Cost-Effectiveness and Patient Benefit Balance of Methotrexate, DMARD Combination Therapy


Combination methotrexate plus bDMARDs, bsDMARDs, and tsDMARDs provided .009 to .33 quality-adjusted life years gained with additional costs of $15,957 to $60,722 when compared with standard of care.

A combination of methotrexate with either biologic disease-modifying antirheumatic drugs (bDMARDs), targeted synthetic DMARDS (tsDMARDs), or biosimilar DMARDs (bsDMARDs) were not cost-effective among a cohort of Thai patients, according to a study published in BMC Health Services Research.1 However, this combination was shown to reduce disease activity and improve patient quality of life. Investigators believe a price negotiation process should be performed to confirm financial value and affordability prior to inclusion in the pharmaceutical reimbursement list.

Cost Effectiveness and Patient Benefit Balance of Methotrexate, DMARD Combination Therapy

Pattara Leelahavarong, PhD


“New bDMARDs, tsDMARDs, and bsDMARDs all showed greater clinical benefits in the treatment of patients with rheumatoid arthritis (RA) with high disease activity, but imposed higher costs than standard treatment,” wrote Pattara Leelahavarong, PhD, researcher at the Health Intervention and Technology Assessment Program (HITAP), Ministry of Public Health, Nonthaburi, Thailand, and colleagues. “This study evaluated the cost-effectiveness of 11 alternative treatment strategies for RA patients with high disease activity whose treatment with three conventional synthetic DMARDs (csDMARDs) failed.”

Combination therapy may be more effective when single DMARD therapy is unsuccessful. For patients with rheumatoid arthritis (RA) who have inadequate response, csDMARDs, such as methotrexate, are often added. New bDMARDs, bsDMARDs, and tsDMARDs have been licensed due to clear clinical benefits regarding disease severity and improved chances for remission, although it costs more when compared with standard treatment.2

Societal perspective was used to develop a Markov model to evaluate relevant costs and health outcomes regarding quality-adjusted life years for a lifetime horizon of 100 years, given a 3% annual discount. The 4 health states according to the Disease Activity Score-28 using erythrocyte sedimentation rate criteria (DAS28-ESR) were defined as high disease activity (DAS28-ESR >5.1), moderate or low disease activity (DAS28-ESR ≥2.6 to 5.1), remission (DAS28-ESR <2.6), or death. Alternative treatments, including 5 bDMARDs, 4 bsDMARDs, and 2 tsDMARDs, in combination with methotrexate, were compared with standard of care (cyclosporine and azathioprine).

Non-medical costs and direct care costs were determined and multiplied by the standard costing menu in 2022. Three advanced tertiary hospitals were used to collect utility and transitional probabilities and the efficacy of each treatment was estimating via a network meta-analysis. Quality-adjusted life years, lifetime cost, and an incremental cost-effectiveness ratio were calculated and compared to the cost-effectiveness threshold of 160,000 Thai baht (TBH) per quality-adjusted life years gained (United States dollar [USD] $4634, where 1 USD = 34.53 THB in 2022). Parameter uncertainties were estimated using probabilistic and one-way sensitivity analyses.

Combination methotrexate plus bDMARDs, bsDMARDs, and tsDMARDs provided .009 to .33 quality-adjusted life years gained with additional costs of 550,986 to 2,095,744 THB (USD $15,957 to $60,722) when compared with standard of care. The incremental cost-effectiveness ratios (ICERs) ranged from 2.3 to 8.1 million THB per quality-adjusted life years (US $65,935 to $234,996) compared with the standard of care.

None of the combinations were deemed cost-effective. Results were sensitive to the mortality hazard ratio of patients exhibiting high disease activity.

Investigators noted the studies of the American College of Rheumatology (ACR) were excluded from the network meta-analysis, although ACR response rates are generally used as a primary outcome to measure the efficacy of DMARDs. Further, the RA treatment sequence currently recommended by the Thai RA treatment guidelines is not aligned with the ACR 2015 guidelines.

“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,” investigators concluded.


  1. Prawjaeng J, Leelahavarong P, Budtarad N, et al. 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. BMC Health Serv Res. 2023;23(1):561. Published 2023 May 31. doi:10.1186/s12913-023-09595-1
  2. Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe DJ, Bombardier C. Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: a network meta-analysis. Cochrane Database Syst Rev. 2016;2016(8):CD010227
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