Anti-TNF therapy for ulcerative colitis in Brazil: a comparative real-world national retrospective multicentric study from the Brazilian study group of IBD (GEDIIB)

Ulcerative colitis (UC) is a chronic and progressive immune-mediated inflammatory bowel disease (IBD) which can affect a variable extension of the large bowel and predominantly impacts individuals in the third and fourth decades of life [1]. The course of the disease is characterized by relapsing and remitting mucosal inflammation and up to 15% of patients may develop severe disease at diagnosis [2]. The aim of treatment is to induce and maintain clinical and endoscopic remission, but the adoption of evolving treatment targets such as histological healing has recently been considered [3]. Biological agents are indicated for patients with moderate to severely active disease, refractory to conventional treatment with aminosalicylates and immunomodulators, as well as for those who are steroid-dependent or refractory [4].

The most commonly used tumor necrosis factor (TNF) alpha inhibitors in UC are infliximab (IFX) and adalimumab (ADA). Golimumab is also approved in UC, but experience with this agent in Brazil is limited. The efficacy of IFX in inducing and maintaining remission in moderate to severe UC, in addition to reducing the need for colectomy is supported by the pivotal ACT 1 and ACT 2 studies [5]. Accordingly, data from the pivotal Phase 3 ULTRA I and II studies demonstrated that treatment with ADA was able to induce and maintain remission in patients with moderate to severe UC and was well tolerated [6].

Although pivotal studies represent an important source of data on the efficacy and safety of a new treatment, their selective designs, with multiple inclusion and exclusion criteria, prevent the generalization of findings for routine clinical practice. Therefore, real world studies are warranted. Even though several European and North American studies have demonstrated real-world experience on the efficacy and safety of anti-TNF agents in the management of UC [7‐11], the phenotype of disease can differ in various ethnic groups, which may be associated to different genetic backgrounds [12]. Thus, it is crucial to have data of specific drug efficacy in diverse populations with different demographic and socioeconomic background, such as Latin America. Possible differences in comparison with North American or European populations may limit extrapolation of available data, what emphasizes the need for specific local studies.

In this scenario, there is lack of data on the efficacy and safety of anti-TNF agents in Brazilian patients in UC, as public and private access to these agents is relatively recent [13]. Therefore, the present study aimed to analyze rates of clinical and endoscopic remission comparatively, between ADA and IFX, in Brazilian UC patients, and evaluate possible factors associated with clinical and endoscopic remission after 1 year of treatment.

This study reports the indirect retrospective comparison between IFX and ADA in a multicenter Brazilian cohort of UC patients. This population of predominantly biological-naive patients (80.6%) showed an overall clinical response rate at week 8 of 61.25%, and the proportion of patients in clinical remission at weeks 8, 26 and 52 was 66.78%, 71.62 and 82.82%, respectively. Clinical remission rates were significantly higher in patients treated with IFX at weeks 26 and 52. Overall, endoscopic remission was observed in 65.98% at week 52, with no differences between the two groups. Older age, no prior exposure to biological therapy, treatment with IFX, clinical response at week 26 and endoscopic remission at week 26 were associated with higher rates of clinical remission at week 52.

Since the approval of IFX [5], the first biological agent for the management of UC, the landscape of medical treatment of the disease has drastically improved, especially for individuals with moderate to severe disease and those refractory to conventional therapies. Biological therapy, mainly TNF-alpha inhibitors, has been associated with clinical remission, endoscopic healing, reduction in the need for hospitalizations and colectomy [16]. Data supported by randomized controlled trials have demonstrated that both IFX and ADA are effective in inducing and maintaining clinical remission in patients with moderate to severely active UC [5, 6], although clinical remission rates after 1 year were not higher than 20.5% for both agents.

The results of the present study are in tune with the reported efficacy of these agents in the real-world scenario, where the proportion of responders after 52 weeks of exposure varies from 30 to 65% for ADA [7‐10, 13, 17, 18] and from 39 to 70% for IFX [11, 19‐22], respectively. The discrepancy in the performance of biologics between the real-world scenario and pivotal studies is usually attributable to the restriction of concomitant treatments that could favor a response and the required washout period between one drug and another in the design of randomized clinical trials. However, it is important to emphasize that there is significant heterogeneity in methodology, patient populations and clinical scoring systems among the available real-world studies in UC, which limits extensive comparisons with our results.

In the present study, there was a statistically significant difference in the proportions of remitters in the IFX group vs. the ADA group favoring ADA at week 8 and IFX in both weeks 26 and 52. The higher efficacy with ADA after 8 weeks in our study is probably a consequence of unadjusted confounding factors indicating more severe disease at baseline in patients treated with IFX, what could have reduced efficacy numbers in the IFX group. In a recent systematic review and network meta-analysis of important trials in biologic-naïve UC patients, IFX, ADA and vedolizumab were superior to placebo, and vedolizumab was superior to ADA for maintenance of clinical remission and endoscopic improvement in patients who responded to induction therapy [23]. Several real-life studies comparing the efficacy of different anti-TNF agents demonstrated controversial findings. A recent observational retrospective Italian study comparing IFX, ADA and golimumab observed a better treatment effectiveness in patients treated with IFX as compared to other treatments with the lowest percentages of response rates in all outcomes in patients treated with golimumab (p < 0.01). However, after applying a propensity analysis, no statistically difference in each outcome evaluated was identified [8]. Accordingly, a recent Korean retrospective study reported no significant differences between IFX and ADA treatment in the rate of clinical remission or clinical response at 8 or 52 weeks [11]. Conversely, the U.S. cohort study using a large administrative claims database showed that the risk of corticosteroid use was significantly lower in IFX-treated patients, as compared to ADA (HR, 0.82; 95% CI, 0.68–0.99), although the risk of hospitalization and serious infections were comparable [24]. These results from different countries demonstrate the variation in findings in the real-world setting.

Despite advances in medical management of UC with the introduction of biologics and small molecules, the potential for disease modification in terms of colectomy rates in the biological era remains unclear. Our study showed a colectomy rate of 4.5% in patients who used ADA and 6.59% with IFX, in a follow-up of 28.93 ± 23.36 and 41.23 ± 33.14 months, respectively. This number can be compared to other similar studies. A recent Swiss population-based study assessing colectomy rates in UC patients demonstrated a significantly decrease in colectomy rates for UC over time after 2005 [25]. Accordingly, a Canadian population-based study showed a significant decrease in the temporal trends of elective colectomy rates from 1997 to 2009, along with a marked increase in the prescriptions of infliximab after 2005 [26]. Although this time-trend decrease might also be related to improvements in care, including earlier diagnosis and adoption of guideline recommendations in clinical practice, the decreasing trend suggests a potential role of biologics as disease-modifying agents in the natural course of UC. It may take time to observe this trend in cohort studies around the globe. More population-based data from Brazil regarding reduction of colectomy rates over time in UC are awaited.

In the present study, prior exposure to another biologic was associated with a lower chance of long-term clinical remission, which may reflect disease severity at baseline. This is a common practice in real setting, what is captured in observational studies as ours. Data evaluating the influence of previous exposure to biologics in response to anti-TNF treatment is conflicting. The randomized, double-blind, placebo-controlled ULTRA 2 trial demonstrated that among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on ADA patients and 6.9% on placebo (p = 0.559); corresponding values for week 52 were 10.2% and 3% (p = 0.039) [6]. Conversely, in a retrospective cohort study from the Spanish ENEIDA registry, response to prior treatment with IFX was the only predictive factor of response to ADA at week 12, which was observed in 90% of IFX remitters, 53.8% of responders and 33.3% of primary non-responders (p = 0.01). These observations should be interpreted with caution given that most of studies do not assess whether previous treatment was discontinued due to pharmacokinetic failure, immunogenicity, or mechanistic failure.

Early response to anti-TNF treatment has consistently been reported as a predictive factor of higher long-term remission rates. Data from an Italian cohort of ADA-treated patients showed that clinical remission and low C-reactive protein at week 12 predicted clinical remission at week 54 (OR 4.17, 95% CI 2.36–19.44; OR 2.63, 95% CI 2.32–14.94, respectively). Likewise, a Swedish retrospective multi-center study of IFX treatment in UC patients identified non-response at 3 months as an independent risk factor for poor outcome, predicting subsequent colectomy [22]. We observed similar results in the present study since clinical response at week 8 was associated with endoscopic remission and clinical response at week 26 was associated either with clinical and endoscopic remission at week 52.

Data derived from two meta-analysis and a pooled analysis of IBD trials have demonstrated no increased risk of serious infections in antitumor necrosis factors-treated patients compared with placebo [27‐29]. In our study, anti-TNF treatment was well tolerated, and no new safety signals were observed, with no difference between the groups. Apart from that, the percentage of adverse events in each group was low in comparison to pivotal trials and other retrospective studies. Comparative safety analyses between different anti-TNFs are limited in the literature. Through the analysis of a health insurance database, it was demonstrated that subcutaneously administered anti-TNFs exhibited a higher risk of serious infections (HR, 1.34; 95% CI, 1.18–1.53) than intravenous anti-TNF [30]. On the other hand, a retrospective study in pediatric IBD patients observed a higher overall incidence of infections in infliximab compared with adalimumab-treated patients [31]. Additionally, a Brazilian retrospective single-center study demonstrated no differences between ADA and IFX patients in CD management (63.2% with IFX and 64.5% with ADA, p = 0.879), with no differences in infections or treatment interruption [32]. The lower numbers of adverse events in our UC multicentric national study are probably associated to limitations in data capturing by different physicians. The infusion site reaction rate was in line with previous reports. Data from TREAT registry reported an incidence of 2.8% with IFX in terms of infusion reactions, most common being headache and arthritis [33] while injection-site reactions were reported in an incidence of 0.1/100 patient-years in the adalimumab safety PYRAMID registry [34]. These numbers were comparable to the findings of our study.

Our study is associated with some limitations which need to be considered before the final analysis of the results. Firstly, the sample size was limited considering the increasing incidence and high estimated prevalence of UC in Brazil (estimated prevalence of 66.45 per 100,000 in 2020) [35]. However, this was unavoidable considering that biologics were just recently reimbursed for UC management in Brazil and that penetration of anti-TNF agents in Latin America is lower in UC as comparable to the rest of the world [36]. Another important limitation was a natural selection bias, a common feature of the retrospective and observational study design, where more severe patients could be directed to IFX use. However, these findings highlight the that physicians may confront in the management of IBD patients in our country [37]. The observational nature of this study carries the inherent biases associated with the retrospective study design. In addition, not all information regarding clinical scores were readily available in all timepoints of interest in medical charts, which limited the assessment of treatment response. No patients with golimumab were included, demonstrating the lack of experience with this agent in our country. Safety analysis was probably underestimated, due to bias in data collection. Another important point is that a systematic evaluation of Mayo endoscopic subscores was not available for the entire population of patients. Lastly, not all patients included in the study presented moderate-to-severe activity at induction, which may have interfered with the final results. As this is the first multicenter study in the country with the aiming to evaluate the use of anti-TNF in patients with UC, we found it interesting to evaluate the scenario and epidemiological profile of all patients with indication for the use of the medication and, therefore, the study inclusion criteria were more comprehensive. We are aware that other study designs would be more appropriate for the study, such as propensity score matching, or the inclusion of biologic naïve patients, exclusively. Further studies can clarify these issues in the future. Despite these limitations, our study provides insightful information as being the first multi-center Brazilian study to report on long-term outcomes of anti-TNF treatment in UC patients, from both private and public settings.

In summary, in this national Brazilian retrospective study, anti-TNF therapy with IFX and ADA were effective in the management of UC. Clinical remission rates were higher with ADA at week 8. On the other hand, IFX was associated with higher rates of clinical remission at weeks 26 and 52 in comparison to ADA. Patients naive to biological therapy presented higher rates of clinical and endoscopic remission.