From March 2015 to October 2018, a total of 109 RA patients who underwent ABN+MTX or conventional disease-modifying antirheumatic drugs (cDMARDs) treatment at ZhuZhou Central Hospital were consecutively enrolled in this study. The screening criteria were referring to the protocol described in our first-stage study . This study was approved by the Ethics Committee of ZhuZhou Central Hospital (Approved No. 2015-K-05010). All procedures were conducted in accordance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients signed the written informed consents. Besides, the study was registered on the Chinese Clinical Trial Registry (ChiCTR) affiliated to World Health Organization (WHO) (www.chictr.org.cn) with registry number ChiCTR2000032534.
After enrollment, the baseline (M0) characteristics of patients were recorded, which included age, gender, disease duration, tender joint count (TJC), swollen joint count (SJC), C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR) level, pain visual analogue scale (VAS) score, patient global assessment (PGA) score, physician global assessment (PhGA) score, Health Assessment Questionnaire Disability Index (HAQ-DI) score and history of treatment. And the disease activity of patients was assessed according to disease activity score with 28 joints based on CRP (DAS28-CRP) and disease activity score with 28 joints based on ESR (DAS28-ESR), which were calculated as follows: DAS28-CRP=0.56∗sqrt(TJC28)+0.28∗sqrt(SJC28)+0.014∗PGA+0.36∗ln(CRP+1)+0.96, DAS28-ESR=0.56∗sqrt(TJC28)+0.28∗sqrt(SJC28)+0.014∗PGA+0.70∗ln(ESR).
After enrollment, 55 patients about to receive ABN+MTX therapy were assigned to ABN+MTX group, and the other 54 patients who scheduled to receive cDMARDs treatment were allocated to control group. The treatment regimens for the two groups were conducted in accordance with the protocol described in our first-stage study . In brief, for the ABN+MTX group, ABN and MTX were administrated to the patients as follows: ABN 25 mg twice a week subcutaneously for 24 weeks or ABN 50 mg once a week subcutaneously for 24 weeks, and MTX 10-20 mg once a week orally for 24 weeks. For the control group, all patients received cDMARDs alone or in combination for 24 weeks, and 23 patients received MTX (10–20 mg once a week orally)+leflunomide (10 mg qd), 31 patients received MTX (10–20mg once a week orally)+sulfasalazine (1 g tid orally)+hydroxychloroquine (400 mg qd).
After initiation of treatment, regular follow-up was conducted for the patients, and the TJC, SJC, ESR level, CRP level, pain VAS score, PGA score, PhGA score, and HAQ-DI score were evaluated at 3rd month (M3), 6th month (M6) and 12th month (M12). During follow-up, 13 patients lost follow-up without any assessment, 6 patients withdrew the informed consents, and those 19 patients were excluded from the final analysis. Therefore, 90 patients were included in the final analysis: 47 cases in the ABN+MTX group and 43 cases in the control group.
The primary outcome of efficacy was DAS28-ESR remission rate, defined as the percentage of patients with DAS28-ESR≤2.6 after treatment. The secondary outcome of efficacy included DAS28-ESR response rate (defined as the percentage of patients with an improvement of DAS28-ESR>1.2 after treatment), DAS28-ESR low disease activity (LDA) rate (defined as the percentage of patients with DAS28-ESR≤3.2 after treatment) and the improvements of TJC, SJC, CRP level, ESR level, pain VAS score, PGA score, PhGA score, HAQ-DI score, DAS28-CRP score and DAS28-ESR score. The DAS28-ESR remission rate, DAS28-ESR response rate and DAS28-ESR LDA rate were assessed at M6 and M12. The changes of TJC, SJC, CRP level, ESR level, pain VAS score, PGA score, PhGA score, HAQ-DI score, DAS28-CRP score and DAS28-ESR score was calculated at M3, M6 and M12.
Direct, indirect and total costs calculation
Direct costs consisted of drug costs and other medical costs. And drug costs for the patients were calculated according to unit cost and the dosages recorded in the case report form (CRF). Other medical costs included outpatient cost, emergency cost and hospitalization cost. Indirect costs included lost productivity costs of patients and caregivers due to working days lost, and calculated by the losing working days multiplying the local average daily wage. Total costs were defined as the sum of drug costs, other medical costs and indirect costs. All unit costs of medication, outpatient, emergency and hospitalization were obtained from the electronic medical records of ZhuZhou Central Hospital.
Cost-effectiveness analysis was used for pharmacoeconomic assessment. The total costs and quality adjusted life-year (QALY) was calculated, and the difference of incremental cost-effectiveness ratio (ICER) between two groups was evaluated by incremental cost divided by incremental QALY . The QALY was defined as the study we published previously, which were estimated form a relation function between HAQ-DI scores and Europe Quality of Life five-dimension (EQ-5D) questionnaire utility values : EQ-5D=0.9567-0.309*HAQ-DI. The threshold of acceptable cost-effectiveness was ICER lower than three times of the annual gross domestic product (GDP) per capita, which was defined referring to the willingness-to-pay (WTP) recommended by the World Health Organization’s (WHO) Choosing Interventions that are Cost-Effective (CHOICE) program . In case of China, GDP per capita was 53980 RMB (¥) in 2016, ¥59660 in 2017, ¥66006 in 2018, ¥70892 in 2019 and the average of GDP per capita from 2016 to 2019 was ¥62634.
To evaluate the uncertainty of market effects on direct or indirect medical costs, the drug price (ABN), other medical cost and indirect cost were varied in sensitivity analyses as follows: (1) fell by 20% and 50% of their base-case prices; (2) rose by 20% and 50% of their base-case prices. Besides, the uncertainty of improvement for HAQ-DI score on cost-effectiveness was also performed by the sensitivity analyses, which was carried out as follows: (1) fell by 20% and 50% of HAQ-DI score in ABN+MTX group; (2) rose by 20% and 50% of HAQ-DI score in ABN+MTX group.
Statistical analysis was performed using SPSS 21.0 statistical software (IBM, USA), and the figure was made with the use of GraphPad Prism 6.01 software (GraphPad Software Inc, USA). Data were presented as mean±standard deviation (SD) or count (percentage). Comparison between two groups was determined by Student’s t-test or Chi-square test. All tests were 2-sided, and P value<0.05 was considered as statistically significant.