Cost-effectiveness of abatacept, tocilizumab and TNF-inhibitors compared with rituximab as second-line biologic drug in rheumatoid arthritis.

OBJECTIVES: The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. METHODS: A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. RESULTS: Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. CONCLUSIONS: TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.

Efficacy and effectiveness of tumour necrosis factor inhibitors in the treatment of rheumatoid arthritis in randomized controlled trials and routine clinical practice.

Objective: Efficacy of TNF inhibitors in the treatment of RA assessed in randomized controlled trials (RCTs) may not be fully comparable to routine care owing to the stringent inclusion criteria. The objective of this study was to observe the effectiveness of TNF inhibitors in real-world patients and assess the patients' potential eligibility for the RCTs. Methods: RA patients starting a TNF-inhibitor treatment between 2004 and 2014 were identified from the National Register for Biologic Treatment in Finland, which is a longitudinal observational cohort study. Effectiveness was measured using the ACR and EULAR response criteria and by studying the proportion of patients reaching DAS28 remission. The patients' baseline characteristics were compared against the inclusion criteria of 27 RCTs. Results: EULAR moderate and good treatment responses at 6 months were achieved by 69 and 40% of the users of the first TNF inhibitor, respectively. ACR20, ACR50 and ACR70 responses were reached by 48, 27 and 13%, respectively. DAS28 remission was reached by 47%. Only 7.6-44% of the patients would have been potentially eligible for the RCTs. The eligible patients had better treatment responses compared with the non-eligible patients. Different TNF inhibitors were mostly equipotent, but the usage of MTX co-therapy had a major influence on treatment response. Conclusion: Only a small proportion of patients would have been eligible for RCTs, and the efficacy of TNF inhibitors assessed in them cannot be generalized directly into Finnish routine health care.

Cost-effectiveness of biologic compared with conventional synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: a Register study.

OBJECTIVE: The aim of this study was to explore the cost-effectiveness of biological DMARDs (bDMARDs) compared with conventional synthetic DMARDs (csDMARDs) for RA using real-world data from Finnish registers. METHODS: RA patients starting their first bDMARD and comparator patients using csDMARDs during 2007-11 were obtained from the National register of biologic treatments in Finland and the Jyväskylä Central Hospital patient records. Propensity score matching was applied to adjust for differences between bDMARD and csDMARD users. Effectiveness was measured in quality-adjusted life years (QALY) and based on the register of biologic treatments in Finland and Jyväskylä Central Hospital patient records, whereas the direct costs were obtained from relevant Finnish national registers. Patients were followed up for 2 years, and both costs and effectiveness for the second year were discounted at 3%. The incremental cost-effectiveness ratio (ICER) with 95% CI was calculated based on bootstrapped mean costs and effectiveness. RESULTS: Of 1581 RA patients meeting study inclusion criteria, 552 bDMARD and 220 csDMARD users were included in analyses after matching. Mean costs for bDMARDs and csDMARDs were €55 371 and €24 879, while mean effectiveness was 1.23 and 1.20 QALYs, respectively. Consequent ICER was €902 210/QALY. Results were confirmed in sensitivity analyses. CONCLUSION: The high incremental cost and the small, non-significant difference in effectiveness resulted in high ICER, suggesting that bDMARDs are not cost-effective. Regardless of matching, latent confounders may introduce bias to the results.

A survey on the medication adherence to methotrexate among rheumatoid arthritis patients treated with self-administered biologic drugs.

OBJECTIVES: Methotrexate (MTX) is the most widely used co-therapy among rheumatoid arthritis (RA) patients using biological disease-modifying anti-rheumatic drugs (bDMARDs). However, adherence to MTX treatment remains a concern with estimates of adherence ranging from 59 to 63%. The objective of this study was to assess the self-reported use and adherence to MTX among RA patients treated with self-administered bDMARDs. METHODS: An electronic questionnaire survey was conducted in 68 community pharmacies in Finland. To be included in the present study patients had to be at least 18 years old, be currently using a self-administered bDMARD and be diagnosed with RA. The results are presented as medians with their respective interquartile ranges (IQR) or percentages. RESULTS: Of the 158 pharmacy customers asked to participate, 135 (85%) consented to complete the questionnaire. The included respondents were predominantly female (72%) with a median age of 55 (IQR 44-65) and rheumatic activity of 3 out of 10 (IQR 2-6.5). The majority (91%) of the included respondents were using TNF-inhibitors and 27% of all patients were on biologic monotherapy. MTX was currently used by 45% of the respondents while 50% were past users. Of the current MTX users, 6.8% identified themselves moderately non-adherent to the treatment. MTX-related adverse events were important factors associated with nonadherence and discontinuation of the treatment. CONCLUSIONS: Only 45% of the respondents were currently using MTX co-therapy, but the ones who did were adherent to their treatment. Self-reported adherence may however be subject to social desirability bias and recall bias.

Effectiveness and Drug Survival of TNF Inhibitors in the Treatment of Ankylosing Spondylitis: A Prospective Cohort Study.

OBJECTIVE: The aim of this research was to describe the effectiveness and drug survival of tumor necrosis factor (TNF) inhibitors in the treatment of ankylosing spondylitis (AS) and to analyze the effect of concomitant treatment with conventional disease-modifying antirheumatic drugs. METHODS: Patients with AS identified from the National Register for Biologic Treatment in Finland starting their first TNF inhibitor treatment between July 2004 and December 2011 were included. Treatment response was measured as an improvement of 50% (or 20 mm) after 6 months of treatment onset compared to the baseline Bath AS Disease Activity Index (BASDAI) score. Treatment response and 2-year drug survival were modeled with logistic regression and time-dependent Cox proportional hazard models, respectively. RESULTS: The study comprised 543 patients, of whom 123 also commenced a second TNF inhibitor during the followup. Treatment was discontinued within 24 months by 25% and 28% of the users of the first and the second TNF inhibitors, respectively. BASDAI response at 6 months was achieved by 52% and 25% of the users of the first and the second TNF inhibitors, respectively. Etanercept (ETN; HR 0.42, 95% CI 0.29-0.62) and adalimumab (ADA; HR 0.48, 95% CI 0.30-0.77) were associated with better drug survival in comparison to infliximab (IFX). Also, concurrent use of sulfasalazine (SSZ; HR 0.70, 95% CI 0.49-0.99) decreased the hazard for treatment discontinuation. CONCLUSION: TNF inhibitors are equipotent in the treatment of AS; however, ETN and ADA were found superior to IFX in drug survival. The use of SSZ improves treatment continuation.

The cost-effectiveness of biologics for the treatment of rheumatoid arthritis: a systematic review.

BACKGROUND AND OBJECTIVES: Economic evaluations provide information to aid the optimal utilization of limited healthcare resources. Costs of biologics for Rheumatoid arthritis (RA) are remarkably high, which makes these agents an important target for economic evaluations. This systematic review aims to identify existing studies examining the cost-effectiveness of biologics for RA, assess their quality and report their results systematically. METHODS: A literature search covering Medline, Scopus, Cochrane library, ACP Journal club and Web of Science was performed in March 2013. The cost-utility analyses (CUAs) of one or more available biological drugs for the treatment of RA in adults were included. Two independent investigators systematically collected information and assessed the quality of the studies. To enable the comparison of the results, all costs were converted to 2013 euro. RESULTS: Of the 4890 references found in the literature search, 41 CUAs were included in the current systematic review. While considering only direct costs, the incremental cost-effectiveness ratio (ICER) of the tumor necrosis factor inhibitors (TNFi) ranged from 39,000 to 1,273,000 €/quality adjusted life year (QALY) gained in comparison to conventional disease-modifying antirheumatic drugs (cDMARDs) in cDMARD naïve patients. Among patients with an insufficient response to cDMARDs, biologics were associated with ICERs ranging from 12,000 to 708,000 €/QALY. Rituximab was found to be the most cost-effective alternative compared to other biologics among the patients with an insufficient response to TNFi. CONCLUSIONS: When 35,000 €/QALY is considered as a threshold for the ICER, TNFis do not seem to be cost-effective among cDMARD naïve patients and patients with an insufficient response to cDMARDs. With thresholds of 50,000 to 100,000 €/QALY biologics might be cost-effective among patients with an inadequate response to cDMARDs. Standardization of multiattribute utility instruments and a validated standard conversion method for missing utility measures would enable better comparison between CUAs.

The EULAR Study Group for Registers and Observational Drug Studies: comparability of the patient case mix in the European biologic disease modifying anti-rheumatic drug registers.

OBJECTIVE: Under the auspices of the European League Against Rheumatism (EULAR), a study group of investigators representing European biologic DMARD (bDMARD) registers was convened. The purpose of this initial assessment was to collect and compare a cross section of patient characteristics and collate information on the availability of potential confounders within these registers. METHODS: Baseline characteristics of patients starting their first bDMARD in an arbitrary year (2008) for the treatment of RA, including demographic and disease characteristics, bDMARD drug details and co-morbidities, were collected and compared across 14 European bDMARD registers. RESULTS: A total of 5320 patients were included. Half the registers had restricted recruitment to certain bDMARDs during the study year. All registers` collected data on age, gender, disease duration, seropositivity for IgM-RF and 28-joint DAS (DAS28). The mean DAS28 ranged from 4.2 to 6.6 and the mean HAQ from 0.8 to 1.9. Current smoking ranged from 9% to 34%. Nine registers reported co-morbidities with varying prevalence. CONCLUSION: In addition to demonstrating European-wide collaboration across rheumatology bDMARD registers, this assessment identified differences in prescribing patterns, recruitment strategies and data items collected. These differences need to be considered when applying strategies for combined analysis. The lack of a common data model across Europe calls for further work to harmonize data collection across registers.

Do biologic drugs affect the need for and outcome of joint replacements in patients with rheumatoid arthritis? A register-based study.

OBJECTIVES: The aim was to study the incidence of joint replacements among biologic drug and disease-modifying anti-rheumatic drug (DMARD) users as well as to investigate the plausible effect of biologic treatment on survival of prostheses in patients with Rheumatoid arthritis (RA). METHODS: The study population comprised 2 cohorts of patients [Register of biologic treatment in Finland (ROB-FIN) and the Central Finland RA database] from 1999 to 2010. Records of joint replacements performed in the study population between 1980 and 2010 were retrieved from the Finnish Arthroplasty Register. Propensity score matching was used to equalize patient characteristics between biologics and DMARD users. The incidence rates of primary and revision operations were compared between the 2 treatment groups. Kaplan-Meier survival analysis was used to analyze prosthesis survival. RESULTS: Of the 2102 biologics and 2710 DMARD users identified from the registries, 1587 were included in both groups after the matching. Median follow-up times were 3.1 and 8.0 years, respectively. There were more primary operations per 100 patient years in the biologics (3.89, CI 95% 3.41-4.41) vs. DMARD (2.63, 2.35-2.94) group but slightly fewer revisions (0.65, 0.46-0.88 vs. 0.83, 0.68-1.01). Biologics users were more likely to receive a joint replacement to small joints (p < 0.001). The survival of the prostheses installed during or prior to follow-up was similar in both treatment groups. CONCLUSIONS: The use of biologic drugs did not reduce the need for joint replacement surgery in patients with a similar on-medication disease activity. Despite possibly lower rate of revisions among biologic users, the durability of prostheses was not improved.

Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: Five-tumour necrosis factor (TNF)-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA) and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT). METHODS: A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE), Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX), in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias. RESULTS: Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo. CONCLUSIONS: No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.