This retrospective study aimed to identify predictors of MTX monotherapy treatment success in RA patients. We found that 59.4% of subjects achieved treatment success (defined as remission or low disease activity) as assessed by DAS28-ESR, with remission achieved in 33% of subjects. The success rate observed in our study was higher than that reported in a previous study from the same centre, which showed treatment success and remission rates of 41.5% and 13.8%, respectively.21 Another multicentre study in Indonesia reported treatment response rates of 43.5% and 24.5%, respectively.22 A study in Thailand demonstrated a proportion of remission and low disease activity of 39.1%.23 Sun et al., in an Asian-Pacific multicentre study, found a MTX remission rate of 35.5%.17 These findings indicate that MTX continues to demonstrate an acceptable response rate in achieving treatment targets as the first-line therapy in RA.
Additionally, notable differences in subject characteristics were observed compared to previous RA studies. Notably, 95.7% of newly diagnosed RA patients in our cohort were female. This aligns with previous epidemiological studies which indicated that RA primarily affects women with a female-to-male ratio of approximately three to one, often presenting with higher disease activity and disability.24 The elevated prevalence of RA among women is corroborated by various studies; for instance, Silva-Fernández et al. found that women constituted 61.5% of RA patients in a population-based national survey in Spain.25 Furthermore, a large epidemiological study across Middle Eastern regions reported an even higher proportion of female patients at 84.9%.26 Our observation of an overwhelmingly female RA population surpasses the female-to-male ratio reported in most previous studies, potentially attributable to ethnic differences and variances in health-seeking behaviour between genders in Indonesia.
Moreover, we noted that the mean BMI in our cohort was 23.8 kg/m², with 36.6% classified as obese. Obesity has been associated with an increased risk of RA, with a notable proportion of RA patients exhibiting obesity.27 For instance, a study in the United Kingdom reported a mean BMI of 27.5 kg/m² among RA subjects.28 This contrasts with studies in the Asia-Pacific region and Indonesia, where mean BMI values of 23.3 kg/m² and 22.5 kg/m², respectively, were reported among RA populations.17,22 These discrepancies in RA patient characteristics warrant further exploration, considering potential influences of genetic variations and socioeconomic factors.
Multivariate analysis revealed four significant predictors of MTX treatment success: lower disease activity at baseline (moderate vs. high disease activity) (OR 1.97, p = 0.04), normal ESR (OR 2.58, p = 0.04), normal weight (OR 2.55, p = 0.00), and tender joint count (TJC) ≤ 5 (OR 2.45, p = 0.00). Sensitivity analysis of these four variables showed that they were consistent predictors of MTX monotherapy treatment success.
Disease activity was a significant predictor of achieving treatment targets in this study, consistent with the results of a cohort study involving 285 subjects that investigated the effectiveness of MTX. Patients with higher disease activity (DAS28 > 5.1) had a higher risk of MTX treatment failure (OR 3.08, 95% CI 1.26–7.52).14 Higher disease activity is considered a poor prognostic factor based on data collected from various randomized controlled trials (RCTs) and cohort studies, in accordance with both EULAR and ACR recommendations.29 Furthermore, results from OPTIMA and PREMIER studies investigating RA patients on MTX also found that higher disease activity (DAS28 6.4) is a predictor of insufficient response to MTX after 6 months of therapy.30
The role of ESR in predicting treatment response has also been investigated in previous studies. In a stratified single-blinded trial involving seven secondary and tertiary care clinics, ESR > 40 mm/hour was associated with approximately threefold the risk of MTX non-response compared to subjects with normal ESR values (OR 2.77; 95% CI 1.58–4.85).14 Another study conducted in Dublin, which conducted synovial sampling through arthroscopy in RA patients with knee arthralgia, demonstrated a positive correlation between ESR values and the level of inflammation.31 Higher ESR is also considered a poor prognostic factor when present with other factors, such as moderate disease activity, RF/ACPA positivity, persistent swollen joints, active synovitis, and the presence of bone erosion.29
Normal BMI was also found to be a predictor of MTX treatment success in our study, consistent with the findings of previous studies. A study investigating predicting factors of insufficient response to MTX among DMARD-naïve RA patients found that obesity was associated with a threefold risk of MTX non-response (OR 3.02; 95% CI 1.31–6.97).14 Moreover, in a meta-analysis conducted by Liu et al., obese patients were found to be 43% more likely to fail to achieve remission, and almost all studies included in the review demonstrated that obesity aggravated disease activity, increased the number of tender joints, increased inflammation markers, and increased levels of pain.32 Another study involving 1,313 RA patients in early and advanced stages of the disease showed that overweight and obese patients required higher doses of MTX, either as monotherapy or in combination with other DMARDs, with an average dose of 20 mg/week, compared to 15 mg/week of MTX in subjects with normal BMI. Aside from the higher dose requirement, overweight or obesity were also associated with a reduced response to therapy in established RA.33
The fourth predicting factor of MTX treatment success identified in this study was the number of tender joints. A study by de Rotte et al. reported that patients with TJC > 3 had twice the higher risk of having an insufficient response to MTX (OR 2.05; 95% CI 1.08–3.89).14 Similarly, results from The Rheumatoid Arthritis Medication Study (RAMS), a large multicentre study involving 38 centres with a total of 1,050 subjects, found that a higher tender joint count was associated with a six percent higher risk of being MTX non-responders.16 A higher joint count (TJC 21) was also found to be a poor prognostic factor in a 6-month study involving 4 RCTs with 775 RA DMARD-naïve patients.34 This is further corroborated by the results of the OPTIMA and PREMIER studies, which demonstrated that subjects with a higher tender joint count (TJC 33) tend to have an insufficient response to MTX after 6 months of therapy.30
In the sensitivity analysis, it was found that there was no difference between the drop out patients and the patients in the research subjects, both in terms of characteristics and in terms of the results of the multivariate analysis.
There are several limitations to this study. This is a retrospective cohort study utilizing data from medical records, thus, there is a limitation in the data available for analysis. The disproportionate sample size of several factors that may be predictive of treatment response also hinders their inclusion in the analysis. Moreover, several variables that might be associated with treatment outcomes, but are not present in medical records, could not be further explored. Further prospective study is recommended to confirm these findings and obtain more robust results.