prevalence rates measured before. In addition, prevalence rates for depressive symptoms did not differ when stratifying the patient sample for DAPSA levels of disease activity measured before the pandemic. These results were confirmed further in a sensitivity analysis, limiting the second PHQ-2 assessment to lockdown periods only. However, longitudinal data on the prevalence of depressive symptoms in patients with rheumatic diseases, in general, and psoriatic arthritis, in particular, are scarce in the context of the COVID-19 pandemic. For a sensible comparison of prevalence rates for depressive symptoms in the future, underlying SARS-CoV-2 infection rates and resulting local healthcare disruptions need to be taken into account, besides the potential use of different depression screening tools to evaluate resulting numbers sensibly and draw corresponding conclusions for patient care., Competing Interests: WV, CD, SK, PB-B, CK, KK, SS-M, PA, and MW are members of RheumaDatenRhePort GbR. RHADAR GbR received honoraria from UCB Pharma GmbH, Sandoz Deutschland/Hexal AG, Lilly GmbH, and Galapagos Biopharma Germany GmbH, and research support from Novartis Pharma GmbH. ME received remunerations from RheumaDatenRhePort GbR for statistical data analyses and consultation for previous projects. The remaining 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 © 2021 Englbrecht, Bartz-Bazzanella, von der Decken, Gauler, Wurth, Aries, Karberg, Kuhn, Schuch, Späthling-Mestekemper, Vorbrüggen, Wendler, Welcker and Kleinert.)

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.

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.

Objective: To define the relationship between bone growth (syndesmophytes) and bone loss (osteoporosis) in ankylosing spondylitis (AS)., Methods: Bone mineral density (BMD) at the spine, hip, and radius was measured by dual-energy x-ray absorptiometry (DEXA), dual-energy quantitative computed tomography (DEQCT), and peripheral quantitative computed tomography (pQCT) in 103 patients with AS. Radiographs of the lumbar spine were used to detect syndesmophytes. Patients were divided in 3 groups according to disease duration., Results: Osteopenia at the hip and spine was found by DEXA in 56% and 41%, respectively, of the patients with disease duration < 5 years (n = 27), with an additional 11% and 15% having osteoporosis. In patients with a longer disease duration, > 10 years (n = 28), 29% were osteoporotic at the hip and only 4% at the lumbar spine. In contrast, using spinal DEQCT, 59% of patients with early disease were found to be osteopenic; 36% of patients with long-standing disease were osteopenic and 18% were osteoporotic. More than half the patients (55%) had syndesmophytes (n = 55). With spinal DEQCT there were more patients with syndesmophytes (63%) in the group with reduced bone density than in the group without (45%). This was similar with DEXA measurements at the hip, where 31% compared to 14% had osteoporosis, respectively. Osteocalcin was elevated in 34% of patients, but was not associated with disease activity or BMD., Conclusion: The majority of patients with AS had reduced bone density. The method of bone density measurement is critical and should be different depending on disease duration. The finding that more patients with syndesmophytes had reduced bone density than those without suggests that bone growth and bone loss occur in parallel, and the role of inflammation in this process warrants further investigation.