Acupuncture decreased the risk of coronary heart disease in patients with rheumatoid arthritis in Taiwan: a Nationwide propensity score-matched study.

BACKGROUND
Patients with rheumatoid arthritis (RA) have a higher risk of coronary heart disease (CHD). Acupuncture, a commonly used treatment for patients with RA, has not been reported to prevent CHD in patients with RA. We aimed to assess the risk of developing CHD in acupuncture users and non-users of patients with RA.


METHODS
We identified 29,741 patients with newly diagnosed RA from January 1997 to December 2010 from the Registry of Catastrophic Illness Patients Database from the Taiwanese National Health Insurance Research Database. Among them, 10,199 patients received acupuncture (acupuncture users), and 19,542 patients did not receive acupuncture (no-acupuncture users). After performing 1:1 propensity score matching by sex, age, baseline comorbidity, conventional treatment, initial diagnostic year, and index year, there were 9932 patients in both the acupuncture and no-acupuncture cohorts. The main outcome was the diagnosis of CHD in patients with RA in the acupuncture and no-acupuncture cohorts.


RESULTS
Acupuncture users had a lower incidence of CHD than non-users (adjusted HR = 0.60, 95% CI = 0.55-0.65). The estimated cumulative incidence of CHD was significantly lower in the acupuncture cohort (log-rank test, p < .001). Subgroup analysis showed that patients receiving manual acupuncture of traditional Chinese medicine style, electroacupuncture, or combination of both all had a lower incidence of CHD than patients never receiving acupuncture treatment. The beneficial effect of acupuncture on preventing CHD was independent of age, sex, diabetes mellitus, hypertension, hyperlipidemia, and statins use.


CONCLUSIONS
This is the first large-scale study to reveal that acupuncture might have beneficial effect on reducing the risk of CHD in patients with RA. This study may provide useful information for clinical utilization and future studies.


Background
Rheumatoid arthritis (RA) is one of the most prevalent chronic and systemic inflammatory disorders, with the characteristics of joint destruction, functional disability, and early death [1]. Autoantibody production, synovial inflammation, cartilage and bone destruction are the main pathological findings in RA patients [2]. Current pharmacotherapies of RA include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying anti-rheumatic drugs (DMARDs) [3]. DMARDs, including synthetic and biological DMARDs, have been demonstrated to suppress inflammation to reduce structural damage.
The high mortality rate of patients with RA was mainly because of the significantly higher risk of cardiovascular diseases in patients with RA than in the general population [4]. The previous study revealed that patients with RA had an approximately twofold higher risk of coronary heart disease (CHD) [5]. The risk of CHD in patients with RA is highly associated with the traditional risk factors of CHD, which include hypertension, diabetes mellitus (DM), hyperlipidemia, smoking, obesity, and physical inactivity [6]. Chronic inflammation and immune dysregulation play an important role in inducing atherosclerosis and endothelial dysfunction in patients with RA [7]. Among current pharmacotherapy of RA, methotrexate (MTX) might prevent ischemic cardiovascular disorders in patients with RA [8]. Etanercept, a tumor necrosis factor-α (TNF-α) inhibitor, was demonstrated to attenuate endothelial dysfunction in a rat model [9]. These findings suggest that anti-inflammatory therapy may reduce the CHD risk in patients with RA.
A previous cohort study revealed that approximately 27.3% of patients with RA were traditional Chinese medicine (TCM) users in Taiwan, and approximately 23.6% of TCM users with RA received acupuncture [10]. The anti-inflammatory mechanisms of acupuncture have been demonstrated in murine models [11,12]. Previous clinical trials have demonstrated that acupuncture suppressed inflammation in patients with RA [13,14]. However, no prior study evaluated whether acupuncture can prevent CHD in patients with RA. To investigate whether acupuncture decreases the incidence of CHD in patients with RA, we conducted this cohort study.

Data sources
The Taiwanese National Health Insurance Research Database (NHIRD) is a good database for the cohort study because it contains the long-term follow-up data of most of the population in Taiwan. The National Health Insurance (NHI) program was implemented in 1995 in Taiwan by the National Health Insurance Administration. TCM services have been reimbursed through the NHI since 1996 [15]. The reimbursed population reached more than 99.5% in 2015 [16]. NHIRD is a big database that can prevent sampling bias [17].
The data source of this study was the Registry of Catastrophic Illness Patients Database; patients with autoimmune diseases, such as RA [18], systemic lupus erythematosus, multiple sclerosis, Sjögren syndrome, and cancer, are included in this database, which is a subsection of the NHIRD [19]. All of the patients with RA in the database are given catastrophic illness certificates based on the clinical and laboratory diagnoses by rheumatologists. The NHI program waived RA patients' copayments for receipt of RA-related treatments, including Western medicine and TCM. In this database, the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were the most

Study cohort identification and covariates
Patients who were newly diagnosed with RA (ICD-9-CM code 714.0) between January 1, 1997 and December 31, 2010 were identified, as shown in Fig. 1. Patients younger than 18 years old or with incomplete information on the age and sex were excluded. Patients who received acupuncture between the initial diagnosis of RA and happening of CHD or December 31, 2010 were identified as the acupuncture cohort. In the acupuncture cohort, we defined the index date as the first time that the patients started to receive acupuncture. The immortal time of the acupuncture cohort was the period between the initial diagnosis of RA and the index date. Patients who suffered from CHD were identified through ICD-9-CM codes 410, 411, 413, 414.0, 414.8, and 414.9. Patients diagnosed as having CHD before the index date or within one year after their initial diagnosis of RA were excluded. Patients were followed up until December 31, 2011 or withdrawn from the NHIRD.
To reduce confounding factors, we used 1:1 propensity-score matching by sex, age (per 5 years), comorbidity, conventional drug use, the initial diagnostic Patients with comorbidity were identified if the ICD-9-CM codes of the selected comorbidity appeared two or more times in the outpatient or inpatient claims. The conventional drugs analyzed in our study included MTX, hydroxychloroquine, sulfasalazine, TNF-α inhibitors, oral steroids, NSAIDs, and statins. Finally, equal numbers of patients in the acupuncture and no-acupuncture cohorts were analyzed in this study. Patients were divided into 3 groups according to their age: 18-39 years old, 40-59 years old, and older than 60 years old.

Statistical analyses
Statistical analysis was performed using SAS 9.4 (SAS Institute, Cary, NC, U.S.A.), and p < 0.05 in two-tailed tests indicate statistical significance. The difference of baseline characteristics between the acupuncture and no-acupuncture cohorts was expressed as standardized mean differences. Standardized mean differences with less than 0.2 s.d. indicated a negligible difference in the mean or proportions between the two cohorts. For each variable, we used Cox proportional hazard regression to analyze the hazard ratios (HRs) and 95% confidence interval (95% CI). The Kaplan-Meier method was used to determine the cumulative incidence of CHD in both cohorts, and the log-rank test was used to compare incidence curves between the acupuncture and no-acupuncture cohorts.

Results
The identified patient numbers in both cohorts were equal after performing the 1:1 propensity score matched method (Fig. 1). There were no significant differences in the sex, age, baseline comorbidity, and conventional drug use between the no-acupuncture and acupuncture cohorts ( Table 1). The included patients were female predominant with a mean age at approximately 50 years old in both cohorts. Almost all patients in both cohorts have used NSAIDs, and more than 90% of patients have also used oral steroids. Approximately 15% of patients took statins in both the no-acupuncture and acupuncture cohorts. Manual acupuncture of the TCM type was the most commonly used acupuncture treatment.
During the follow-up period, 909 patients in the acupuncture cohort and 1233 patients in the no-acupuncture cohort developed CHD (Table 2). Compared with the no-acupuncture cohort, the incidence of CHD was significantly lower in the acupuncture cohort (adjusted HR = 0.60, 95% CI = 0.55-0.65). RA patients with old age, DM, or hypertension were prone to developing CHD.
The beneficial effect of acupuncture on the incidence of CHD was observed in both women and men (Table 3, adjusted HR = 0.62 in women, 95% CI = 0.56-0.68; adjusted HR = 0.58 in men, 95% CI = 0.48-0.70). Acupuncture significantly decreased the incidence of CHD in all age groups. Regardless of whether patients had DM, hypertension, hyperlipidemia, or stroke, acupuncture lowered the risk of CHD. Moreover, the beneficial effect of acupuncture in preventing CHD was independent of conventional drug use, including statins, MTX, hydroxychloroquine, sulfasalazine, oral steroids, and TNF-α inhibitors. Overall, the cumulative Table 2 Cox model with hazard ratios and 95% confidence intervals for coronary heart disease in patients with rheumatoid arthritis who did or did not receive acupuncture treatment  incidence of CHD from the index date was significantly lower in the acupuncture cohort (Fig. 3). Subgroup analysis was performed to evaluate whether different types of acupuncture had any correlation and difference on preventing CHD in patients with RA (Table 4). Patients receiving only manual acupuncture, only electroacupuncture, or combination of manual acupuncture and electroacupuncture all had a lower incidence of CHD than patients never receiving acupuncture.
Among the different types of CHD, patients with acupuncture had a significant lower incidence of chronic ischemic heart disease (Table 5). However, there was no significant difference in the incidence of angina pectoris between the two groups. The effect on acute myocardial infarction was not analyzed (data not shown; only 11 patients had acute myocardial infarction in two groups). Table 6 showed the top five disease categories, which represented the reasons for clinical visits, in the acupuncture cohort. Most patients with RA received acupuncture because of musculoskeletal disease.

Discussion
To the best of our knowledge, this nationwide population-based study is the first report to reveal that acupuncture decreased the risk of CHD in patients with RA. Our study found that the beneficial effects of acupuncture for developing CHD in patients with RA were independent of sex, age, DM, and hypertension. Moreover, acupuncture decreased the risk of CHD in patients with RA who took statins, which was reported to reduce the risk of cardiovascular diseases [20]. Among different types of CHD, our results demonstrated that patients with acupuncture had a significant lower incidence of Table 3 Incidence rates, hazard ratio and confidence intervals for coronary heart disease in rheumatoid arthritis patients who did or did not receive acupuncture treatment, stratified by sex, age, comorbidity and drug use (Continued) Abbreviations: IR, incidence rates per 1000 person-years; HR, hazard ratio; and CI, confidence interval Adjusted HR: adjusted for acupuncture use, age, sex, diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, cerebral vascular diseases, depression, anxiety, alcoholism, tobacco dependence, obesity, Methotrexate, Hydroxychloroquine, Sulfasalazine, TNF-α inhibitors, oral steroids, NSAIDs and statins in Cox proportional hazard regression *: p < 0.05; **: p < 0.01; and ***: p < 0.001 chronic ischemic heart disease than patients without receiving acupuncture treatment. The risk of CHD in patients with RA is highly associated with the conventional risk factors of CHD, such as hypertension, DM, hyperlipidemia, and physical inactivity [6]. Our study also demonstrated that RA patients with comorbidities, including DM, hypertension, or hyperlipidemia, had a higher risk of CHD. Even in RA patients with DM, hypertension, or hyperlipidemia, our study indicated that acupuncture decreased the incidence of CHD. Previous clinical trials indicated that acupuncture improved swelling and range of motion of knee joints, physical activity, and quality of life in patient with RA [14,21,22]. Improved physical activity might be one of the possible explanations that acupuncture can prevent CHD in patients with RA. However, we also found that for those RA patients with the comorbidity of congestive heart failure, acupuncture did not reduce the risk of CHD.
The previous study stated that endothelial dysfunction contributed to atherosclerosis and induced cardiovascular disorders [23]. The current conventional drugs for RA treatment, including glucocorticoids [24] and etanercept (a TNF-α inhibitor) [9], have been demonstrated to improve endothelial dysfunction through the anti-inflammatory effect in RA rat models. However, the protective effect of glucocorticoids remains controversial because glucocorticoids also enhance the risk of cardiovascular disorders based on their negative effects on blood pressure, lipid, insulin resistance and obesity [25]. The protective effect of MTX at a low dose against CHD in patients with RA was also demonstrated in a previous meta-analysis study although it did not attenuate hyperlipidemia or insulin resistance [8]. Our study also indicated that patients with RA who took MTX or TNF-α inhibitors had a lower risk of CHD. In addition, regardless of whether patients used TNF-α inhibitors or MTX, acupuncture significantly decreased the risk of CHD in those patients.
Chronic inflammation plays an important role in the pathogenesis of RA and its comorbidities, including DM, hypertension, and CHD [7]. As a result, amelioration of inflammatory activity should be considered in the CHD preventive strategy for patients with RA. The anti-inflammatory mechanisms of acupuncture have been evaluated in murine models of inflammatory disorders [11,12]. Acupuncture corrected the imbalance between Th17 and Treg cells to attenuate the severity of RA in a rat RA model [26]. IL-17, cytokine secreted by Th17 cells, has been demonstrated to be important in the pathogenesis of RA, and it has been demonstrated to be associated with CHD [27]. Further mechanistic studies are needed to evaluate whether acupuncture can suppress IL-17 in RA to prevent CHD. Previous clinical trials have demonstrated that acupuncture suppressed inflammation in patients with RA [13,14]. Based on these studies, acupuncture not only had a traditionally  recognized analgesic effect, it had an anti-inflammatory effect. Anti-inflammation might be one of the mechanisms by which acupuncture decreased the incidence of CHD in RA patients. In addition, previous studies demonstrated that the combination of acupuncture with current conventional treatment had additive effects on hypertensive patients [28] and diabetic patients [29], which could contribute to how acupuncture decreased the risk of CHD in RA patients with comorbidity or conventional treatment. The mechanistic study is needed in the future. We have established a collagen-induced arthritis murine model and designed a clinical trial to investigate whether acupuncture is effective on the immunological modulation in RA. The strength of this study was the comprehensive large-scale database, Taiwan's NHIRD, which provides a large sample size and reduces selection bias while including long-term follow-up data [17]. Although there were a few clinical trials investigating the efficacy of acupuncture for the treatment of patients with RA [13,14,21,22,[30][31][32][33][34][35], none of them addressed the question whether acupuncture treatment reduces the risk of cardiovascular disease among patients with RA.
Some limitations merit attention in our study. First, the detailed information about severity of RA, including pain scores, the severity of inflammation, or the destruction of cartilage and bone were not provided in the database. Because patients with different severities may receive different conventional treatments, we performed a 1:1 propensity score matching to minimize this confounding factor. We found that there were no difference in percentages of patients who used analgesic drugs, including NSAIDs and oral steroids, in the acupuncture and no-acupuncture cohorts. The second limitation is that lifestyle data, such as smoking, alcohol drinking, and body mass index (BMI), were unavailable in the datasets. We were able to acquire information of the illnesses that resulted from these personal habits and lifestyles, including alcoholism, tobacco dependence, and obesity. However, an underestimation of smoking exposure and alcohol drinking in both cohorts still may exist. The third limitation was that the datasets did not provide detailed information of selected acupoints and treatment protocols. Usually, TCM doctors selected acupoints for each patient according to the TCM diagnosis, which may vary during the disease progression. In addition, the duration or visit times of acupuncture in the current study might be underestimated because the NHI program only covers maximal 15 times of acupuncture per month and maximal 2-3 times per week, some patients may use self-pay for additional acupuncture treatment, which could not be identified from the NHIRD database. Future clinical trials should consider comparing the effects of a set of fixed acupoints versus flexible acupoints and different duration/times of acupuncture treatment. Although there are some limitations in the current retrospective cohort study, it's a "real-world evidence" that can reflect actual use in practice [36] from a comprehensive large-scale database. Evidences gathered from future clinical trials should be able to provide more information regarding the selection of acupoints.  Maximal of three ICD-9-CM codes could be recorded in one visit