Cost-utility analysis of biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic DMARDs (tsDMARDs) and biosimilar DMARDs (bsDMARDs) combined with methotrexate for Thai rheumatoid arthritis patients with high disease activity

Rheumatoid arthritis (RA) is a chronic progressive inflammatory disorder of unknown etiology characterized by symmetric polyarticular joint involvement that can cause joint destruction. The goals of treatment are to induce complete remission or decrease disease activity. Additional goals include controlling joint pain, delaying joint damage that leads to disability, and maintaining or improving both the ability to function in daily activities and the patient’s quality of life [1]. In 2015, the incidence and prevalence of RA were estimated to be 0.15% and 1.6% of the total Thai population, respectively [2]. Ineffective RA treatment can cause high disease activity, leading to a 2.43-fold increase in mortality rate compared to RA patients with low disease activity (hazard ratio 2.43; 95% CI 1.64 to 3.61) [3]. It can also lead to lifelong disability, which reduces quality of life and reduces productivity [4]. According to the Thai RA clinical practice guidelines, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), anti-inflammatory drugs, analgesics, and low-dose corticosteroids are recommended as first-line therapies. Treatments with csDMARDs such as methotrexate (MTX), sulfasalazine (SSZ), chloroquine (CQ), and hydroxychloroquine (HCQ) can be initiated as a monotherapy or a combination therapy in the first-line treatment. Combination therapy with two or more csDMARDs may be effective when single-DMARD treatments are unsuccessful or in RA patients presenting with several prognostic factors, such as elevated levels of inflammatory markers (e.g., Erythrocyte Sedimentation Rate [ESR] and C-reactive protein [CRP]), multiple swollen joints, and extra-articular manifestations. The treatment response and dose titration are typically assessed every 1–3 months using multiple criteria, such as ESR and CRP levels, joint pain and swelling, and evaluations from both the patient and physician. Treatment switching usually occurs at 6-month intervals after the initial treatment failure [5, 6]. For those patients exhibiting RA with inadequate response, a series of csDMARDs was sequentially added, namely methotrexate (MTX) + sulfasalazine (SSZ) + leflunomide (LEF) [5]. In the last decade, new biologics (bDMARDs) and their biosimilars (bsDMARDs) as well as targeted synthetic DMARDs (tsDMARDs) for the treatment of RA have been licensed because of their clear clinical benefits in terms of ameliorated disease severity and improved chances for remission [7, 8], albeit at greater costs than the standard treatment [7‐9]. In Thailand, when RA patients fail three csDMARDs or experience csDMARD toxicity, only rituximab is reimbursed and then only through the Civil Service Medical Benefit Scheme (CSMBS), one of three available healthcare schemes, via a special program, namely the Rheumatic Disease Prior Authorization (RDPA) [5, 6]. Patients with RA, who are insured under the universal health coverage scheme (UCS) and the social security scheme (SSS) that cover around 90% of the population, can typically access only csDMARDs (such as cyclosporine and azathioprine). In 2019, the National List of Essential Medicines (NLEM) subcommittee, which oversees the Thai pharmaceutical reimbursement list for these three healthcare schemes, required evidence of cost-effectiveness before determining whether bDMARDs, tsDMARDs or bsDMARDs should be included in the essential list as treatments for patients exhibiting RA with high disease activity. This study aims to evaluate the cost-utility of bDMARDs, tsDMARDs and bsDMARDs combined with MTX in RA patients who have had an inadequate response to the typical combination of three csDMARDs (i.e., MTX, SSZ, and LEF) in the Thai context.

The costs and health outcomes for the novel treatments were compared with those of the conventional treatment using a model-based economic evaluation. The modelled population consists of RA patients with inadequate responses to the standard combination of three csDMARDs, namely methotrexate (MTX) + sulfasalazine (SSZ) + leflunomide (LEF). Treatment options consisted of the current treatment (i.e., csDMARDs) and one of the seven patented bDMARDs or tsDMARDs, which can be divided into four main groups: 1) anti-TNF-α, i.e., etanercept, infliximab, and golimumab; 2) anti-IL6, i.e., tocilizumab; 3) anti-CD20, i.e., rituximab; and 4) JAK inhibitor, i.e., tofacitinib and baricitinib (Table 1). In addition, the following bsDMARDs that have been approved by the Thai Food and Drug Administration (FDA) were also included as treatment options: biosimilars to infliximab (Remsima® and Ixifi®), a biosimilar to the TNF-α inhibitor adalimumab (Amgevita®), and a biosimilar to rituximab (Truxima®). As recommended by the Thai Health Technology Assessment (HTA) Guideline [10], the analysis was conducted from a societal perspective to estimate lifelong costs and health outcomes (i.e., quality-adjusted life years or QALYs). Both estimated costs and QALYs were discounted by 3% per year. All costs were adjusted for the year 2022 using the consumer price index (CPI) [11]. The cost-effectiveness ceiling threshold of 160,000 THB per QALY gained (US $4,634, 1 USD = 34.53 THB in 2022) was used as recommended by the Health Economic Working Group under the Subcommittee for the Development of the National List of Essential Medicine (NLEM) [12].

A Markov model was constructed using Microsoft Excel (Microsoft Corp., Redmond, Washington, USA) to simulate disease progression. Four health states were classified according to the Disease Activity Score-28 for RA with ESR (DAS28-ESR) criteria [13‐16], consisting of 1) high disease activity, defined as DAS28-ESR > 5.1; 2) moderate or low disease activity, defined as DAS28-ESR ≥ 2.6 to 5.1; 3) remission defined as DAS28-ESR < 2.6; and 4) death (Fig. 1). The model was constructed with a cycle length of 6 months to measure treatment response using DAS28-ESR criteria [6]. The cohort population of the analysis was composed of 56-year-old RA patients with high disease activity (DAS28-ESR > 5.1) who had an inadequate response to three csDMARDs. The second-treatment sequence for RA patients with inadequate response was implemented as follows: 1) Those on the novel treatment + MTX regimen would be switched to the SoC + MTX treatment; and 2) Those already on the SoC + MTX regimen would remain on this treatment course. Supportive care, involving the use of corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs), supplemented both treatment arms, resulting in an SoC + MTX + supportive care regimen for all patients with inadequate response (Additional file 1). To manage RA patients in remission for 6–12 months, the Thai clinical practice guideline recommends several strategies, including dose tapering, increasing dosing intervals, or discontinuing bDMARDs, tsDMARDs or bsDMARDs [6]. In this study, RA patients who achieved remission would receive treatment for six months before discontinuing all treatments except for MTX, which would continue unchanged. Patients who experienced a serious adverse event (SAE) discontinued their current regimen for 6 months while they received treatment for their SAE before the resumption of RA treatment. The model assumptions were validated and approved by experts and stakeholders during a consultation meeting according to the second edition of the Thai HTA Guideline [10] and the Thai HTA process guideline [17].

Lifetime costs, QALYs, and ICERs are shown in Table 3. In combination with MTX, the lifetime cost of novel treatments ranged from 0.8 to 2.3 million THB (US $23,102 to $65,935). Golimumab had the highest lifetime cost of 2.3 million THB (US $65,935), followed by infliximab at 1.9 million THB (US $54,202), and etanercept at 1.2 million THB (US $35,771). The remaining novel treatments had lifetime costs ranging from 0.8 to 1.1 million THB (US $23,102 to $25,990). In contrast, the SoC had the lowest lifetime cost at 0.2 million THB (US $7,145). Life year (LY) and QALY values, under the discounted annual rate, were comparable between the novel treatments and the SoC (LYs of 5.70–5.97 vs. 5.61 and QALYs of 4.90–5.14 vs. 4.80 for the new treatments versus the SoC, respectively). Compared to the SoC, all new treatments had substantially higher costs with only slightly improved QALYs. In the Thai setting, none of the new treatments were cost-effective compared to the ceiling threshold of 160,000 THB (US $4,634) per QALY gained [12]. The ICER values of the new treatments ranged from 2.3 to 8.1 million THB (US $65,935 to $234,996) per QALY gained, with the biosimilar infliximab having the lowest ICER value at 2.3 million THB (US $65,935) per QALY gained (Fig. 3).

Given a national ceiling threshold of 160,000 THB (US $4,634) per QALY gained, our results show that neither bDMARDs, tsDMARDs nor bsDMARDs combined with MTX treatment for eligible RA patients were cost-effective in the Thai setting [12]. The sensitivity analysis confirms the robustness of the estimated results. In addition, uncertainty in treatment prices, any of which can result in higher costs than conventional treatments using csDMARDs from the current health coverage reimbursement list, had no effect on the cost-effectiveness.

In this multicenter study, data on clinical outcomes (DAS28-ESR values) for the current treatment regimen were collected from three centers and aligned with the evaluation of a patient's outcome in clinical practice [5], making it relevant to the local context. In addition, the quality of life related to health among Thai patients with RA was directly collected using the EQ-5D questionnaire and reanalyzed to conform to the analytical model used in this study [17, 20]. Furthermore, following the recommendation of the national guidelines for the evaluation of health technologies [10, 26], this study examined all available treatments involving bDMARDs, tsDMARDs, and bsDMARDs that were licensed and approved by the Thai FDA for patients with RA and compared all costs and health outcomes, making it the first economic evaluation of this kind in Thailand. This study also used a systematic review and network meta-analysis (SR-NMA) to estimate the efficacy of each treatment option, as opposed to prior economic evaluation studies [27] that assessed cost-utility based on the “generic name” of biologic DMARDs and relied on efficacy data from randomized clinical trials (RCTs) of the original product, with the assumption that treatment outcomes for biosimilar DMARDs and their original products were equivalent.

Our findings are consistent with those of previous studies in Sweden [28], Iran [29], the Netherlands [30] and the United Kingdom [31] indicating that bDMARDs or tsDMARDs were not cost-effective across many contexts due to their high cost. However, previous studies were conducted in patients with RA with moderate disease activity, where bDMARDs or tsDMARDs were used when MTX therapy failed, whereas our RA patients had more severe disease activity and failed multiple lines of treatment, i.e., inadequately responded to three csDMARDs. It has been established that disease progression, as a consequence of consecutive treatment failures and the delayed addition of bDMARDs / tsDMARDs to a methotrexate regimen, leads to reduced efficacy rates and adverse health outcomes [32]. As a result, the prior studies reported better health outcomes owing to the earlier use of bDMARDs / tsDMARDs in the treatment of eligible patients. Furthermore, bDMARDs and tsDMARDs could be relatively cost effective compared to one another, but they were never cost effective overall when compared to the SoC. For example, adalimumab was found to be cost-effective compared to the TNF antagonist that was included in the national list of essential medicines in Sweden [28].

This analysis has certain limitations. First, the response rates of the American College of Rheumatology (ACR) are widely used as a primary outcome to measure the efficacy of bDMARDs, tsDMARDs, and their bsDMARDs. However, the studies with ACR results were excluded from our SR-NMA because the present study used DAS28-ESR values as the outcome of interest, as suggested by the clinical practice guidelines [5]. Second, because of limited resources, the RA treatment sequence recommended by the Thai RA treatment guidelines is not aligned with the ACR 2015 / EULAR 2016 guidelines [33, 34]. Therefore, the efficacies of bDMARDs, tsDMARDs, and their bsDMARDs obtained from the SR-NMA were only compared with that of MTX, whereas the SoC in this study was cyclosporine or azathioprine combined with MTX. Third, although there were efficacy assumptions, they were transparently validated by rheumatologists in stakeholder consultation meetings. These included (1) assuming that treatments without efficacy data in the “transition from high disease activity to remission” would be equivalent to the efficacy values for the same treatments where data was available, and (2) assuming that the efficacy of the “transition from moderate / low disease activity to remission” would be comparable to the “transition from high disease activity to remission.” Fourth, although practitioners using bDMARDs, tsDMARDs, and bsDMARDs reported different serious adverse events (i.e., tuberculosis, herpes zoster, thromboembolism, neoplasm, and serious infection), the study rheumatologist was most concerned with serious infection during treatment. As a result, values for the relative risks of serious infection obtained from the SR-NMA were chosen to represent serious adverse events from the use of bDMARDs, tsDMARDs, and bsDMARDs. Nonetheless, all treatment options were adjusted with the baseline probability of all serious adverse events analyzed from the national health administrative database. Lastly, the risk of death in RA patients with high disease activity was calculated using the mortality hazard ratio of an observational study in Germany, adjusted with the value for the risk of death in the Thai general population. This parameter had an impact on the increase in mortality with age and significantly influenced the incremental cost-effectiveness result, encouraging further research in the Thai RA registry to evaluate mortality classified by disease severity. It can also be applied contextually as real-world evidence for the next HTA research and encourages efficient monitoring and treatment in Thai RA patients with high disease activity.

The combination of MTX with bDMARDs, tsDMARDs or bsDMARDs for the treatment of RA patients with high disease activity showed a clinically-relevant reduction in disease activity and an increased chance of remission, leading to an improvement in patient quality of life related to health. However, based on the Thai ceiling threshold of 160,000 THB (US $4,634) per QALY, none of these treatment options were cost-effective at their current prices. The findings of this study can be used as evidence for the National List of Essential Medicines (NLEM) subcommittee, comprised of decision makers for the Thai pharmaceutical reimbursement list, to guide its price negotiation process and ensure that these effective drugs are financially affordable before they are added to the NLEM.