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.

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.

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.

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.

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.

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 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.

Prevalence of Depressive Symptoms in Patients With Psoriatic Arthritis: Have Numbers Changed During the COVID-19 Pandemic?

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.

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.

Accuracy, patient-perceived usability, and acceptance of two symptom checkers (Ada and Rheport) in rheumatology: interim results from a randomized controlled crossover trial.

BACKGROUND: Timely diagnosis and treatment are essential in the effective management of inflammatory rheumatic diseases (IRDs). Symptom checkers (SCs) promise to accelerate diagnosis, reduce misdiagnoses, and guide patients more effectively through the health care system. Although SCs are increasingly used, there exists little supporting evidence. OBJECTIVE: To assess the diagnostic accuracy, patient-perceived usability, and acceptance of two SCs: (1) Ada and (2) Rheport. METHODS: Patients newly presenting to a German secondary rheumatology outpatient clinic were randomly assigned in a 1:1 ratio to complete Ada or Rheport and consecutively the respective other SCs in a prospective non-blinded controlled randomized crossover trial. The primary outcome was the accuracy of the SCs regarding the diagnosis of an IRD compared to the physicians' diagnosis as the gold standard. The secondary outcomes were patient-perceived usability, acceptance, and time to complete the SC. RESULTS: In this interim analysis, the first 164 patients who completed the study were analyzed. 32.9% (54/164) of the study subjects were diagnosed with an IRD. Rheport showed a sensitivity of 53.7% and a specificity of 51.8% for IRDs. Ada's top 1 (D1) and top 5 disease suggestions (D5) showed a sensitivity of 42.6% and 53.7% and a specificity of 63.6% and 54.5% concerning IRDs, respectively. The correct diagnosis of the IRD patients was within the Ada D1 and D5 suggestions in 16.7% (9/54) and 25.9% (14/54), respectively. The median System Usability Scale (SUS) score of Ada and Rheport was 75.0/100 and 77.5/100, respectively. The median completion time for both Ada and Rheport was 7.0 and 8.5 min, respectively. Sixty-four percent and 67.1% would recommend using Ada and Rheport to friends and other patients, respectively. CONCLUSIONS: While SCs are well accepted among patients, their diagnostic accuracy is limited to date. TRIAL REGISTRATION: DRKS.de, DRKS00017642 . Registered on 23 July 2019.

Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. METHODS: RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score <2·6 units). Eligible patients were recruited consecutively from 14 German hospitals or rheumatology practices and randomly assigned (1:1:1) without stratification and regardless of baseline treatment, using a sequence that was computer-generated by the study statistician, to continue 100% dose DMARD (continue group), taper to 50% dose DMARD (taper group), or 50% dose DMARD for 6 months before stopping DMARDs (stop group). Neither patients nor investigators were masked to the treatment assignment. Patients were assessed every 3 months and screened for disease activity and relapse. The primary endpoint was the proportion of patients in sustained DAS28-ESR remission without relapse at 12 months, analysed using a log-rank test of trend and Cox regression. Analysis by a trained statistician of the primary outcome and safety was done in a modified intention-to-treat population that included participants with non-missing baseline data. This study is completed and closed to new participants and is registered with ClinicalTrials.gov (NCT02779114). FINDINGS: Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3-90·0) in the continue group, 58·6% (49·2-70·0) in the taper group, and 43·3% (34·6-55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69-5·40; p=0.0003) for the taper group and 4·34 (2·48-7·60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9). INTERPRETATION: Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. FUNDING: None.

Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion.

Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.

New insights into the prevalence of depressive symptoms and depression in rheumatoid arthritis - Implications from the prospective multicenter VADERA II study.

OBJECTIVES: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease. METHODS: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation. RESULTS: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy. CONCLUSIONS: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms. CLINICAL TRIAL REGISTRATION NUMBER: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).

Cost-effective Tapering Algorithm in Patients with Rheumatoid Arthritis: Combination of Multibiomarker Disease Activity Score and Autoantibody Status.

OBJECTIVE: To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)-tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission. METHODS: The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status 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 direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. RESULTS: RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83. CONCLUSION: Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.

Prevalence and Characteristics of Persistent Clonal T Cell Large Granular Lymphocyte Expansions in Rheumatoid Arthritis: A Comprehensive Analysis of 529 Patients.

OBJECTIVE: Up to one-third of patients with T cell large granular lymphocyte (T-LGL) leukemia display symptoms of rheumatoid arthritis (RA). In Crohn's disease and psoriasis, treatment with tumor necrosis factor (TNF) inhibitors is associated with hepatosplenic γδ T cell lymphoma and with clonal expansion of γδ T cells, respectively. This study was undertaken to determine the prevalence of clonal T-LGL cells in patients with RA and define risk factors for this rare hematologic malignancy. METHODS: A total of 529 RA patients were recruited between November 2013 and August 2015. Eight-color flow cytometry (fluorescence-activated cell sorting [FACS]) was performed to screen for aberrant T cell populations of LGLs. Molecular analysis of the T cell receptor was used to confirm the diagnosis in patients with suggestive FACS findings. Electronic patient files were used to determine risk factors. Patients with clonal populations were monitored prospectively for up to 4 years. RESULTS: The median patient age was 61 years, and 74% were female. The median duration of RA was 12 years. The median Disease Activity Score in 28 joints was 2.8, and 69.9% of patients had ever been treated with biologic disease-modifying antirheumatic drugs. We identified clonal T-LGL expansions in 19 patients, equaling a prevalence of 3.6%. The T-LGL cell clone was constant over time in most patients and was significantly associated with the duration of the exposure to TNF-blocking agents (P = 0.01). No other risk factors could be detected. CONCLUSION: RA patients with long-term exposure to TNF-blocking agents were at a greater risk of developing clonal expansions of LGLs. This finding may prompt clinicians to refrain from using these substances in RA patients with known T cell aberrations.

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.