Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial.

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.

Radiographic and non-radiographic axial spondyloarthritis are not routinely distinguished in everyday clinical care: an analysis of real-world data from rheumatology practices.

The categorization of axial spondyloarthritis (axSpA) into radiographic (r-axSpA) and non-radiographic (nr-axSpA) subtypes is important in clinical trials but may be of less value in clinical practice. This exploratory cross-sectional, multi-center study evaluated patients with axSpA under routine care at German clinical rheumatology sites (RHADAR real-world database), with a focus on imaging data used for diagnostic classifications. Our analyses included 371 patients with axSpA. The mean (standard deviation [SD]) age was 50.9 (14.0) years, disease duration was 16.4 (13.5) years, and 39.6% were female. Based on the rheumatologist's final assessment, almost half of patients had definite r-axSpA (n = 179; 48.2%), 53 (14.3%) had suspected r-axSpA, 112 (30.2%) had non-radiographic-axSpA (nr-axSpA), and 27 (7.3%) had undefined axSpA. Patients assessed with definite or suspected r-axSpA were more likely to be treated with disease-modifying antirheumatic drugs (DMARDs) (62.0% and 64.2%, respectively) compared with nr-axSpA or undefined axSpA patients (37.5% and 48.1%, respectively). Almost all patients (348/371; 93.8%) had sacroiliac joint imaging data (radiographs or magnetic resonance imaging) documented in their charts, but only 216 (58.2%) had conventional radiographs required for formal diagnosis of r-axSpA by modified New York criteria. Follow-up radiographic imaging in nr-axSpA patients was uncommon (23/216 [25.0%]) but confirmed r-axSpA in 9/23 patients (39.1%). In conclusion, radiographs were available for slightly more than half of axSpA patients. Follow-up imaging was infrequent during rheumatology care in Germany but confirmed r-axSpA in ~ 40% of patients originally considered to have nr-axSpA. The distinction between r-axSpA and nr-axSpA may be ill-defined in routine clinical practice.

Analyzing web searches for axial spondyloarthritis in Germany: a novel approach to exploring interests and unmet needs.

Axial spondyloarthritis (axSpA) is an underdiagnosed condition with a high disease burden. Due to delayed diagnosis and limited access to specialist care, conventional health data might not sufficiently capture the perspective of affected individuals. The aim of this study was to assess public interest, unmet needs, and disease burden of axSpA in Germany through the analysis of thematic, geographic, and temporal patterns in national web search data. Google Ads Keyword Planner was used to identify axSpA-related keywords and their monthly search volume in Germany between January 2017 and December 2020. Identified keywords were qualitatively categorized into six categories. Overall, 265 axSpA-related keywords with a search volume of 3,881,490 queries were identified. Nearly 81% of the total search volume was assigned to the category terms and definition, while 19% referred to either outcomes, symptoms, diagnosis, management, or causes. In the category outcomes, prognostic outcomes like "life expectancy" generated more searches than physical manifestations like "pain". Less populated cities showed significantly more searches per 100,000 inhabitants than larger cities. Searches were seasonally stable with a Germany-wide peak in July 2017. This study provides an overview of public interest in axSpA based on web search data in Germany. The identified search patterns could be used to guide public health campaigns and optimize axSpA management in Germany.

Impairment in cognitive function in patients with axial spondyloarthritis and psoriatic arthritis.

Spondyloarthritis may contribute to deficits in cognition. The objective of this study was to compare cognitive abilities in patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) with matched reference groups. This investigator-initiated, cross-sectional, exploratory study of adults with axSpA or PsA was conducted at two German rheumatology centres (November 2018-September 2019). All data on patient and disease characteristics and cognitive abilities were collected at a single visit. Cognitive function was assessed by the previously validated Memory and Attention Test subscores of selective attention, episodic working memory, and episodic short-term memory and compared with subscores from healthy age-, sex-, and education-matched reference subjects. The mean patient age was 51.1 and 55.8 years in the axSpA (n = 101) and PsA (n = 117) groups, respectively, and mean symptom duration was 13.7 and 10.3 years. Compared with matched reference subjects, axSpA and PsA patients showed significant impairments in selective attention (mean difference of -6.5 and -4.5, respectively, on a 45-point scale; P < 0.001 for both) and no significant differences in episodic working memory. The PsA cohort, but not the axSpA cohort, had significantly better episodic short-term memory subscores compared with matched reference subjects (mean change of 2.0 on a 15-point scale; P < 0.001). Explorative subgroup analyses were unable to identify factors influencing cognitive changes, including disease activity, pain, and function, but may have been underpowered. We conclude that impairments in selective attention may impact the ability of axSpA and PsA patients to process information. These findings warrant additional studies, including longitudinal analyses, in patients with spondyloarthritis.

Comparison of physician and artificial intelligence-based symptom checker diagnostic accuracy.

Symptom checkers are increasingly used to assess new symptoms and navigate the health care system. The aim of this study was to compare the accuracy of an artificial intelligence (AI)-based symptom checker (Ada) and physicians regarding the presence/absence of an inflammatory rheumatic disease (IRD). In this survey study, German-speaking physicians with prior rheumatology working experience were asked to determine IRD presence/absence and suggest diagnoses for 20 different real-world patient vignettes, which included only basic health and symptom-related medical history. IRD detection rate and suggested diagnoses of participants and Ada were compared to the gold standard, the final rheumatologists' diagnosis, reported on the discharge summary report. A total of 132 vignettes were completed by 33 physicians (mean rheumatology working experience 8.8 (SD 7.1) years). Ada's diagnostic accuracy (IRD) was significantly higher compared to physicians (70 vs 54%, p = 0.002) according to top diagnosis. Ada listed the correct diagnosis more often compared to physicians (54 vs 32%, p < 0.001) as top diagnosis as well as among the top 3 diagnoses (59 vs 42%, p < 0.001). Work experience was not related to suggesting the correct diagnosis or IRD status. Confined to basic health and symptom-related medical history, the diagnostic accuracy of physicians was lower compared to an AI-based symptom checker. These results highlight the potential of using symptom checkers early during the patient journey and importance of access to complete and sufficient patient information to establish a correct diagnosis.

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.

OBJECTIVES: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. RESULTS: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. CONCLUSIONS: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.

A Real-World Rheumatology Registry and Research Consortium: The German RheumaDatenRhePort (RHADAR) Registry.

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.

Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs.

OBJECTIVE: To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. METHODS: Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0-1/10, 2-5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0-3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. RESULTS: Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0-1/10 reactivities) to 34% (2-5/10) and 55% (>5/10). With respect to specificity groups (0-3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. CONCLUSIONS: The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. TRIAL REGISTRATION NUMBER: 2009-015740-42; Results.

Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study.

OBJECTIVE: To prospectively analyse the risk for disease relapses in patients with rheumatoid arthritis (RA) in sustained remission, either continuing, tapering or stopping disease-modifying antirheumatic drugs (DMARDs) in a prospective randomised controlled trial. METHODS: Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre, randomised controlled, parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and/or biological DMARDs in patients with RA in stable remission. Patients (disease activity score 28 (DAS28)<2.6 for least 6 months) were randomised into three arms, either continuing DMARDs (arm 1), tapering DMARDs by 50% (arm 2) or stopping DMARDs after 6 months tapering (arm 3). The primary endpoint was sustained remission during 12 months. RESULTS: In this interim analysis, the first 101 patients who completed the study were analysed. At baseline, all patients fulfilled DAS28 remission and 70% also American College of Rheumatology- European League Against Rheumatism Boolean remission. 82.2% of the patients received methotrexate, 40.6% biological DMARDs and 9.9% other DMARDs. Overall, 67 patients (66.3%) remained in remission for 12 months, whereas 34 patients (33.7%) relapsed. The incidence of relapses was related to study arms (p=0.007; arm 1: 15.8%; arm 2: 38.9%; arm 3: 51.9%). Multivariate logistic regression identified anticitrullinated protein antibodies (ACPA) positivity (p=0.038) and treatment reduction (in comparison to continuation) as predictors for relapse (arm 2: p=0.012; arm 3: p=0.003). CONCLUSIONS: This randomised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment. Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA. TRIAL REGISTRATION NUMBER: 2009-015740-42.

Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment.

OBJECTIVE: To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. METHODS: MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. RESULTS: Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3%) and MBDA-ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). CONCLUSIONS: MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. TRIAL REGISTRATION NUMBER: EudraCT 2009-015740-42.

The impact of prior biologic therapy on adalimumab response in patients with rheumatoid arthritis.

OBJECTIVES: The aim of this study is to use data from a non-interventional study of adalimumab in patients with rheumatoid arthritis (RA) during routine clinical practice to evaluate the impact of prior treatment with biologics on the effectiveness of current therapy. METHODS: Efficacy parameters were evaluated for all patients with values at baseline and month 12. Subgroup analyses were performed on patients with 0, 1, or ≥2 prior biologic agents. Key outcome measures included Disease Activity Score- 28 joints (DAS28) and Funktionsfragebogen Hannover (FFbH) functional ability score. RESULTS: A total of 4700 RA adalimumab-treated patients were included in this analysis. Baseline disease activity increased with an increasing number of prior biologic agents and therapeutic response diminished. After 12 months of adalimumab therapy, DAS28 and FFbH scores showed improvements in all groups, but the group with 0 prior biologic agents had the best outcomes, while the group with ≥2 prior biologic agents had the worst. Clinical response (EULAR and DAS28-dcrit) and remission rates showed a similar pattern. Nevertheless, 44% to 67% of patients treated with ≥2 prior biologic agents achieved a clinical response. Multiple regression analyses identified prior biologic therapy as a significant negative predictor for response to therapy. CONCLUSIONS: Treatment with adalimumab leads to decreases in disease activity and improvements in function. Improvements are most pronounced in patients with 0 or 1 prior biologic agent, but a substantial proportion of patients treated with ≥2 prior biologic agents experience significant benefit from adalimumab therapy.

Drug survival superiority of tumor necrosis factor inhibitors and interleukin-17 inhibitors over Janus kinase inhibitors and interleukin-12/23 inhibitors in German psoriatic arthritis outpatients: retrospective analysis of the RHADAR database.

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 2023. Kaplan-Meier Curves and Cox regression modelling were used to compare drug survival rates. 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.

Physical Function of RA patients Tapering Treatment-A Post Hoc Analysis of the Randomized Controlled RETRO Trial.

Several studies have shown that tapering or stopping disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in sustained remission is feasible. However, tapering/stopping bears the risk of decline in physical function as some patients may relapse and face increased disease activity. Here, we analyzed the impact of tapering or stopping DMARD treatment on the physical function of RA patients. The study was a post hoc analysis of physical functional worsening for 282 patients with RA in sustained remission tapering and stopping DMARD treatment in the prospective randomized RETRO study. HAQ and DAS-28 scores were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and HAQ and DAS-28 scores were evaluated every 3 months. The effect of treatment reduction strategy on functional worsening was assessed in a recurrent-event Cox regression model with a study-group (control, taper, and taper/stop) as the predictor. Two-hundred and eighty-two patients were analyzed. In 58 patients, functional worsening was observed. The incidences suggest a higher probability of functional worsening in patients tapering and/or stopping DMARDs, which is likely due to higher relapse rates in these individuals. At the end of the study, however, functional worsening was similar among the groups. Point estimates and survival curves show that the decline in functionality according to HAQ after tapering or discontinuation of DMARDs in RA patients with stable remission is associated with recurrence, but not with an overall functional decline.

In vivo effects of the anti-interleukin-6 receptor inhibitor tocilizumab on the B cell compartment.

OBJECTIVE: Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature. METHODS: Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24. RESULTS: Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P = 0.04). In parallel, CD19+IgA+ and CD19+IgG+ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P = 0.01). IgG+ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P = 0.007) and 2.8% at week 24 (P = 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA+ B cells with serum IgA at week 24. CONCLUSION: Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG+ and IgA+ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients.

Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study.

The objective of this study was to use data from a noninterventional study to evaluate the effectiveness of adalimumab in rheumatoid arthritis (RA) patients during routine clinical practice and to explore the potential impact of patient and disease characteristics in response to adalimumab therapy. A total of 2,625 RA patients with specified data at baseline (prior to initiating adalimumab treatment) and 12 months entered this study between April 2003 and March 2009. We evaluated response to adalimumab therapy and conducted stepwise regression and subgroup analyses of factors influencing therapeutic response. During the 1-year adalimumab treatment period, disease activity decreased from a baseline mean disease activity score-28 joints (DAS28) of 5.9-3.9, while functional capacity improved from 59.0 to 68.4 Funktionsfragebogen Hannover (FFbH) percentage points. In multivariate regression models, high baseline DAS28 was the strongest positive predictor for decrease in disease activity, and high baseline functional capacity was associated with reduced gains in functional capacity. Male gender was a positive predictor of therapeutic response for both disease activity and functional capacity, while older age and multiple previous biologics were associated with a reduced therapeutic response. Subset analyses provided further support for the impact of baseline DAS28, FFbH, and prior biologic therapy on therapeutic response during treatment. We conclude that treatment with adalimumab leads to decreased disease activity and improved function during routine clinical practice. Patients with high disease activity and low functional capacity are particularly benefitted by adalimumab therapy.

Vaccination survey in patients with rheumatoid arthritis: a cross-sectional study.

The objective of this study is to evaluate the vaccination status in rheumatoid arthritis (RA) patients during routine clinical practice, data from a German non-interventional cross-sectional study. In this prospective study, patients with rheumatoid arthritis were interviewed using a standardized questionnaire focusing on vaccination. Available vaccination documents were evaluated, and titers for common vaccination antigens (hepatitis B, rubella, mumps, measles, diphtheria, tetanus) were analyzed with special regard to the underlying treatment and age of patients. A total of 301 RA patients treated with conventional DMARDs alone (cohort I, n = 125), TNF-blocking agents (cohort II, n = 117), or B-cell depletion with rituximab (cohort III, n = 59) have been studied. Significantly more patients in the biologic cohorts II and III were aware of an increased risk of infections (I: 67.7%, II: 83.8%*, III: 89.9%*, P < 0.05). Pneumococcal vaccination rate was significantly higher (I: 20.2%, II 36.8%* and III: 39.0%*, P < 0.05) compared with cohort I. Differences were less evident for influenza. Significantly more patients ≥60 years of age have been vaccinated against Streptococcus pneumoniae and influenza. An obvious discrepancy existed between vaccination awareness and actual vaccination rates for all cohorts. No significant differences in vaccination titers could be seen between the three cohorts. Awareness of infectious complications was more present in patients treated with biologicals, and also, the rate of patients vaccinated against Streptococcus pneumoniae increased significantly depending on the underlying treatment. Nevertheless, there was a discrepancy between vaccination awareness and actual vaccination rates for all cohorts.

Machine learning-based improvement of an online rheumatology referral and triage system.

Introduction: Rheport is an online rheumatology referral system allowing automatic appointment triaging of new rheumatology patient referrals according to the respective probability of an inflammatory rheumatic disease (IRD). Previous research reported that Rheport was well accepted among IRD patients. Its accuracy was, however, limited, currently being based on an expert-based weighted sum score. This study aimed to evaluate whether machine learning (ML) models could improve this limited accuracy. Materials and methods: Data from a national rheumatology registry (RHADAR) was used to train and test nine different ML models to correctly classify IRD patients. Diagnostic performance was compared of ML models and the current algorithm was compared using the area under the receiver operating curve (AUROC). Feature importance was investigated using shapley additive explanation (SHAP). Results: A complete data set of 2265 patients was used to train and test ML models. 30.5% of patients were diagnosed with an IRD, 69.3% were female. The diagnostic accuracy of the current Rheport algorithm (AUROC of 0.534) could be improved with all ML models, (AUROC ranging between 0.630 and 0.737). Targeting a sensitivity of 90%, the logistic regression model could double current specificity (17% vs. 33%). Finger joint pain, inflammatory marker levels, psoriasis, symptom duration and female sex were the five most important features of the best performing logistic regression model for IRD classification. Conclusion: In summary, ML could improve the accuracy of a currently used rheumatology online referral system. Including further laboratory parameters and enabling individual feature importance adaption could increase accuracy and lead to broader usage.

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study.

Background: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules. Methods: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40. Findings: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69). Interpretation: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases. Funding: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.

Impact of IL-6 receptor inhibition on human memory B cells in vivo: impaired somatic hypermutation in preswitch memory B cells and modulation of mutational targeting in memory B cells.

OBJECTIVE: Interleukin 6 (IL-6) receptor (IL-6R) inhibition by tocilizumab is a novel anti-inflammatory therapy for rheumatoid arthritis (RA) patients. As IL-6 is a late differentiation factor of B cells the authors asked if IL-6R inhibition impacts on the mutational differentiation of human memory B-cell antigen receptors in vivo. METHODS: 1733 immunoglobulin receptors (IgR) of single cell sorted preswitch and postswitch memory B cells were prospectively analysed from 11 RA patients under IL-6R inhibition (7 patients) or tumour necrosis factor (TNF) inhibition (4 patients). RESULTS: The results show a reduced mutational frequency in IgR of preswitch memory B cells (p=0.0001) during week 12, week 24 and 1 year of tocilizumab therapy. Mutational hotspot RGYW/WRCY motifs indicated significantly decreased targeting (p<0.05) in preswitch and postswitch memory B cells. Anti-TNFα therapy had no effect on mutational frequency and mutational hotspot targeting motifs in memory B-cell subsets. CONCLUSIONS: These data suggest that preswitch and postswitch memory B cells are susceptible to IL-6R inhibition in vivo. Acquisition of mutations was substantially altered in preswitch memory B cells, while targeting of mutational hotspots affected preswitch and postswitch memory B cells. The results indicate that preswitch and postswitch memory B cells have a differential dependence on the IL-6/IL-6R system for differentiation, which can be influenced by tocilizumab in vivo.