Indicators of suboptimal response to anti-tumor necrosis factor therapy in patients from China with inflammatory bowel disease: results from the EXPLORE study

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic, relapsing disease of the gastrointestinal tract [1]. While the burden of IBD is greatest in North America and Europe, the incidence of IBD is rapidly increasing in newly industrialized countries in Asia [2]. This includes China, where the crude incidence of IBD is increasing at a faster rate than other countries in Asia, ranging from 0.54 to 3.44 per 100,000 individuals in 2011 [3, 4]. While the age-standardized incidence of IBD in China remains about one-third of that in the US, the growing burden of disease, particularly if it is not well managed, presents a significant challenge for the Chinese healthcare system [2]. This observation is most likely related to urbanization and environmental and lifestyle changes; however, an increased awareness of IBD may also be contributing to this changing pattern [5].

Anti-tumor necrosis factor (anti-TNF) therapy was the first class of biologic therapy approved for patients with moderate-to-severe IBD or who have had an inadequate response to conventional therapy, such as aminosalicylates, corticosteroids, or immunomodulators [6‐8]. However, more than half of patients with IBD either do not respond to anti-TNF therapies (primary non-response), or lose response over time (secondary loss of response) within 2 years of initiating treatment [7, 9]. Therefore, these patients often require dose escalation or discontinuation, switching, non-biologic therapy initiation or escalation, or surgery [10]. These indicators of suboptimal therapy were found to be common in patients with IBD in Western nations [7]. In China, infliximab was the only approved anti-TNF therapy for patients with CD until December 2019, and data on the outcomes of infliximab use in IBD from China are limited.

The EXPLORE study assessed the incidence and indicators of suboptimal response to first-line anti-TNF therapy in patients with IBD in real-world clinical practice across 10 newly industrialized countries and regions across Asia–Pacific, Latin America, Russia and the Middle East [5]. This subgroup analysis further investigates the characteristics of patients with IBD in mainland China and describes their response to anti-TNF therapy. Local barriers to prescribing anti-TNF therapy were also investigated.

To our knowledge, the EXPLORE study is the first to comprehensively describe the suboptimal responses among patients with IBD treated with anti-TNF therapy in real-world clinical practice in China. We found that more than 1 in 2 patients with IBD in China were at risk of experiencing a suboptimal response to first-line anti-TNF therapy at 2 years post-initiation. The most frequently reported sub-optimal response indicators were anti-TNF discontinuation (for UC), IBD-related hospitalization (for CD) and augmentation with non-biologic therapy (for both UC and CD). Although conducted in only a small number of physicians, our survey also found that IBD specialists in mainland China remain skeptical about the use of anti-TNF therapy due to concerns about associated safety risks and immunogenicity. Together, our study highlights the substantial unmet medical need and suboptimal treatment outcomes with anti-TNF agents for the treatment of IBD in China.

The interpretation of data from the present study should take into consideration the fact that, at the time of this study, infliximab was the only approved anti-TNF for treating CD in China and marketing approval had not been granted for the use of infliximab in UC. As such, relatively few patients with UC were included in this study, the majority of whom had severe disease. Disease severity could be one explanation for the high suboptimal response rate to first-line anti-TNF therapy in the UC cohort. Our data among patients with CD may better reflect the real-world clinical pattern of patients with IBD in China. Within the CD cohort, IBD-related hospitalization was the most frequently reported first indicator of suboptimal response, reported in approximately one-third of patients receiving anti-TNF therapy. It is of concern that no prior indicator of suboptimal response, such as dose escalation, anti-TNF discontinuation, or augmentation with non-biologic therapy, was reported in these patients, as hospitalization is associated with substantial economic burden and may expose patients to nosocomial infections [15, 16]. It also highlights the suboptimal effectiveness of anti-TNF therapies in a substantial proportion of patients with IBD, which was further confirmed in our finding that 1 in 3 patients with CD experienced primary non-response to anti-TNF therapy. Interestingly, the anti-TNF discontinuation rate in patients with CD is low despite high rates of IBD-related hospitalization and primary non-response, potentially due to the lack of alternative therapies. In contrast, the anti-TNF discontinuation rate was high among patients with UC, possibly related to the fact that anti-TNF therapies were used in an off-label manner at that time. Together, our data highlight the suboptimal effectiveness of anti-TNF therapies as used in China in IBD as well as the lack of treatment options beyond anti-TNF therapies, at the time the study was conducted.

Augmentation with non-biologic therapy was also frequently reported as an indicator of suboptimal response in patients with CD. Concomitant immunosuppressive therapy is recommended in patients with CD receiving infliximab to reduce the risk of immunogenicity [17]. Our multivariate analysis of patients with CD in this subgroup analysis indicated that combining anti-TNF treatment with immunosuppressant therapy reduced the risk of a suboptimal response. However, combination use of anti-TNF therapy and thiopurines is associated with increased risk of malignancies including skin cancer and lymphoma [18‐21]. This association may contribute to the perceived safety risks of anti-TNF therapies among physicians, as reported in our physician survey.

The cumulative incidences of suboptimal response observed were numerically higher than those observed in the overall EXPLORE population (2 years: UC, 76% vs 33%; CD, 57% vs 41%) [5], but are largely consistent with other real-world studies [7, 9]. A retrospective, multicenter chart review study in Europe and Canada found 64% of patients with UC and 58% of patients with CD were at risk of experiencing suboptimal therapy at 2 years of initiating anti-TNF treatment [7]. A separate US study reported a suboptimal response rate of 86% after 2 years of anti-TNF therapy [9]. Median times to first suboptimal response in this analysis (UC: 7.2 months, CD: 14.3 months) were substantially shorter than those in the multinational chart review in Europe and Canada (UC: 12.5 months, CD: 17.5 months) [7] and were characterized by a high proportion of patients (> 30%) having a primary non-response to anti-TNF treatment. The differences in the level of and time to suboptimal responses reported in China versus other regions is multifactorial but may be attributed to differences in prescribing patterns for anti-TNF therapy. In particular, affordability was frequently cited as a perceived barrier to biologic prescribing for patients with IBD in China. At the time the survey was undertaken, infliximab was not reimbursable for the treatment of IBD in China. Accordingly, a typical patient with IBD treated with anti-TNF therapy in China is likely to have been treated with a biologic therapy relatively later than patients in Western countries.

Real-world studies in Western IBD populations have reported dose escalation and discontinuation of therapy as the most common indicators of a suboptimal response [7, 9]. Notably, dose escalation was rare in China (0–3.3%) compared with the US (30–34% of patients within 2 years) and the European and Canadian study (21–30%), likely due to cost barriers favoring a switch to non-biologic immunomodulators. Furthermore, patients in Europe and Canada with CD were more likely to have been prescribed a non-biologic therapy at the index date (70.6%) compared with the population in mainland China investigated in this study (42.9%), potentially limiting the use of augmentation as a treatment strategy in earlier studies [7]. Notably, the augmentation approach was favored over dose escalation in this subgroup analysis, despite Asian populations also having a high prevalence of NUDT15 polymorphisms (10–20%) that are associated with thiopurine-related leukopenia [22]. In addition, the absence of routine therapeutic drug monitoring for patients with IBD in China at the time this study was undertaken, alongside cost barriers and infusion capacity, was likely a major limiting factor in the use of dose escalation as a treatment strategy to overcome suboptimal responses. However, the proportion of patients with CD in China requiring IBD-related hospitalization (32.1%) after 2 years was comparable with the overall post-1990 10-year rate for surgery among patients with CD reported in a systematic review and meta-analysis (38.7%) [23].

Several limitations need to be considered when interpreting the results of this post-hoc analysis. The nature of retrospective chart review studies means that suboptimal response indicators may be underestimated due to insufficient or inconsistent information being recorded in patient medical records and the reasoning for clinicians adjusting treatment regimen and patient outcomes (biochemical, clinical, endoscopic or quality of life) have not been captured. The off-label use of anti-TNF therapy and low numbers of patients with UC mean that the data set analyzed here must be interpreted with caution. While only 10 centers in mainland China participated in this study, potentially limiting the generalizability of the results, centers were located in North, East and South China, and included some of the largest anti-TNF prescribing centers in the country. Nonetheless, this study provides insights on the outcomes following first-line treatment with an anti-TNF therapy for IBD in China; the definition of suboptimal outcomes in this study was well established and aligned with a previous multinational chart review, allowing meaningful comparisons between countries [7, 9].

To the authors’ knowledge, these data are the first to demonstrate that over half of the patients with IBD in China who were prescribed anti-TNF therapy as their first-line biologic therapy are at risk of experiencing suboptimal response at 2 years of anti-TNF initiation. The most common indicators of suboptimal response were IBD-related hospitalization and anti-TNF discontinuation. We also found that approximately 1 in 3 patients with IBD experienced primary non-response. With the evidence for high risk of suboptimal response and primary non-response, the need for biologics with new mechanisms of action as alternative treatment options to anti-TNF agents is warranted in China. Our study adds to the current evidence base on the unmet need associated with anti-TNF therapies in China, where earlier recognition of treatment failures to allow timely alternative treatment decisions, revised reimbursement policies and/or new therapeutic options may improve long-term outcomes in patients with IBD.