Prediction of ineffectiveness of biological drugs using machine learning and explainable AI methods: data from the Austrian Biological Registry BioReg.

OBJECTIVES: Machine learning models can support an individualized approach in the choice of bDMARDs. We developed prediction models for 5 different bDMARDs using machine learning methods based on patient data derived from the Austrian Biologics Registry (BioReg). METHODS: Data from 1397 patients and 19 variables with at least 100 treat-to-target (t2t) courses per drug were derived from the BioReg biologics registry. Different machine learning algorithms were trained to predict the risk of ineffectiveness for each bDMARD within the first 26 weeks. Cross-validation and hyperparameter optimization were applied to generate the best models. Model quality was assessed by area under the receiver operating characteristic (AUROC). Using explainable AI (XAI), risk-reducing and risk-increasing factors were extracted. RESULTS: The best models per drug achieved an AUROC score of the following: abatacept, 0.66 (95% CI, 0.54-0.78); adalimumab, 0.70 (95% CI, 0.68-0.74); certolizumab, 0.84 (95% CI, 0.79-0.89); etanercept, 0.68 (95% CI, 0.55-0.87); tocilizumab, 0.72 (95% CI, 0.69-0.77). The most risk-increasing variables were visual analytic scores (VAS) for abatacept and etanercept and co-therapy with glucocorticoids for adalimumab. Dosage was the most important variable for certolizumab and associated with a lower risk of non-response. Some variables, such as gender and rheumatoid factor (RF), showed opposite impacts depending on the bDMARD. CONCLUSION: Ineffectiveness of biological drugs could be predicted with promising accuracy. Interestingly, individual parameters were found to be associated with drug responses in different directions, indicating highly complex interactions. Machine learning can be of help in the decision-process by disentangling these relations.

Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the 'JAK-pot' study).

BACKGROUND: In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept. OBJECTIVE: Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population. METHODS: Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the 'JAK-pot' collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi. RESULTS: Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97). CONCLUSION: While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design.

After JAK inhibitor failure: to cycle or to switch, that is the question - data from the JAK-pot collaboration of registries.

OBJECTIVES: The expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi. METHODS: This is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders. RESULTS: 365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies. CONCLUSIONS: After failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi.

Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the 'JAK-pot' collaboration.

BACKGROUND: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. METHODS: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. RESULTS: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA. CONCLUSION: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

Guidelines for the conduct of pharmacological clinical trials in hand osteoarthritis: Consensus of a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

OBJECTIVES: To gather expert opinion on the conduct of clinical trials that will facilitate regulatory review and approval of appropriate efficacious pharmacological treatments for hand osteoarthritis (OA), an area of high unmet clinical need. METHODS: The European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) organized a working group under the auspices of the International Osteoporosis Foundation (IOF) and the World Health Organization (WHO). RESULTS: This consensus guideline is intended to provide a reference tool for practice, and should allow for better standardization of the conduct of clinical trials in hand OA. Hand OA is a heterogeneous disease affecting different, and often multiple, joints of the thumb and fingers. It was recognized that the various phenotypes and limitations of diagnostic criteria may make the results of hand OA trials difficult to interpret. Nonetheless, practical recommendations for the conduct of clinical trials of both symptom and structure modifying drugs are outlined in this consensus statement, including guidance on study design, execution, and analysis. CONCLUSIONS: While the working group acknowledges that the methodology for performing clinical trials in hand OA will evolve as knowledge of the disease increases, it is hoped that this guidance will support the development of new pharmacological treatments targeting hand OA.

The Short Form Score for the Assessment and Quantification of Chronic Rheumatic Affections of the Hands in Daily Clinical Routines-Its Sensitivity to Change and Preliminary Patient Relevant Variation Values: A Pilot Study.

OBJECTIVE: The SF-SACRAH was developed to assess the involvement of the hand in rheumatoid arthritis (RA) and hand osteoarthritis (HOA) patients in daily clinical routines. In this pilot study, its sensitivity to change will be assessed longitudinally, and preliminary thresholds for patient relevant changes are derived. METHODS: Ninety-nine outpatients suffering from HOA (n = 55) or RA (n = 44) completed the SF-SACRAH once initially. After approximately 3 months, patients repeated the SF-SACRAH. At both visits, patients rated their satisfaction (PATSAT) with the state of their disease (1 = very good to 5 = unsatisfactory). For assessing its sensitivity to change, SF-SACRAH changes in patients with stable, improving, or worsening conditions according to PATSAT were calculated in HOA and RA patients. The respective medians and highest values were used to estimate patient relevant variation values. SF-SACRAH changes and positive or negative PATSAT changes in HOA as well as RA patients were analyzed by applying the Kruskal-Wallis test. In RA patients, the DAS28 was also calculated. Spearman's rho was calculated to correlate SF-SACRAH changes with the EULAR response criteria. RESULTS: In HOA and RA patients, a statistically high correlation between PATSAT changes and SF-SACRAH values was revealed (p < 0.0001 in HOA and p < 0.01 in RA patients, respectively). The median changes in SF-SACRAH in patients with improving, stable, or worsening conditions according to PATSAT were HOA patients: PATSAT improving: ΔSF-SACRAH -1.6, PATSAT stable: ΔSF-SACRAH +0.8, PATSAT worsening: ΔSF-SACRAH +1.0; RA patients: PATSAT improving: ΔSF-SACRAH -0.9, PATSAT stable: ΔSF-SACRAH +0.2, PATSAT worsening: ΔSF-SACRAH +0.8. In RA patients, there is a moderate, but significant, correlation between DAS28 EULAR response criteria and SF-SACRAH changes (ΔDAS28 improving >0.6: ΔSF-SACRAH -0.4, ΔDAS28 <0.6: ΔSF-SACRAH +0.0, ΔDAS28 worsening >0.6: ΔSF-SACRAH +0.5; r = 0.433, p < 0.01). CONCLUSION: The SF-SACRAH constitutes a reliable tool for the assessment of hand impairment in patients with chronic rheumatic diseases. It proved to be sensitive to change in this short-term evaluation in both HOA and RA patients. Additionally, preliminary patient variation values for improvement (-1.60) and deterioration (+1.0) could be derived.

RADAI-5 and electronic monitoring tools.

Tighter monitoring of patients is regarded one of the key approaches to improve management of rheumatoid arthritis (RA). It could be demonstrated that the patient relevant disease course is not simply the linear link between two observation points, but fluctuates significantly in up to 80% of patients surveyed three times over two months, which understandably compromises quality of life. Patient self-report questionnaires such as the Rheumatoid Arthritis Disease Activity Index-Five (RADAI-5) have been shown to provide reliable information about disease activity, functionality, and other important aspects of daily life. The internal consistency of such questionnaires was shown to be significantly higher than the one of the DAS28 or the CDAI. Innovative electronic tools can be easily foreseen to constitute the media to enhance the dialogue between healthcare professionals and patients to improve disease care. These tools collect patient-recorded outcomes (PROs) data, through which physicians can monitor the course of the individual disease. Electronic versions can enable patients to receive additional medical attention between visits and provide a more detailed record of disease course over time. Applying the RADAI-5 or other questionnaires in electronic assessment tools will allow for the individual assessment of health levels, well-being, joint pain and the quality of life. Such tools will enable more frequent patient monitoring, with the potential to improve the patient's situation as well as to enhance physicians' time management, and to prioritise patients who may need further attention.

Validity of data collected in BIOREG, the Austrian register for biological treatment in rheumatology: current practice of bDMARD therapy in rheumatoid arthritis in Austria.

BACKGROUND: The purpose of the present study was to check the validity of data collected in BIOREG, the Austrian register for biological treatment in rheumatology, and to elucidate eventual differences with respect to disease activity (DA) in patients with rheumatoid arthritis (RA) on established biological DMARDs (bDMARDs) before inclusion into the register (EST) and beginners at the time point of inclusion (NEW) after 1 year of treatment. METHODS: RA patients with a complete follow-up of 1 year in BIOREG were divided into EST and NEW and compared with respect to DA, remission rates, concomitant synthetic DMARDs (csDMARDs) and glucocorticoid therapy (GC) at baseline and after 1-year follow-up. Safety concerns are listed. Descriptive statistics are applied. RESULTS: For 346 RA patients (284 EST, 62 NEW) out of 970 RA patients included into BIOREG, a full data set for a 1-year follow-up was available. No differences in DA were observed after 1 year as expressed by DAS28 or RADAI-5, and small differences as expressed by remission rates according to DAS28, RADAI-5 or Boolean criteria (namely approximately 1/2, 1/3 to 1/4 and 1/4 to 1/5 of the patients respectively). Sixty-four adverse events (AEs) were noted in 56 (20 %) of EST and 20 in 19 (31 %) of NEW patients. Malignancy occurred in four patients. After 1 year, 48 % of EST patients but only 16 % of NEW patients were on bDMARD monotherapy. CONCLUSION: Regarding DA, the date collected in BIOREG appeared to be valid. After 1 year of bDMARD therapy, all patients, whether EST or NEW, achieved a similar level of DA. AEs occurred more frequently during the early phase of bDMARD treatment. Austrian rheumatologists initiate bDMARD therapy in patients with lower disease levels than in other European countries, leading to high remission rates.

Diacerein: Benefits, Risks and Place in the Management of Osteoarthritis. An Opinion-Based Report from the ESCEO.

Diacerein is a symptomatic slow-acting drug in osteoarthritis (SYSADOA) with anti-inflammatory, anti-catabolic and pro-anabolic properties on cartilage and synovial membrane. It has also recently been shown to have protective effects against subchondral bone remodelling. Following the end of the revision procedure by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) constituted a panel of 11 experts to better define the real place of diacerein in the armamentarium for treating OA. Based on a literature review of clinical trials and meta-analyses, the ESCEO confirms that the efficacy of diacerein is similar to that of non-steroidal anti-inflammatory drugs (NSAIDs) after the first month of treatment, and superior to that of paracetamol. Additionally, diacerein has shown a prolonged effect on symptoms of several months once treatment was stopped. The use of diacerein is associated with common gastrointestinal disorders such as soft stools and diarrhoea, common mild skin reactions, and, uncommonly, hepatobiliary disorders. However, NSAIDs and paracetamol are known to cause potentially severe hepatic, gastrointestinal, renal, cutaneous and cardiovascular reactions. Therefore, the ESCEO concludes that the benefit-risk balance of diacerein remains positive in the symptomatic treatment of hip and knee osteoarthritis. Furthermore, similarly to other SYSADOAs, the ESCEO positions diacerein as a first-line pharmacological background treatment of osteoarthritis, particularly for patients in whom NSAIDs or paracetamol are contraindicated.

Is the state of health of rheumatoid arthritis patients receiving adequate treatment, predictable? - Results of a survey.

BACKGROUND: A survey was conducted to evaluate whether a steady improvement in the quality of life of Rheumatoid Arthritis (RA) patients as frequently reported in clinical studies, does actually occur. The focus of this study laid on the personal perception of RA patients. How do patients who have been treated along accepted guidelines see the state of their health and their joint pain at different points in time? METHODS: RA patients were asked to complete a questionnaire and return it to an opinion research centre. The questionnaire, which was developed by the authors, was divided into the areas: demography, symptom description and medical care, as well as the illness in a personal context. Three telephone interviews followed in monthly intervals when the patients' feelings about their illness, their every-day coping mechanisms and their social lives were rated. Intra-subject correlation and the level of agreement among patients when assessed at three different points within a two month period, was determined. RESULTS: 127 patients replied to the questionnaire. RA exerts a significant impact on a patient's daily life. Average ratings of current state of health and joint pain (answered on a 5-part scale extending from 1 (very good) to 5 (very bad)) range between 2.6 and 2.9 all three times. However, intra-subject correlation between the different assessment times, is in general quite modest. Concerning the question: "How is your join pain today?" only 14 of 127 participants express identical ratings all three times , while in one third of the participants, a difference of two digits on the 5-part scale, at least twice had to be noticed. Intra-class correlation coefficients between answers at different points are often much smaller than 0.5. Results were similar in all subgroups analysed (men vs. women; patients receiving biologics vs. those not receiving biologics; disease duration ≤3 years vs. 4 to 10 years vs. ≥11 years). CONCLUSION: On an individual level personal assessments of health, well-being and joint pain are nevertheless unsteady even within the timeframe of two months. This is why, even now, RA patients still cannot plan their lives as non-affected people can.

Patient-centered psoriatic arthritis (PsA) activity assessment by Stockerau Activity Score for Psoriatic Arthritis (SASPA).

BACKGROUND: To investigate whether a modified Rheumatoid Arthritis Disease Activity Index-5 could be applied as a routine assessment tool for psoriatic arthritis (PsA) patients. METHODS: Ninety-seven PsA outpatients (mean age 49.78 years; age range 23-80 years; 49 male, 48 female), completed a prototype questionnaire. Tender and swollen joint counts, including enthesiopathy, physician's assessment of disease activity on a visual analog scale (MDglob), erythrocyte sedimentation rate, and patient satisfaction with disease status (PatSat: 1 = excellent to 5 = unsatisfactory) were recorded. Factorial analysis was performed and alpha, as a measure of reliability, and tau were calculated. The ultimate five-item questionnaire, calculated by (Q1 + Q2 + Q3 + Q4 + Q5)/5, was then handed over to 152 PsA outpatients (mean age 54.02 years; age range 26-80 years; 82 male, 70 female), and analyzed accordingly. RESULTS: Analyzing the internal consistency of the prototype questionnaire revealed the highest alpha value of 0.849, on deleting the question targeting disease course. Alpha for the final Stockerau Activity Score for Psoriatic Arthritis (SASPA) was 0.875, with all items contributing to the final result (item loading from 0.573 to 0.910). Kendall's tau for the relationship between SASPA scores and swollen joint count, tender joint count, and MDglob was 0.34, 0.416, and 0.392, respectively. The sensitivity of the questionnaire to change was demonstrated in patients starting treatment with a tumor necrosis factor blocker (standardized mean difference: 2.1). CONCLUSION: The SASPA questionnaire constitutes a fully patient-administered tool to monitor PsA activity. Its reliability, convergent validity, and sensitivity to change were demonstrated.

Quality of care of rural rheumatoid arthritis patients in Austria.

OBJECTIVES: To determine how fast rheumatoid arthritis (RA) was diagnosed in a group of patients in a rural area and whether medical care and patient satisfaction were adequate in a predominantly non-urban settlement. METHODS: When visiting their rheumatologist, patients with RA were asked to complete a questionnaire at home after the consultation and then return it to an independent opinion research centre, where the data were collected and analysed. The form comprised various areas, namely demography, aspects of the diagnosis, medical care, therapeutic measures and the illness in a personal context. RESULTS: Of 150 patients, 127 answered the questionnaire. A total of 63 % of the patients lived in settlements of less than 5,000 inhabitants, and a further 18 % in settlements of more than 5,000-50,000 inhabitants. The rheumatologist attended could be reached within 1 h for 90 % of the patients. In slightly fewer than 30 % of the respondents, the diagnosis of RA was made within 3 months, and in 44%, within 6 months. In 75 %, the diagnosis was made by a rheumatologist. After experiencing the first symptoms, 80 % of the respondents contacted their general practitioner. A high degree of satisfaction appears to originate from the information supplied by the rheumatologist attended. Most patients believed they were involved in decision making regarding their therapy. CONCLUSION: The majority of the respondents came from rural areas. RA was diagnosed within 6 months for almost half of the patients questioned. Most patients believed they were well informed and involved in therapeutic decision making.

Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative.

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. The level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.