Sandhya C. Nair

Personalized biological treatment for rheumatoid arthritis: a systematic review with a focus on clinical applicability

OBJECTIVES To review studies that address prediction of response to biologic treatment in RA and to explore the clinical utility of the studied (bio)markers. METHODS A search for relevant articles was performed in PubMed, Embase and Cochrane databases. Studies that presented predictive values or in which these could be calculated were selected. The added value was determined by the added value on prior probability for each (bio)marker. Only an increase/decrease in chance of response ⩾15% was considered clinically relevant, whereas in oncology values >25% are common. RESULTS Of the 57 eligible studies, 14 (bio)markers were studied in more than one cohort and an overview of the added predictive value of each marker is presented. Of the replicated predictors, none consistently showed an increase/decrease in probability of response ⩾15%. However, positivity of RF and ACPA in case of rituximab and the presence of the TNF-α promoter 308 GG genotype for TNF inhibitor therapy were consistently predictive, yet low in added predictive value. Besides these, 65 (bio)markers studied once showed remarkably high (but not validated) predictive values. CONCLUSION We were unable to address clinically useful baseline (bio)markers for use in individually tailored treatment. Some predictors are consistently predictive, yet low in added predictive value, while several others are promising but await replication. The challenge now is to design studies to validate all explored and promising findings individually and in combination to make these (bio)markers relevant to clinical practice.

A Personalized Approach to Biological Therapy Using Prediction of Clinical Response Based on MRP8/14 Serum Complex Levels in Rheumatoid Arthritis Patients

Objectives Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA). We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents. Methods Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab. We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks. MRP8/14 levels along with clinical variables at baseline were investigated. We also investigated how the predictive effect of MRP8/14 was modified by drug type. A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined. Finally, we present the utility of using this treatment algorithm in clinical practice. Results The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28). Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response. Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made. The predicted response rates matched the observed response in the cohort well. On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation. Conclusions Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness.

Do Radiographic Joint Damage and Disease Activity Influence Functional Disability Through Different Mechanisms? Direct and Indirect Effects of Disease Activity in Established Rheumatoid Arthritis

Objective. To explore the relationship between rheumatoid arthritis (RA) disease activity and functional disability over time, considering indirect (predictive) and direct (concurrent) associations as well as the influence of radiographic joint damage and treatment strategy. Methods. Functional disability [Health Assessment Questionnaire (HAQ)], disease activity [28-joint Disease Activity Score (DAS28)], and radiographic joint damage [Sharp/van der Heijde score (SHS)] were measured in 4 consecutive randomized controlled trials with increasingly intensive (tight control) treatment strategies. Average followup time for the 3 cohorts was 97, 53, and 50 months, respectively. Next to current DAS28, the previous DAS28 was used to study the predictive effect of a change in DAS28 on progression of functional disability (HAQ). Finally, it was investigated whether SHS mediated the predictive effect of DAS28. Results. In patients treated with intensive treatment strategies, the progression of HAQ over time was statistically significantly less (p < 0.0001). The predictive influence of DAS28 on HAQ progression increased over the duration of the disease. SHS was not found to influence HAQ progression and did not mediate the predictive effect of DAS28. In the less intensively treated patients, the direct effect of disease activity decreased with disease duration, and contrarily, SHS did influence HAQ progression, but was not found to (fully) mediate the predictive effect of DAS28. Conclusion. In patients with RA treated with modern treatment strategies, there is less functional decline over time. Further, disease activity does predict functional decline but joint damage does not. This might indicate that factors associated with cumulative disease activity but not visible on radiographs can influence functional decline in patients with RA. This further underlines the importance of disease activity as a treatment target in early RA and in established RA.

Knee Joint Distraction Compared to Total Knee Arthroplasty for Treatment of End Stage Osteoarthritis: Simulating Long-Term Outcomes and Cost-Effectiveness.

Objective In end-stage knee osteoarthritis the treatment of choice is total knee arthroplasty (TKA). An alternative treatment is knee joint distraction (KJD), suggested to postpone TKA. Several studies reported significant and prolonged clinical improvement of KJD. To make an appropriate decision regarding the position of this treatment, a cost-effectiveness and cost-utility analysis from healthcare perspective for different age and gender categories was performed. Methods A treatment strategy starting with TKA and a strategy starting with KJD for patients of different age and gender was simulated. To extrapolate outcomes to long-term health and economic outcomes a Markov (Health state) model was used. The number of surgeries, QALYs, and treatment costs per strategy were calculated. Costs-effectiveness is expressed using the cost-effectiveness plane and cost-effectiveness acceptability curves. Results Starting with KJD the number of knee replacing procedures could be reduced, most clearly in the younger age categories; especially revision surgery. This resulted in the KJD strategy being dominant (more effective with cost-savings) in about 80% of simulations (with only inferiority in about 1%) in these age categories when compared to TKA. At a willingness to pay of 20.000 Euro per QALY gained, the probability of starting with KJD to be cost-effective compared to starting with a TKA was already found to be over 75% for all age categories and over 90–95% for the younger age categories. Conclusion A treatment strategy starting with knee joint distraction for knee osteoarthritis has a large potential for being a cost-effective intervention, especially for the relatively young patient.

OP0149 Evaluating the cost-effectiveness of personalized treatment with adalimumab using serum drug level and anti-adalimumab antibodies in rheumatoid arthritis patients

Background High costs and safety concerns of biologicals warrant rational use of these drugs, preferably tailoring them to the individual patient. Objectives To evaluate the cost effectiveness of tailored biological treatment for rheumatoid arthritis (RA) using adalimumab serum drug level (DL) and anti-adalimumab antibodies (ADA) tests. Methods In 272 RA patients starting adalimumab treatment, DL, ADA, DAS28 and biological use was measured over 3 years. A treatment protocol for personalized care was defined in which EULAR response, DL and ADA test results at 6 months defined whether adalimumab treatment continued or discontinued, dosing was altered or, in case of non response, a next biological treatment was started. Using a patient level Markov model, outcome in terms of DAS28 and HAQ and biological use for a personalized care group was simulated and compared to the observed drug use and disease course. Mean direct and indirect costs, QALYs (both based on DAS28 and HAQ) and the ICER from a societal and health care perspective with 95 percentile range were calculated. Results Effectiveness was higher in the simulated personalized care group and the average difference in QALYs was 3.32 (95 percentile range -4.80 to 11.2). Costs were saved in the personalized care group as compared to usual care group: mean savings €667,513 (95 percentile range -€1,060,260 to -€294,384) and €665,630 (-€1,032,715 to -€319,539) for direct and total costs respectively. In total €643,275 was saved on biological drug costs and testing costs amounted to €12,116. This resulted in an averageICER of -€ 200,916per QALY gained. In 79% of simulations personalized care saved costs and was more effective (dominant) and in 21% cost-saving and less effective. From the healthcare perspective the average ICER was -€6,874/QALY with also 79% of simulations dominant and 21% more expensive and less effective. There was a 99% probability that personalized care is cost-effective from the societal perspective when the willingness to pay for one extra QALY is €20,000. Results of further sensitivity analyses and scenario analyses will follow later. Conclusions Tailoring biological treatment to individual RA patients using DL and ADA tests to evaluate short-term outcomes is cost effective. Although these tests were specific to adalimumab, the results underline the potential cost-effectiveness for personalized treatment in RA, specifically with biologicals. Disclosure of Interest C. Krieckaert: None Declared, S. Nair: None Declared, M. Nurmohamed Grant/Research support from: Abbott, Roche, Pfizer, Consultant for: Abbott, Roche, Pfizer, MSD, UCB, SOBI, BMS, Speakers Bureau: Abbott, Roche, Pfizer, C. van Dongen: None Declared, W. Lems: None Declared, F. Lafeber: None Declared, J. Bijlsma: None Declared, G. Wolbink Grant/Research support from: Pfizer, Speakers Bureau: Pfizer, Amgen, P. Welsing: None Declared

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 (R(2)) 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.

Generalization and extrapolation of treatment effects from clinical studies in rheumatoid arthritis.

Pragmatic clinical trials have been proposed as a solution for nongeneralizability of randomized clinical trial (RCT) results. We investigated whether treatment effects of pragmatic clinical trials are indeed generalizable to clinical practice and how efficacy estimates from published RCTs can be translated to daily practice populations.

AB0239 Personalized Biological Treatment for Rheumatoid Arthritis: A Systematic Review with a Focus on Clinical Applicability

Background Biological treatments have dramatically improved the outcome of RA patients. A substantial number of patients, however, fails to clinically respond to these therapies. Prediction of therapeutic (non) response before start of treatment could aid in clinical decision making of a personalized treatment approach. Numerous studies have previously addressed this topic. Objectives To review studies that address prediction of response to biological treatment in rheumatoid arthritis (RA) and to explore the added value in clinical applicability of these (bio)markers. Methods A search for relevant articles was performed in PUBMED, EMBASE and COCHRANE databases. Studies which presented predictive values or in which these could be calculated were selected. The added value was determined upon sensitivities, specificities and the added value on prior probability for each (bio)marker univariately. An increase/decrease in chance of response of ≥15% was considered clinically relevant enough, whereas in oncology values >25% are common. Results Out of the 52 eligible studies, 14 (bio)markers were studied multiple times and were compared for the additive predictive effect of each (bio)marker. Of the replicated predictors, none consistently showed an increase/decrease in chance of response of ≥15%. The TNF-alpha 308 polymorphism modestly predicted response to TNF-alpha inhibitors (decrease of 3.7-30.1%), and rheumatoid factor (RF) and anti-citrullinated antibodies (ACPA) predicted response to rituximab (increase of 1.9-8.9% and 1.1-7.5% resp.). Besides these, 71 (bio)markers studied once, showed remarkably high (but not validated) predictive values. Conclusions We were not able to indicate truly clinically useful baseline (bio)markers for individually tailored treatment. Few predictors are consistently predictive yet low in added predictive value, while several others are promising but await replication. The challenge now is to design studies to validate all explored and promising findings individually and in combination, to make these (bio)markers relevant to clinical practice. Disclosure of Interest None declared

SAT0088 Economic Evaluation of A Tight-Control Treatment Strategy Using an Imaging Device (HANDSCAN) for Monitoring Joint Inflammation in Early Rheumatoid Arthritis

Background Nowadays treat-to-target by means of tight-control is generally accepted as the standard treatment principle in early rheumatoid arthritis (RA) (Schoels et.al.). However, this requires frequent (monthly) visits including comprehensive clinical measurement of disease activity which is often not feasible in rheumatology outpatient clinics. The handscan is a non-invasive imaging system for monitoring the inflammatory status of RA patients and might be a solution in terms of quick, easy and objective measurement of disease activity of patients. No studies have reported on the cost effectiveness of such a tight-control strategy as compared to a non-tight control strategy. Objectives To evaluate the cost-effectiveness of a tight-control treatment strategy with the use of the handscan (TCHS) compared to tight-control using only clinical assessments (TC) and compared to a general non-tight-control treatment strategy (usual care; UC) in early RA. Methods Data from 299 early RA patients from the computer-assisted management in early RA (CAMERA) trial was used. Clinical outcomes were extrapolated to Quality Adjusted Life Years (QALYs) and costs using a Markov model. These were compared between the TC and UC arms of CAMERA and a third simulated strategy TCHS. This last strategy was based on a modification of the intensive strategy from the CAMERA trial. Incremental cost-effectiveness ratios (ICERs) were calculated and several scenario analyses performed. The scenarios included full rheumatologist visit instead of half, increase and decrease in handscan cost, using adalimumab instead of cyclosporine, increasing and decreasing effectiveness of handscan and increasing efectiveness of UC. All analyses were performed probabilistically to obtain confidence intervals. Results In TCHS, €4,660 (95% CI -€11,516 to €2,045) was saved and 0.06 (95% CI 0.01 to 0.11) QALYs were gained, when compared to UC, with an ICER of €77,670 saved per QALY gained. This resulted in 91% simulation in the quadrant less expensive with QALY gain. The probability of cost effectiveness was above 99% at a willingness to pay (WTP) of €20,000 per QALY. TCHS resulted in only limited savings compared to TC, €642 (95% CI -€6,903 to €5,601). TCHS was found to be dominant in only 31% of simulations and in 23% inferior (i.e. more expensive and less effective) as compared to TC. The different scenarios also found TCHS and TC to be highly cost effective when compared to UC. The scenarios regarding increasing clinical effectiveness of TCHS, UC and the use of adalimumab instead of cyclosporine had the largest influence on cost-effectiveness results when comparing TCHS and UC. Conclusions A tight control treatment strategy is highly cost-effective compared to a non-tight control approach in early RA. Using the handscan as a monitoring device in a tight control treatment strategy might facilitate implementation of tight control with similar costs and effects, which should be investigated further. References Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Annals of the rheumatic diseases. 2010;69:638-43. Epub 2010/03/20. Acknowledgements This research was supported and reviewed by the Center for Translational Molecular Medicine (CTMM) and the Reumafonds (TRACER). We would like to thank all the participating rheumatologists, patients and research nurses of the CAMERA trial for their specific contribution. We would also like to thank Hemics for their contribution to this work. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2890

SAT0010 Generalization and Extrapolation of Treatment Effects from Clinical Studies in Rheumatoid Arthritis

Background Randomized clinical trials (RCTs) are accepted as the ‘gold standard’ to evaluate the efficacy/effectiveness of treatment. However, generalizing results from RCTs to daily practice poses a challenge with treatment effectiveness often being different. Pragmatic clinical trials have been posed as a solution. Objectives To identify whether pragmatic clinical trials are indeed generalizable to clinical practice and investigate how efficacy estimates from RCTs can be translated into effectiveness estimates for daily practice populations. Methods Data from pragmatic clinical trials of the Utrecht Rheumatoid Arthritis Study Cohort and the observational Nijmegen inception cohort study with comparable inclusion criteria (RA < 1 year disease duration and no prior DMARD use) were used. Patient characteristics were compared between the studies. The treatment effectiveness of MTX and Hydroxychloroquine both compared to the so-called Pyramid approach were compared between the pragmatic trials and observational data using a modified comprehensive cohort design analysis. Change from baseline in DAS28 and HAQ and EULAR good- and moderate response both at 6 months were the outcomes studied in the regression analyses. To study extrapolation of the treatment effect from Phase II/III clinical trials to clinical practice, published results from recent clinical trials evaluating biological treatment compared to control therapy were used. A metaregression analysis was performed to study the influence of population and treatment characteristics on ACR50% response at 6 months. Relative risk (RR) and risk difference (RD) were studied as outcome. Results Age, higher disease activity and response to treatment were higher in patients included in the pragmatic trial as compared to daily practice and rheumatoid factor positive patients were lower. DAS28 and HAQ generally improved more in trial patients as compared to daily practice. Using EULAR response as outcome, the relative effect of treatment (relative risk) was not found to be different. For extrapolating RCT results, glucocorticoid use, disease duration and co treatment with DMARD increased the RR in the study. Higher values of baseline DAS28 and HAQ decreased RD and the use of corticosteroids increased RD. Conclusions Pragmatic clinical trials might be directly generalizable only regarding relative treatment effects. In extrapolating RCT results to daily practice, population characteristics associated with disease activity, disease duration and treatment history or co-treatment need to be taken into account, regardless whether the treatment effect is expressed absolute or relative. Extrapolations of RCT results could also considerably impact costs-effectiveness results. Disclosure of Interest None Declared