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.

Assessment of Involuntary PFM Contractions in Comparison with Existing Literature and IUGA/ICS Terminology Reports.

INTRODUCTION AND HYPOTHESIS: Involuntary pelvic floor muscle (PFM) contractions are thought to occur during an increase in intra-abdominal pressure (IAP). Although no studies have assessed their presence in women with normal pelvic floor (PF) function, existing literature links the absence of involuntary PFM contractions to various PF dysfunctions. This study rectifies this lacuna by evaluating involuntary PFM contractions during IAP in healthy nulliparous women with no PF dysfunction, using visual observation and vaginal palpation. Results were compared with the literature and the IUGA/ICS Terminology Reports. METHODS: Nulliparous (n=149) women performed three sets of three maximal coughs. Visual observation and vaginal palpation were conducted in the standing and supine positions. The women were not instructed to contract their PFMs. Occurrence rates were calculated for each assessment method and position; differences between positions were analyzed using the Chi-squared test. RESULTS: Rates of occurrence of involuntary PFM contraction were low across both assessments and positions (5-17%). Significant differences were found between standing (5%) and supine (15%) positions for visual observation, but not vaginal palpation (15%, 17% respectively). Occurrence rates also differed compared with the literature and terminology reports. CONCLUSIONS: Contrary to clinical expectations, rates of occurrence of involuntary PFM contraction among our cohort of nulliparous women were extremely low. Digital palpation results showed high agreement with the terminology reports, but only partial agreement was observed for the visual observation results. Our study underscores the need for more research aimed at defining normal involuntary PF functions, a review of our understanding of involuntary PFM contractions, and better standardized guidelines for involuntary PFM assessment methods.

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.

[Metastase from lobular breast carcinoma on the ileal patch of augmentation]. / Métastase de carcinome lobulaire mammaire sur un patch iléal d'entérocystoplastie.

Patients treated with bladder augmentation have a higher risk of developing bladder cancer than the general population. In these patients, tumours are most frequently primary bladder cancers. Metastasis in an augmentation cystoplasty is extremely rare and here we describe the first case of metastasis from lobular breast carcinoma in an ileal patch. A 52-year-old woman, with a medical history of invasive lobular breast cancer, presented with gross hematuria seven years after an ileal augmentation cystoplasty. A large bladder mass was found exclusively on the enteric patch, with lymphadenopathies from iliac vessels to right kidney hilum. Asurgical resection of the ileal segment with trigonal preservation was performed, associated with a complete cytoreduction. The bladder was reconstructed with a new ileal segment. Pathology confirmed the diagnosis of metastatic lobular breast carcinoma. Patients treated with augmentation cystoplasty need a close and long follow-up to detect the warning signs of tumor development. We herein report our experience of a metastatic lesion on the enteric part of a cystoplasty. Unusual characteristics of the bladder tumor and personal oncologic history of the patient may be suggestive of a secondary lesion.

Les patients traités par entérocystoplastie d'agrandissement présentent un risque plus important que la population générale de développer un cancer de vessie. Chez ceux-ci, les masses vésicales sont le plus souvent des cancers primitifs de la vessie. Les métastases au niveau d'iléocystoplasties sont très rares et nous décrivons le premier cas de métastase d'un carcinome lobulaire du sein sur patch iléal. Il s'agit d'une patiente de 52 ans, se présentant pour hématurie macroscopique survenue sept ans après une iléocystoplastie d'agrandissement. Elle a également été traitée antérieurement pour un carcinome lobulaire du sein. Une large masse vésicale est visualisée sur le patch intestinal uniquement, avec des adénopathies s'étendant des vaisseaux iliaques au hile rénal droit. Nous réalisons une exérèse du segment iléal avec préservation du trigone, associée à une cytoréduction tumorale complète. La vessie est reconstruite avec un nouveau segment d'iléon. L'analyse pathologique confirme le diagnostic de carcinome lobulaire métastatique. Les patients porteurs d'entérocystoplastie d'agrandissement nécessitent un suivi à long terme pour détecter les signes évocateurs d'une tumeur vésicale. Nous rapportons notre expérience d'une lésion métastatique exceptionnelle sur patch iléal d'agrandissement vésical. Des caractéristiques inhabituelles de la tumeur vésicale ainsi que l'historique oncologique du patient pouvaient suggérer une lésion métastatique.

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.