Costs associated with failure to respond to treatment among patients with rheumatoid arthritis initiating TNFi therapy: a retrospective claims analysis

Rheumatoid arthritis (RA) affects a relatively small subset of the American population—an estimated 1.3 million people in 2005 [1]—yet, the condition exerts an outsize impact on total healthcare expenditures as well as on overall quality of life, including lost productivity and early mortality [2]. When direct, indirect, and intangible costs are considered, RA annual costs have been estimated at over $56 billion in the United States (in 2016 U.S. dollars) [3]. Biologic therapies contribute substantially to these costs [4] and should be used as effectively as possible.

Achievement of clinical remission or low disease activity has been shown to reduce pain, prevent joint damage, and preserve functional ability, and is the goal of RA treatment [5‐7]. Because the course and severity of RA vary across patients and even for an individual patient over time, treatment regimens should be individualized [8]. Guidelines issued by the American College of Rheumatology in 2015 for the treatment of RA recommend initial treatment with methotrexate (MTX) for patients with established RA, with the addition of another conventional or targeted synthetic or biologic (tumor necrosis factor inhibitors [TNFi] or non-TNFi) disease-modifying antirheumatic drug (DMARD) if symptoms persist at moderate or high disease activity [5]. Treatment changes (i.e., drug addition, switch, or dose changes) are recommended as often as every 3 months, depending on the treatment regimen being used and the change being considered [5].

TNFi agents are often used as the first biologic therapy after patients have an inadequate response or intolerance to MTX [9, 10]. Researchers in a number of studies have evaluated the treatment costs associated with treatment response among TNFi users [11‐15]. For example, one recently published U.S. study concluded that the total RA-associated costs in patients with treatment response ranged from $25,086 to $36,107 per patient-year, depending on the specific TNFi agent used [11]. Less is known about cost differences between treatment responders and nonresponders, which is important for evaluating treatment cost-effectiveness. Results of one study suggested that patients in Canada treated with TNFi agents and achieving low disease activity or remission were associated with lower healthcare costs than those with persistent moderate or high disease activity; however, drug costs were not included in this analysis [16]. In a study using Medicare data in the United States, researchers came to a similar conclusion but also did not take drug costs into consideration [17].

The present study was designed to gain a better understanding of the real-world clinical and economic outcomes between patients with RA who responded to TNFi therapies (treatment responders) and those who did not (nonresponders), accounting for medical as well as drug costs. Differences across cohorts would highlight the importance of close monitoring of patients with RA for appropriate treatment adjustments based on their treatment response. Furthermore, this research provides important input on medical cost offsets associated with treatment response for future cost-effectiveness assessments. Using a large administrative claims database, we analyzed differences in healthcare resource utilization (HCRU) and costs between treatment responders and nonresponders, and we explored the potential for cost savings associated with the response. Matching techniques and sensitivity analysis were used to address potential differences in characteristics between the patient cohorts. RA treatment responders were identified using a claims-based algorithm [18]. The algorithm was originally developed to measure the clinical effectiveness of RA treatments and has acceptable performance characteristics for identifying responders based on validation studies using clinical outcomes (e.g., low disease activity/remission or meaningful change in the Disease Activity Score in 28 joints based on erythrocyte sedimentation rate) as the gold standard (positive predictive value 76%, 95% confidence interval (CI) 71% to 81%; negative predictive value 90%, CI 88% to 92%; sensitivity 72%, CI 67% to 77%; specificity 91%, CI 89% to 93%) [18, 19].

Results of this real-world analysis indicate that patients with RA initiating treatment with TNFi who responded to treatment had consistently lower medical HCRU, medical costs, and nonbiologic pharmacy costs than those who did not respond. These findings were observed over the first year of follow-up (during which some of the costs were related to achievement of the treatment response) as well as over the second and third years of follow-up (the downstream costs of maintaining/failing to maintain treatment response). Comprehensive matching and regression adjustments were performed to account for observed differences between cohorts at baseline. Robustness of the results was confirmed by the sensitivity analysis.

The algorithm for treatment response required high adherence to the index TNFi, resulting in higher biologic therapy pharmacy costs in responders, which was observed in all 3 years. The reductions in medical costs may be considered as the cost offset for this investment, particularly in years 2 and 3 of the analysis. Compared with nonresponders, RA-related mean pharmacy costs were $8579 higher among responders, whereas all-cause mean medical and pharmacy costs (excluding biologics) were $6092 lower, achieving a cost offset of 71%. Our results do not necessarily reflect rebates and discounts on medications that payers may receive from manufacturers. Such discounts would be expected to increase the value of the cost offset and potentially be cost-saving overall. At a 30% discount, for example, biologics would be cost-saving, and the total costs in the responder cohort would be less than those in the nonresponder cohort. In the future, perhaps newer therapies and the availability of biosimilars might make this magnitude of discounting attainable in some settings. Our analysis also considered all TNFi therapies in the aggregate; estimating cost differences across responders and nonresponders specific to each TNFi may be a valuable target for future research.

From a payer perspective, biologic therapy acquisition costs and effective use are crucial elements in the successful management of care for these patients. Quantitative information about the cost savings associated with treatment response, as described in our study, allows informed decision-making on the part of payers. For example, there may be patients who initiate a new drug and are kept on it despite little progress, with the therapy eventually failing. For such nonresponders with high adherence (accounting for 1025 patients [19%] among the 5460 nonresponders identified in our study), resources may be used more efficiently in other ways, and our study provides an estimate of the cost savings associated with response. Similar opportunities for cost savings may exist in situations where patients do not respond well to their initial treatment and are switched to a different treatment, but not in a timely manner, or where existing treatments are titrated with little clinical benefit or cost savings as compared with switching. Health plans may consider aligning their preauthorization processes in such a way as to facilitate switching across different biologic therapies to accelerate patients’ getting a treatment to which they respond. From a physician’s perspective, our study findings also reinforce the benefits of close monitoring of patients’ treatment responses and demonstrate the potential costs of clinical inertia.

Mean medical costs increased over the 3 years of follow-up in both cohorts, possibly owing to disease progression over time. At the same time, pharmacy costs—particularly for biologics—decreased slightly during the follow-up period, perhaps partly because of treatment discontinuation. It is important to note that the study sample used for the 3-year analysis included only those patients who had continuous health plan enrollment for at least 3 years. Costs may have been different for these patients than for those who switched to different types of health plans. Furthermore, patients who were initially responding may have had no response in later years (and vice versa), because the algorithm was implemented only in the first year after TNFi initiation.

Our findings add to previous claims-based research using the same validated algorithm to evaluate treatment effectiveness. The results produced by using the algorithm in the HIRD are consistent with results in other datasets; that is, approximately 30% of patients initiating biologics respond adequately to the treatment [12‐14, 18, 19]. Although this proportion may appear low, it is consistent with an American College of Rheumatology 50% improvement metric rate in an MTX- or TNF-inadequate response population participating in large RA clinical trials [28].

Most previous studies have been focused on assessing the costs of specific biologic therapies among responding patients rather than on comparing them with nonresponders. For example, two algorithm-based analyses of patients responding to TNFi therapy concluded that etanercept, which was also the most commonly used medication in our study, had the lowest disease-related medical plus pharmacy cost per patient-year in response [11], as well as the lowest average cost per effectively treated patient [14]. In a separate study of drug costs over 1 year in responders, researchers found that the highest effectiveness rates were among patients using etanercept and adalimumab, and that subcutaneous TNFi agents were more effective and less costly than intravenous biologics [15]. This may be due to the high costs associated with potential dose escalation of an intravenous therapy such as infliximab. Researchers in two studies compared economic outcomes across responders and nonresponders. In a Canadian study assessing response by disease activity measures, Barnabe and colleagues showed economic benefits for patients achieving remission or low disease activity with TNFi treatment, although drug costs were not included in their study [16]. A similar finding was reported by authors of a recent analysis linking lower RA disease activity to reduced medical costs in a Medicare population [17]. Our study extends these results by accounting for DMARD costs, looking at trends over time, and using a large, real-world U.S. patient population.

Our results nevertheless should be interpreted in light of some limitations. The algorithm used for assessing response did not originally include certolizumab pegol and golimumab. It also has not been validated in the HIRD; however, it has been validated in another similar claims database and used in several others [12, 13, 15, 19]. Patients’ discontinuation was the primary factor in defining treatment nonresponse; however, patients might discontinue a therapy for nonclinical reasons as well, such as financial burden. All patients were members of a large U.S. commercial health plan, and the results may not be generalizable to patients with other types of insurance or to those living outside the U.S. Although not fully generalizable, comparisons of the HIRD against U.S. Census data indicate the patient population contained within the HIRD is mostly representative of the general U.S. population. There are some differences with respect to geographic regions and age profiles; for example, the HIRD overrepresents ages between 30 and 64 years and underrepresents ages 65+ years [20]. Costs were obtained from one health plan and may not represent costs incurred by other health plans, nor may they reflect purchasing discounts or rebates. Biologic drugs administered under the plan’s medical benefit are not consistently identifiable in the claims; our reported drug costs are focused on treatments administered under the pharmacy benefit and may underestimate the full biologic cost burden. Our analysis included patients who initiated TNFi agents between 2007 and 2014, with approximately 53% of patients initiating between 2010 and 2014. RA treatment patterns are rapidly evolving, and our results are limited to observed patterns during this time frame. Last, use of claims data limits the ability to assess certain risk factors (e.g., weight, RA disease severity) that may influence treatment response and costs.

Findings derived from this real-world analysis suggest that patients with treatment response, compared to patients without response, had lower all-cause medical, pharmacy, and total costs (excluding biologics) over up to 3 years from initiation of TNFi therapy. Responders also had lower RA-related medical and overall HCRU and costs. However, RA-related pharmacy costs among responders were higher than among nonresponders, owing to higher adherence to the index biologic therapy. Findings derived from our trend analysis further suggest that the increased costs among nonresponders were consistent over time and that the differences across cohorts remained unchanged. Differences in HCRU and medical costs between the two cohorts represent an offset to the cost of RA treatment and should encourage close monitoring of treatment response to minimize disease progression with appropriate therapy choices. Future researchers may consider examining the presence of such cost offsets for other RA treatments (e.g., non-TNFi biologics). Health plan decision-making may also be improved when taking treatment response based on available claims data into account, and facilitating switching, especially in light of the forthcoming biosimilar medications, where cost will be a driving consideration.