|Ahead of print publication
Conventional synthetic disease-modifying antirheumatic drug use by race/ethnicity and factors associated with initiating biologics in Malaysian patients with rheumatoid arthritis
Suad Mohammed1, Lydia Say Lee Pok2, Ying Chew Tee2, Fariz Yahya2
1 Department of Medicine, Division of Rheumatology, University of Malaya, Kuala Lumpur, Malaysia; Department of Internal Medicine, Academic Charity Hospital, Khartoum, Sudan
2 Department of Medicine, Division of Rheumatology, University of Malaya, Kuala Lumpur, Malaysia
Department of Medicine, Division of Rheumatology, University of Malaya, Lembah Pantai, 60300 Kuala Lumpur
Source of Support: None, Conflict of Interest: None
Aims: The aim of the study was to evaluate the treatment patterns of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), drug survival, and the factors in initiating biologic DMARDs based on race and ethnicity in rheumatoid arthritis (RA) patients.
Materials and Methods: Data on RA patients, including race/ethnicity, who were attending University Malaya Medical Centre, Kuala Lumpur, Malaysia, and started on csDMARDs between January 2006 and December 2016, were collected retrospectively from the review of patients' medical records. Factors in initiating biologic DMARDs were identified.
Results: A total of 369 RA patients received at least one csDMARD; 325 (88.1%) were female, and 271 (73.4%) were seropositive. Three main races were identified: Malay (28.7%), Chinese (33.1%), Indian (36.3%), and others (1.9%). Malay race patients were initiated on a csDMARD at a younger age (48.6 years, standard deviation [SD]: 12.4) due to younger age at onset compared to other races (P < 0.001). Overall, methotrexate was the most common csDMARD used, and 39 (11%) patients were on triple-combination therapy. Disease activity score 28–erythrocyte sedimentation rate improved at 3 months post-csDMARD treatment for all races (P < 0.001). Twenty-six (7%) patients received biologics, with a mean age at initiating first biologic of 49.8 (SD: 18.3) years. There were no significant differences in age at initiating first biologic between the race groups (P = 0.83). In fully adjusted models, race was not a factor in initiating biologics.
Conclusion: CsDMARDs in RA were required at a younger age for a certain race due to younger age at onset. However, race does not predict the initiation of biologics and no significant difference in the use of combination csDMARDs between races.
Keywords: Biologics, disease-modifying antirheumatics, factors, race, rheumatoid arthritis
|How to cite this URL:|
Mohammed S, Lee Pok LS, Tee YC, Yahya F. Conventional synthetic disease-modifying antirheumatic drug use by race/ethnicity and factors associated with initiating biologics in Malaysian patients with rheumatoid arthritis. Indian J Rheumatol [Epub ahead of print] [cited 2019 Sep 22]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=265811
| Introduction|| |
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease associated with progressive joint damage and disability with premature mortality., Appropriate treatment can prevent or limit joint damage, prevent loss of function, reduce pain, and improve overall quality of life.,
Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were considered the cornerstone of RA treatment. However, the availability of biologic DMARDs has hailed a new era in the treatment of RA.,, Treatment recommendations are moving toward targeted therapy (i.e., either remission or low disease state) with early use of biologics as a more aggressive treatment strategy if csDMARDs are considered not effective., However, the option of a “step-up” therapy from csDMARDs is not always possible in clinical practice. For patients who respond inadequately to the initial methotrexate (MTX) monotherapy, the use of a triple therapy regimen has been reported to be noninferior to a biologic.
Previous studies have reported racial disparities in the care and treatment of RA.,, Asian patients were reported to have more pain and disability and shorter duration of DMARDs compared to European RA patients., In the United States (US), African-American race was reported to less likely be prescribed with DMARDs. Another US study reported that even though general improvement was seen across all racial/ethnic groups, minority groups had higher disease activity levels and achieved lower rates of clinical remission. However, the various factors in initiating DMARDs or biologics potentially differ in various regions. Hence, data based on race or ethnicity on the use of DMARDs and biologics are still lacking, especially in the region of Southeast Asia where the population is even more diverse.
To address this, we conducted this study in a cohort of RA patients to determine the treatment patterns, reasons for discontinuation, and drug survival of csDMARDs and to identify factors in initiating biologic DMARD treatment based on race and ethnicity from a rheumatology specialist center in Kuala Lumpur, Malaysia.
| Materials And Methods|| |
Patients and study design
Adult patients with physician-verified diagnosis of RA, who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010, classifications and received treatment with at least one course of csDMARD at University Malaya Medical Centre, Kuala Lumpur, Malaysia, were included in the study. Data collected were from January 2006 to December 2016. Data were collected retrospectively from the review of patients' medical records. This study was approved by the local ethics committee and in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments.
We assessed demographics and baseline characteristics including self-reported race (Malay, Chinese, and Indian) and/or ethnicity (others), age, sex, smoking status, financial support, age at diagnosis, age at initiation of first csDMARD and biologic, duration from diagnosis to the initiation of csDMARDs, the type and duration of DMARDs used, the number of csDMARD exposure before initiating biologic treatment, and the reasons for treatment discontinuation. Factors in initiating first biologic treatment were identified. A “course” is defined when a patient received a specific csDMARD. For instance, two patients on the same csDMARD will be regarded as two “courses” of csDMARDs.
Data on disease-related markers including the number of joint involvement at baseline, disease activity score-28–erythrocyte sedimentation rate (DAS28-ESR) at baseline and at 3 months posttreatment, rheumatoid factor and/or anticitrullinated protein antibodies status, and the presence of radiographic erosion at baseline were included. The use of biologic and targeted synthetic DMARDs was also recorded.
We conducted statistical analysis using the Statistical Package of the Social Sciences (SPSS) Statistics version 22.0 (IBM Corp., NY, USA). Nonparametric testing, including Mann–Whitney and Chi-square, was used to compare between groups; Wilcoxon signed-rank test was used for comparison within the groups. One-way ANOVA was used to determine differences in means among three or more independent groups. Survival probabilities were estimated using the Kaplan–Meier method and compared using the log-rank test. Factors of initiating first biologic treatment were identified. Logistic regression analysis was used to assess the factors of initiating biologic. Multivariable models were used when adjusted for race, age, sex, smoking status, financial support, serology, erosions and disease activity at baseline, and exposure to csDMARDs. P < 0.05 is considered statistically significant.
| Results|| |
We included 369 patients (n = 325, 88.1% – female) with RA who started on at least one csDMARD. Three main races were identified: Malay (n = 106, 28.7%), Chinese (n = 122, 33.1%), Indian (n = 134, 36.3%), and others (n = 7, 1.9%). The mean age at diagnosis was 51.9 (standard deviation [SD]: 12.4) years, the mean age at first csDMARD initiation was 51.9 (SD: 12.4) years, and the mean age at first biologic was 54.1 (SD: 13.2) years. Malay race patients were diagnosed younger (48.5, SD: 12.4) and were initiated on first csDMARD at a younger age (48.6, SD: 12.4) (P <0.001) [Figure 1]. The mean duration of symptom to diagnosis was similar across all races (9.1–10.1 months) (P = 0.89). Further demographic details are summarized in [Table 1].
|Figure 1: Age at initiating first conventional synthetic disease-modifying antirheumatic drug based on race|
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|Table 1: Demographics of patients treated with disease-modifying antirheumatic drugs based on race|
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Extra-articular manifestations were identified in 51 (13.8%) patients – 28 (7.6%) with interstitial lung disease, 18 (4.9%) with eye involvement, and 5 (1.3%) with rheumatoid nodules.
One hundred and forty-two (38.5%) patients were eligible for reimbursements under the local government financial coverage for biologic treatment. Other sources for treatment funding include personal insurance, corporate insurance, and from nongovernmental organizations. However, the patients who were not eligible for any reimbursement or financial support consisted of Malay (n = 30, 8.1%), Chinese (n = 51, 13.8%), Indian (n = 51, 13.8%), and others (n = 6, 1.6%).
Treatment with disease-modifying antirheumatic drugs
CsDMARDs used were MTX, leflunomide (LEF), sulfasalazine (SSZ), and hydroxychloroquine (HCQ). There were 649 courses of csDMARDs used in total with MTX starts of 323 courses, SSZ of 125, HCQ of 124, and LEF of 50. One hundred and seventy-eight (48.2%) patients were on a csDMARD monotherapy, of which 87% monotherapy was MTX, and 125 (33.9%) were on double-combination therapy. Forty-seven (12.7%) patients received triple-combination therapy [Table 2]. The remaining 19 (5%) patients were exposed to a combination of four csDMARDs. There were no significant differences between the races in patients requiring dual- or triple-csDMARD therapy [Table 2].
|Table 2: Combination conventional synthetic disease-modifying antirheumatic drug regimens used based on race|
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There was a significant improvement of DAS28-ESR from baseline to 3 months post-csDMARD treatment (P < 0.001), and 58.6% of patients achieved low disease activity and/or remission at 3 months. The mean DAS28-ESR improvement after 3 months posttreatment for Malay was 2.28 (95% confidence interval [CI]: 2.09, 2.47), Chinese 2.26 (95% CI: 2.09, 2.44), Indian 2.16 (95% CI: 2.01, 2.32), and others 2.20 (95% CI: 1.49, 2.92) (P = 0.754).
Overall, MTX drug survival was superior compared to other csDMARDs (P = 0.002). Long-term drug survival rates for MTX were 90.2% at 1 year and 68.3% at 5 years for all races. There were no significant differences between the race groups (log-rank P = 0.059) [Figure 2]. Adverse effect was the most common reason for discontinuation of therapy across all csDMARDs [Table 3]. However, there were no differences between the race groups for the reasons for discontinuation of MTX (P = 0.291), LEF (P = 0.937), SSZ (P = 0.643), or HCQ (P = 0.110).
|Figure 2: Survival rates of methotrexate based on race.P< 0.05 is considered statistically significant|
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|Table 3: Reasons for conventional synthetic disease-modifying antirheumatic drug discontinuation for all races|
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Twenty-six (7%) patients from the entire cohort received added treatment with biologics (Malay, n = 12; Chinese, n = 9; Indian, n = 4; and others, n = 1). Biologics used were etanercept, adalimumab, infliximab, golimumab, certolizumab, rituximab, and tocilizumab. The mean age at initiating biologics was 49.8 (SD: 18.3) years – Malay: 48.4 (SD: 3.8) years, Chinese: 48 (SD: 26.5) years, Indian: 52.8 (SD: 17.4), and others: 65 years (P = 0.83). The significant factors in initiating treatment with biologics were the presence of radiographic changes at baseline, high DAS28-ESR at baseline, and exposure to four csDMARDs (all P < 0.05) [Table 4].
|Table 4: Univariate and multivariate analyses predicting biologic initiation|
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There were 4 (1.1%) patients on tofacitinib, in which three patients on tofacitinib had previous exposure to biologics.
| Discussion|| |
In this study, we explored the association between race/ethnicity and the use and initiating DMARDs in a country with a multiethnic background. We found that the disease duration was not significantly different between the ethnic groups but a younger age at onset in the Malay race, which led to receiving a first csDMARD at a younger age. Improvements in disease activity levels after 3 months of initial csDMARDs were similar across all races. However, once csDMARD treatment has been started and in cases where additional therapy is required, there were no differences between the groups for the age at initiating biologics and race was not a factor in initiating biologics.
The presence of genetic factors has been suggested to influence the manifestations of RA, and in several populations, its prevalence is consistently significantly higher in indigenous populations., We found that Malay race patients had a younger age at onset and that there were more active smokers compared to other races. Potentially genetic differences between race groups and the negative effects of smoking to disease outcomes and treatment could contribute to the younger clinical presentation of RA.,, The clinical practice to initiate csDMARDs early is reflected in this context as guided by improved outcomes in starting RA treatment early.,
CsDMARDs are widely available throughout the country with higher accessibility and more affordable in comparison to biologics. MTX, being a relatively inexpensive medication, was the most commonly prescribed csDMARD monotherapy in our cohort, and MTX-SSZ combination was the most common csDMARD combination therapy. However, the use of multiple csDMARDs may not always be ideal as this may result in the increased risk of adverse effects from polydrug prescribing. The Malay race and the use of multiple DMARDs have been reported with higher risk of failing to achieve treatment target in RA. In addition, fear of adverse effects due to poor education, noneffective communication on drug prescribing, and cultural differences in attitudes to chronic RA are also challenges in initiating or optimizing DMARDs in different ethnic groups.
As the use of biologics in the developing world is still believed to be relatively low compared to developed countries, 7% of patients from our cohort were treated with biologic therapy. Older age and lower annual income have been reported to decrease the use of biologics, whereas patients with previous use of steroids and nonbiologic DMARDs were twice as likely to be given biologic DMARDs. However, our study found that race was not a factor in initiating biologics, although patients with radiographic erosions, high disease activity at baseline, and the use of multiple csDMARDs were more likely to receive biologic treatment in our cohort. These are known poor prognostic markers which have already been adapted into both EULAR and ACR treatment recommendations, allowing the earlier use of biologics.,,
The strength of our study is that it was conducted in a multiracial country from the developing world, and most of the patients from our cohort are from a diverse of sub-Asian race groups. It was not designed as a cost-effectiveness study. However, our study has limitations. It was a single-center study in a specialist center based in an urban area of Malaysia. Hence, the results of this study are limited by the small size of the cohort and may not be generalized as the population might also have a slightly higher income scale as compared to rural regions. There were no data available on education level and financial status of our cohort. Race was self-reported, and we did not include mixed-race category. Due to the retrospective design of the study and complete reliance on clinical records, there may be underreporting of adverse events and disease activity scores.
| Conclusion|| |
CsDMARDs in RA patients were required at a younger age for a certain race due to younger age at onset. Race does not predict the initiation of biologics, and there was no significant difference in the use of combination csDMARDs between races in this single-center study. However, region-wide large-scale studies are recommended to examine the association between race, ethnicity, and RA treatment in the Asian population.
Financial support and sponsorship
Conflicts of interest
Fariz Yahya has received speaker's fees and/or consultancy from Novartis, Pfizer, AbbVie, Janssen, Lilly, and Gilead and received grants and on advisory boards for AbbVie and Novartis. All other authors have no competing interests to declare.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]