The usage of biological DMARDs and clinical remission of rheumatoid arthritis in China: a real-world large scale study

The aims of this study are to characterize the biological disease-modifying antirheumatic drug (bDMARD) usage patterns in real-life and examine the remission rate of rheumatoid arthritis (RA) patients receiving bDMARDs in routine clinical practice in China. Consenting RA patients (≥18 years) from 15 teaching hospitals and receiving marketed bDMARDs were included. In total, 802 patients (81.3 % women, 49.0 ± 13.9 years) were included; 89.5 % were receiving a combination of bDMARDs and conventional synthetic DMARDs (csDMARDS), whereas 10.5 % were receiving bDMARD monotherapy. Etanercept (including Enbrel® and local brand Yi Sai Pu® and Qiangke®), tocilizumab, adalimumab, and infliximab were used by 66.6 %, 17.0 %, 7.5 %, and 6.6 % patients, respectively. Etanercept was used at a mean weekly dose of 38.2 ± 15.6 mg for 25.5 ± 47.0 weeks and tocilizumab at 94.5 ± 21.9 mg for 4.7 ± 7.5 weeks. Overall rate of remission was 12.6 %, 5.4 % , and 3.5 % based on DAS28, CDAI, and SDAI scores, respectively. Compared with patients receiving bDMARDs for <3 months, those receiving bDMARDs for ≥3 months exhibited significantly lower DAS28 scores (p < 0.0001), and a significantly higher proportion of patients who received bDMARDs for ≥12 months achieved the treatment goal (remission or low disease activity, 62.5 % vs. 18.3 %, p < 0.0001). Patients receiving combination therapy with csDMARDs exhibited lower DAS28 scores than patients receiving bDMARD monotherapy (4.3 vs. 4.8, p = 0.011). This large-scale real-world study showed that bDMARD usage patterns in routine clinical practice in China were in accordance with international guidelines for RA management despite the short treatment duration. Longer duration of bDMARD usage and combination therapy showed a favored outcome of RA.


Introduction
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with progressive joint damage and disability. The prevalence of RA is 0.24 % globally and between 0.3 and 1 % in developed countries [1,2]. In Mainland China, the prevalence of RA has been reported to be 0.28 % [3,4]. As shown by recent studies, RA is becoming one of the most common disabling and costly disease in China [5][6][7]. Chou et al. reported a significantly higher RA prevalence in urban areas than in rural areas of Taiwan [8]. Socioeconomic and genetic factors might contribute to the lower prevalence in China compared with Western countries [9].
Disease-modifying antirheumatic drugs (DMARDs) are the standard treatment for patients with RA [10]. In addition to conventional synthetic DMARDs (csDMARDs), such as methotrexate, biological DMARDs (bDMARDs), including inhibitors targeting tumor necrosis factor (TNF)-α, T cells, B cells, and interleukin-6, have been increasingly used in recent years [10,11]. According to the 2013 European League Against Rheumatism (EULAR) and the 2012 American College of Rheumatology (ACR) recommendations, csDMARDs such as methotrexate should be chosen as the first-line treatment [10,11]. However, the recommendations suggest bDMARDs for patients who fail to achieve low disease activity (LDA) or remission after receiving csDMARDs [10,11]. Although a combination therapy of csDMARDs and bDMARDs is recommended and commonly practiced, real-life registry data show that approximately 30 % of patients receive bDMARDs as monotherapy in Western countries [12]. In a double-blind randomized trial, Dougados et al. found that the efficacy of tocilizumab monotherapy was comparable to a combined therapy of tocilizumab plus methotrexate in patients who had insufficient responses to methotrexate [13]. Emery et al. systematically reviewed trials evaluating bDMARD monotherapy and found that only tocilizumab monotherapy appeared to show efficacy equivalent to combination therapy with methotrexate [12]. In a recent large observational study, Gabay et al. found that patients receiving tocilizumab with or without concomitant csDMARD showed comparable clinical response [14].
Until the end of patient enrollment of this study, a total of six bDMARDs have beenapprovedfor use in RA inChina, including the interleukin-6 receptor inhibitor, tocilizumab, and five TNF inhibitors (infliximab, adalimumab, and etanercept, including Enbrel® and local brand Yi Sai Pu® and Qiangke®). In recent years, bDMARDs have been increasingly prescribed in routine clinical practice in China. However, the Breal-world^data on bDMARD usage patterns in China might be different from those in developed countries owing to socioeconomic factors. The objective of this cross-sectional study was to characterize the usage patterns of bDMARDs in Chinese patients with RA and examine the association between disease activity and clinical remission, andtheduration andpattern of bDMARD therapy,with thegoal to optimize the management of RA in China.

Study design
This multicenter observational cross-sectional study was conducted in 15 hospitals across different regions of China. The study was approved by the Institutional Review Board of Peking University and independent ethics committees responsible for each investigating site. The study was conducted in compliance with the Declaration of Helsinki and in accordance with Good Clinical Practice and relevant ethical guidelines. Written informed consent was obtained from each participant.

Participants
Patients aged ≥18 years with confirmed RA according to the ACR 1987 criteria [15] and receiving bDMARDs at the time of interview were enrolled in the study. Patients were excluded if their physicians believed that the patients were not appropriate to participate in the study. Non-consenting patients were excluded.

Data collection
Questionnaires were administered through face-to-face interviews in each center by trained participating investigators with eligible patients. Data on age, sex, RA duration, total joint count, swollen joint count, and visual analogue scale (VAS) were collected on enrollment visit. The levels of C-reactive protein, hemoglobin, erythrocyte sedimentation rate, rheumatoid factor, and anti-cyclic citrullinated peptides measured within 2 weeks of the enrollment visit were obtained from medical records. Disease activity was evaluated according to the Disease Activity Score based on 28-joint count (DAS28) (remission: DAS28 < 2.6; low disease activity: 2.6 ≤ DAS28 < 3.2; moderate disease activity: 3.2 ≤ DAS28 < 5.1; high disease activity: DAS28 ≥ 5.1 [16,17]), the Simplified Disease Activity Index (SDAI) (remission: SDAI ≤3.3; low disease activity: 3.3 < SDAI ≤11; moderate disease activity: 11 < SDAI ≤26; high disease activity: SADI >26), and the Clinical Disease Activity Index (CDAI) (remission: CDAI ≤2.8; low disease activity: 2.8 < CDAI ≤10; moderate disease activity: 10 < CDAI ≤22; high disease activity: CDAI >22).). Quality of life of patients was assessed using health assessment questionnaire disability index (HAQ-DI) on enrollment visit. Visual analog scales on enrollment visit (from 0 to 10 cm) were used to assess fatigue and pain levels, with increasing values representing more severe fatigue and pain.
Data on usage patterns of bDMARDs, including information on monotherapy or combination therapy, the drug(s) used, frequency, treatment duration, and dosage of bDMARDs, were collected. The reasons for discontinuation or switching of bDMARDs and information about previous bDMARDs, including drug name and treatment duration, were recorded. All the AE information of using the common biologic agents was recorded and followed until return to stabilized.

Sample size estimation
The formula to calculate sample size in a prevalence survey was used [18,19]. Based on European and US registry data, approximately one third (33 %) of RA patients receive bDMARDs as monotherapy. Thus, with the assumption that the proportion of patients in China receiving bDMARD monotherapy is also 33 % and a confidence level of 95 % with maximum relative error of 10 %, the required sample size was estimated to be 800.

Statistical analysis
The statistical analysis was performed using the statistical software SAS 9.2 (Cary, North Carolina, USA). Continuous data are presented as mean and standard deviation (SD), median, and range. Two-group comparisons were performed using Student t test (p values were two-sided with a significance level of 0.05). Multiple-group comparisons were performed by analysis of variance with Bonferroni correction. Laboratory tests performed in different hospitals were standardized by statistical adjustment [20]. Categorical data, tabulated as frequencies and percentages, were analyzed using chi-square test. Missing values were excluded from the analyses.

Patient characteristics and bDMARD usage patterns
A total of 808 patients were enrolled between December 2013 and August 2014. Six patients were excluded for violating the inclusion criteria (five patients were diagnosed with ankylosing spondylitis and one patient was <18 years old). Available data from 802 patients were analyzed. As shown in Table 1, patients (mean age of 49.0 ± 13.9 years) had a mean disease course of 3.2 ± 5.8 years. Abnormal C-reactive protein and erythrocyte sedimentation rate levels were exhibited by 60.8 % and 70.1 % of patients, respectively. The majority of the patients were positive for rheumatoid factor (77.6 %) or anticyclic citrullinated peptides (83.2 %). Disease activity in the patients varied widely, as reflected by a broad range of DAS28, CDAI, and SDAI scores. The patients reported good quality of life and medium levels of fatigue and pain.
The three top reasons for discontinuing bDMARDs (n = 58) were clinical improvement (31.0 %), financial burden (24.1 %), and AEs (13.8 %). Among patients switching to different bDMARDs (n = 93), the main reasons for switching were unsatisfactory efficacy of the previous bDMARD (58.1 %), AEs (14.0 %), improvement of disease condition (10.8 %), and financial burden (10.8 %). Among the 802 patients, only 5 (0.6 %) reported at least one AE after initiation of this study, including one case of mild pruritus and another case of rash, which were suspected to be associated with etanercept. No bDMARDs-related serious AE was reported. Further analyses of disease activity revealed that the overall rate of remission was 12.6 %, 5.4 %, and 3.5 % based on DAS28, CDAI, and SDAI scores, respectively.

The effects of treatment regimen on disease activity
Patients receiving combination therapy of bDMARDs and csDMARDs showed significantly lower mean DAS28 scores than patients on bDMARD monotherapy (4.3 vs. 4.8, p = 0.0108, Table 5). However, the percentage of patients achieving treatment target was not significantly different a Percentage was calculated using the total number of patients (N = 802) as the denominator b bDMARD monotherapy represents bDMARD alone without combination with csDMARDs; the percentage of each bDMARD was calculated using the total number of patients on monotherapy (n = 84) as the denominator c bDMARD + csDMARD combination therapy represents combination of bDMARDs and csDMARDs; the percentage of each bDMARD was calculated using the total number of patients on combination therapy (n = 718) as the denominator d The percentage of each type of csDMARD was calculated using the total number of patients on bDMARD + csDMARD combination therapy (n = 718) as the denominator e Among the 238 patients on concomitant glucocorticoids, 73.1 and 23.1 % patients were receiving oral prednisone and methylprednisolone at a mean (SD) weekly dose (mg) of 57.8 (31.9) and 59.7 (151.6), respectively  Table 5).

Discussion
This is the first large-scale multicenter study to characterize real-life bDMARD usage patterns and disease activity in routine practice in Chinese patients with RA receiving bDMARDs. The results show that combination therapy of bDMARDs and csDMARDs was substantially more common than bDMARD monotherapy in real-world clinical practice in China. Methotrexate was the predominant csDMARD administered to Chinese patients. The usage pattern of bDMARDs in China is in accordance with the guidelines for management of RA, in which methotrexate is recommended as the first-line agent and bDMARDs are used as secondary agents, mostly in combination with csDMARDs [10]. This study found that the proportion of patients receiving bDMARD monotherapy in China was only 10.5 %, considerably lower than that in other countries. Yazici et al. investigated the RA patient cohort in the Thomson Healthcare MarketScan Research databases and found that 30 % of adults with RA received bDMARD monotherapy in the USA [19]. Gabay et al. examined the data from the Swiss Clinical Quality Management in Rheumatic Diseases registry for RA patients and found that bDMARD monotherapy was prescribed for up to 39 % of treatment courses [21]. Kaufmann   [22]. Overall, disease control in our patient cohort was not optimal despite the use of bDMARDs. The majority (75 %) of patients were classified as having moderate-or high-disease activity per DAS28 scores. The substantially shorter mean treatment duration of bDMARD therapy (4.7-34.5 weeks) in our study population versus that shown in other studies [23,24] may be responsible for the suboptimal remission rates that we observed. The mean duration of treatment with etanercept, adalimumab, and infliximab in Italian patients with RA from the Italian Group for the Study of Early Arthritis registry was 3.1, 2.6, and 2.7 years, respectively [23]. Patients with RA from the Swiss Clinical Quality Management in Rheumatic Diseases registry received anti-TNF therapy for a median duration of 37 months [24]. The possible reason for the short treatment duration in the Chinese patients in the current study may be associated with poor socioeconomic condition, poor patient compliance, and the limitation of cross-sectional study. bDMARDs are relatively expensive and are not covered by the national health insurance reimbursement policies in China.
This study demonstrated that the proportion of remission + LDA was the highest in patients with ≥12 months of treatment, indicating that long-time treatment maximizes the benefits for patients. These results are in line with those of a previous 4year follow-up study of infliximab therapy in refractory RA patients, which showed that longer duration of infliximab therapy resulted in lower DAS28 score [25]. Nam et al. found that maintenance of clinical responses was higher with bDMARD continuation [26]. Thus, our results suggest that, to achieve the best treatment outcome, patients with RA should continue bDMARD therapy for longer than 12 months. Furthermore, this study revealed that the remission rate in Chinese patients receiving bDMARDs was 12.6 % (DAS28), 5.4 % (CDAI), and 3.5 % (SDAI). In a multicenter cross-sectional study of RA in Chinese patients receiving csDMARDs, bDMARDs, and/or glucocorticoids, Wang et al. found the remission rate to be 8.6 % (DAS28), 8.2 % (CDAI), 8.4 % (SDAI), and 6.8 % (Boolean) [27]. In Qatari, the remission rate of patients with RA receiving bDMARDs and/or csDMARDs was 49 % by DAS28 score [28]. In the QUEST-RA study including patients with RA from 25 mostly European countries, remission rate was 13.8 % and 19.6 % by CDAI and DAS28, respectively [29]. These results indicate that treatment for Chinese patients with RA is insufficient. Further, the inhibitory costs of biologics ($15,000-$25,000 per patient per year) [30] present challenges in developing countries [31] and may result in early treatment discontinuation or dose reduction, resulting in flaring of the disease. While the guidelines do not recommend treatment discontinuation, Bstep-down^or tapering strategies by careful dose reduction or injection spacing can maintain a disease-free status in patients who have achieved remission or low disease activity [32]. Studies have shown that patients in remission after bDMARD mono or combination therapy continued to maintain their remission status after careful dose tapering or treatment discontinuation [33,34]. Further, in order to maintain the alleviating effect, the dose of traditional DMARDS may be increased or treatment options such as double and triple combination treatment may be prescribed. Therapy can be reinitiated when necessary, making this approach desirable from a safety viewpoint and curbing unnecessary healthcare expenditure. Careful patient selection based on clinical and practical considerations may also improve outcomes with continuous bDMARD use in the developing world.
The current RA management regimen in China should be optimized to allow patients to benefit from more aggressive treatment. Given the comparable efficacy and costeffectiveness of triple DMARD combinations in comparison with bDMARDs and methotrexate [35,36], further studies are needed to assess the use of triple DMARD combination therapy in comparison with biologics in China.
Although the 2013 EULAR guidelines for RA management recommend bDMARDs to be used concomitantly with csDMARDs [10], the 2015 ACR guidelines take monotherapy into consideration [37] and bDMARDs monotherapy is also used in clinical practice as needed [12]. In some studies, bDMARD monotherapy has been shown to be as effective as the combination therapy of csDMARDs and bDMARDs. In terms of DAS28 score, ACR responses, and swollen and tender joint counts, tocilizumab and methotrexate combination therapy was not superior to tocilizumab monotherapy [13,38]. Consistently, the current study also demonstrated that DAS28 score in patients receiving tocilizumab monotherapy was similar to that in patients receiving tocilizumab and csDMARD combination therapy. In the current study, although the average DAS28 score was significantly higher in patients receiving bDMARD monotherapy than in patients receiving combination therapy, the rate of reaching treatment target was similar in patients receiving monotherapy versus combination therapy. Interestingly, the current study found that patients with tocilizumab monotherapy showed significantly lower DAS28 score and higher proportion of reaching treatment target than patients receiving other types of bDMARD monotherapy. These findings suggest that tocilizumab monotherapy may be a promising option for patients with RA. Simplification and optimization of the treatment for RA are beneficial for both patients and physicians.
This cross-sectional study design presents a Bsnapshot^of bDMARD usage in Chinese patients with RA. It is difficult to infer causal relationships between bDMARD usage pattern and disease activity of RA, although longer duration of bDMARD therapy was associated with lower DAS28 score and higher rate of achievement of treatment goal through ad hoc analysis. Confounding factors that might affect the relationship between duration of bDMARD therapy and disease activity, such as the disease status prior to receiving bDMARD therapy and other concomitant therapies, were not considered in this study.
In conclusion, the usage of bDMARDs in Chinese patients with RA is in accordance with the global recommendations despite the short treatment duration. The bDMARDs are commonly used in combination with csDMARDs. Longer duration of bDMARD therapy appears to be associated with lower DAS28 scores and higher proportion of achievement of treatment target. These results should be kept in mind by the clinicians while treating patients with RA who do not achieve the treatment goal within 3 to 6 months of therapy. To achieve the best treatment outcome, patients with RA should continue bDMARD therapy for longer than 12 months. Our results provide a strong evidence base for the government to make decisions for the benefit of a greater number of patients with RA. Tocilizumab monotherapy may be a promising option for patients with RA. Further prospective studies are needed to assess the impact of bDMARD usage on RA remission among the Chinese population.
Acknowledgments This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Medical writing services were provided by Cactus Communications and paid for by Shanghai Roche Pharmaceuticals Ltd., China. The authors retained full control of manuscript content.
Compliance with ethical standards The study was approved by the Institutional Review Board of Peking University and independent ethics committees responsible for each investigating site. The study was conducted in compliance with the Declaration of Helsinki and in accordance with Good Clinical Practice and relevant ethical guidelines. Written informed consent was obtained from each participant.
Disclosures Jing Liu and Yu Bi are employees of Shanghai Roche Pharmaceutical Ltd., and funding for this study was provided by Shanghai Roche Pharmaceutical Ltd.
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