Multiomics and Machine Learning Accurately Predict Clinical Response to Adalimumab and Etanercept Therapy in Patients With Rheumatoid Arthritis

Objective: To predict response to anti–tumor necrosis factor (anti-TNF) prior to treatment in patients with rheumatoid arthritis (RA), and to comprehensively understand the mechanism of how different RA patients respond differently to anti-TNF treatment. Methods: Gene expression and/or DNA methylation profiling on peripheral blood mononuclear cells (PBMCs), monocytes, and CD4+ T cells obtained from 80 RA patients before they began either adalimumab (ADA) or etanercept (ETN) therapy was studied. After 6 months, treatment response was evaluated according to the European League Against Rheumatism criteria for disease response. Differential expression and methylation analyses were performed to identify the response-associated transcription and epigenetic signatures. Using these signatures, machine learning models were built by random forest algorithm to predict response prior to anti-TNF treatment, and were further validated by a follow-up study. Results: Transcription signatures in ADA and ETN responders were divergent in PBMCs, and this phenomenon was reproduced in monocytes and CD4+ T cells. The genes up-regulated in CD4+ T cells from ADA responders were enriched in the TNF signaling pathway, while very few pathways were differential in monocytes. Differentially methylated positions (DMPs) were strongly hypermethylated in responders to ETN but not to ADA. The machine learning models for the prediction of response to ADA and ETN using differential genes reached an overall accuracy of 85.9% and 79%, respectively. The models using DMPs reached an overall accuracy of 84.7% and 88% for ADA and ETN, respectively. A follow-up study validated the high performance of these models. Conclusion: Our findings indicate that machine learning models based on molecular signatures accurately predict response before ADA and ETN treatment, paving the path toward personalized anti-TNF treatment

Effectiveness of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease-modifying antirheumatic drugs (TOPIRA): study protocol for a pragmatic trial

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. METHODS: In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. DISCUSSION: This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. TRIAL REGISTRATION: This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set

Return to Sport and Work after Randomization for Knee Distraction versus High Tibial Osteotomy: Is There a Difference?

Knee joint distraction (KJD) is a novel technique for relatively young knee osteoarthritis (OA) patients. With KJD, an external distraction device creates temporary total absence of contact between cartilage surfaces, which results in pain relief and possibly limits the progression of knee OA. Recently, KJD showed similar clinical outcomes compared with high tibial osteotomy (HTO). Yet, no comparative data exist regarding return to sport (RTS) and return to work (RTW) after KJD. Therefore, our aim was to compare RTS and RTW between KJD and HTO. We performed a cross-sectional follow-up study in patients <65 years who previously participated in a randomized controlled trial comparing KJD and HTO. Out of 62 eligible patients, 55 patients responded and 51 completed the questionnaire (16 KJDs and 35 HTOs) at 5-year follow-up. The primary outcome measures were the percentages of RTS and RTW. Secondary outcome measures included time to RTS/RTW, and pre-and postoperative Tegner's (higher is more active), and Work Osteoarthritis or Joint-Replacement Questionnaire (WORQ) scores (higher is better work ability). Patients' baseline characteristics did not differ. Total 1 year after KJD, 79% returned to sport versus 80% after HTO (not significant [n.s.]). RTS <6 months was 73 and 75%, respectively (n.s.). RTW 1 year after KJD was 94 versus 97% after HTO (n.s.), and 91 versus 87% <6 months (n.s.). The median Tegner's score decreased from 5.0 to 3.5 after KJD, and from 5.0 to 3.0 after HTO (n.s.). The mean WORQ score improvement was higher after HTO (16 ± 16) than after KJD (6 ± 13; p = 0.04). Thus, no differences were found for sport and work participation between KJD and HTO in our small, though first ever, cohort. Overall, these findings may support further investigation into KJD as a possible joint-preserving option for challenging young knee OA patients. The level of evidence is III

Return to Sport and Work after Randomization for Knee Distraction versus High Tibial Osteotomy: Is There a Difference?

Knee joint distraction (KJD) is a novel technique for relatively young knee osteoarthritis (OA) patients. With KJD, an external distraction device creates temporary total absence of contact between cartilage surfaces, which results in pain relief and possibly limits the progression of knee OA. Recently, KJD showed similar clinical outcomes compared with high tibial osteotomy (HTO). Yet, no comparative data exist regarding return to sport (RTS) and return to work (RTW) after KJD. Therefore, our aim was to compare RTS and RTW between KJD and HTO. We performed a cross-sectional follow-up study in patients <65 years who previously participated in a randomized controlled trial comparing KJD and HTO. Out of 62 eligible patients, 55 patients responded and 51 completed the questionnaire (16 KJDs and 35 HTOs) at 5-year follow-up. The primary outcome measures were the percentages of RTS and RTW. Secondary outcome measures included time to RTS/RTW, and pre- and postoperative Tegner's (higher is more active), and Work Osteoarthritis or Joint-Replacement Questionnaire (WORQ) scores (higher is better work ability). Patients' baseline characteristics did not differ. Total 1 year after KJD, 79% returned to sport versus 80% after HTO (not significant [n.s.]). RTS <6 months was 73 and 75%, respectively (n.s.). RTW 1 year after KJD was 94 versus 97% after HTO (n.s.), and 91 versus 87% <6 months (n.s.). The median Tegner's score decreased from 5.0 to 3.5 after KJD, and from 5.0 to 3.0 after HTO (n.s.). The mean WORQ score improvement was higher after HTO (16 ± 16) than after KJD (6 ± 13; p = 0.04). Thus, no differences were found for sport and work participation between KJD and HTO in our small, though first ever, cohort. Overall, these findings may support further investigation into KJD as a possible joint-preserving option for challenging "young" knee OA patients. The level of evidence is III

Polymorphisms in the multidrug-resistance 1 gene related to glucocorticoid response in rheumatoid arthritis treatment

A substantial proportion of rheumatoid arthritis (RA)-patients experience an insufficient response to glucocorticoids, an important therapeutic agent in RA. The multidrug-resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is an efflux pump that actively transports substrates, such as glucocorticoids, out of the cell. We investigated if the variation in response might be explained by single-nucleotide polymorphisms (SNPs) in the MDR1 gene. RA-patients treated with intravenous methylprednisolone pulses (n = 18) or oral prednisone/prednisolone (n = 22) were included in a prospective cohort, and clinical response was measured after 5 and 30 days, respectively. The C1236T, G2677A/T, and C3435T SNPs were determined, and the functionality of P-gp was assessed by flow cytometry (Rhodamine efflux assay). Carriage of the G2677A/T SNP was significantly associated with response (OR = 6.18, p = 0.035), the other SNPs showed trends. Stratified for received treatment, the effect was only present in methylprednisolone treated patients. Mutant allele carriage significantly decreased functionality of P-gp in B cells, though had a smaller impact in other PBMC subtypes. Carriage of a MDR1 SNP was related to a response to methylprednisolone in this study, which his suggests that RA-patients carrying wild-type alleles might benefit from P-gp inhibition or administration of glucocorticoid analogues that are non-P-gp substrates

Does disease activity add to functional disability in estimation of utility for rheumatoid arthritis patients on biologic treatment?

Objective. Treatment in general is mostly directly aimed at disease activity, and measures such as the DAS28 might therefore present important additional information. Our aim was to develop and validate a model that uses a combination of disease activity (DAS28) and HAQs to estimate EuroQoL 5-dimension scale (EQ5D) utilities. Methods. Longitudinal data from a cohort study in RA patients from the Utrecht Rheumatoid Arthritis Cohort study Group (Stichting Reumaonderzoek Utrecht) who started treatment with a biologic drug were used for mapping and validation. All 702 observations, including DAS28, HAQ and EQ5D assessed at the same time points, were used. The observations were randomly divided into a subset for development of the model (n = 428 observations) and a subset for validation (n = 274). A stepwise multivariable regression analysis was used to test the association of DAS28 (components) and HAQ (domains) with EQ5D. Model performance was assessed using the explained variance (R2) and root mean square errors. Observed and predicted utility scores were compared to check for under- or overestimation of the scores. Finally, the performance of the model was compared with published mapping models. Results. Lower DAS28 score and HAQ items dressing and grooming, arising, eating, walking and activities were associated with higher EQ5D scores. The final model had an explained variance of 0.35 and a lower root mean square error as compared with other models tested. The agreement between predicted and observed scores was fair. Conclusion. HAQ components estimate EQ5D better than total HAQ. Adding DAS28 to HAQ components does not result in better utility estimations

Does disease activity add to functional disability in estimation of utility for rheumatoid arthritis patients on biologic treatment?

Objective. Treatment in general is mostly directly aimed at disease activity, and measures such as the DAS28 might therefore present important additional information. Our aim was to develop and validate a model that uses a combination of disease activity (DAS28) and HAQs to estimate EuroQoL 5-dimension scale (EQ5D) utilities. Methods. Longitudinal data from a cohort study in RA patients from the Utrecht Rheumatoid Arthritis Cohort study Group (Stichting Reumaonderzoek Utrecht) who started treatment with a biologic drug were used for mapping and validation. All 702 observations, including DAS28, HAQ and EQ5D assessed at the same time points, were used. The observations were randomly divided into a subset for development of the model (n = 428 observations) and a subset for validation (n = 274). A stepwise multivariable regression analysis was used to test the association of DAS28 (components) and HAQ (domains) with EQ5D. Model performance was assessed using the explained variance (R2) and root mean square errors. Observed and predicted utility scores were compared to check for under- or overestimation of the scores. Finally, the performance of the model was compared with published mapping models. Results. Lower DAS28 score and HAQ items dressing and grooming, arising, eating, walking and activities were associated with higher EQ5D scores. The final model had an explained variance of 0.35 and a lower root mean square error as compared with other models tested. The agreement between predicted and observed scores was fair. Conclusion. HAQ components estimate EQ5D better than total HAQ. Adding DAS28 to HAQ components does not result in better utility estimations