Comparison of Long-Term Outcomes of Infliximab and Adalimumab Therapy in Biologic-Naive Patients with Ulcerative Colitis

Abstract

Background

Data comparing their long-term efficacy and safety of Infliximab (IFX) and adalimumab (ADA) in moderate to severe ulcerative colitis (UC) is limited. In this study we aimed to compare the long-term effectiveness and safety of IFX and ADA in UC who had not previously received biologic therapy.

Methods:

Data from patients treated between 2007 and 2021 was collected and analyzed. Outcomes evaluated included UC-related hospitalization, colectomy, steroid use, and serious infections leading to treatment cessation.

Results

Of 86 UC patients, 41 received IFX and 45 received ADA. No differences were found in terms of demographics, risk factors, baseline Mayo scores and treatment history. During anti-TNF therapy, steroid use was significantly higher in the ADA group (44.4%) compared to the IFX group (14.6%). UC-related hospitalization and colectomy rates were similar between the two groups, as were rates of serious infection leading to treatment cessation. These outcomes were similar in UC patients treated with IFX or ADA monotherapy or in combination with an immunomodulator. The Kaplan-Meier analysis showed that the duration of discontinuation of the drug due to secondary loss of response was longer in the IFX group compared ADA the other group, although the difference was not statistically significant (72.5% versus 46.7%, p = 0.057).

Conclusion

Overall, the study suggests that IFX and ADA may be similar in terms of clinical outcomes for UC patients who are new users of anti-TNF agents, but the higher rate of steroid use in the ADA group should be noted.

Introduction

Ulcerative colitis (UC) is a chronic disease characterized by mucosal inflammation of the colon and rectum. Biologic therapies, such as infliximab (IFX) and adalimumab (ADA), which inhibit tumor necrosis factor (TNF)-α receptors, are among the most effective treatments for moderate to severe UC. [1, 2]. While IFX is also used to induce remission in patients with acute severe UC who do not respond to steroids, ADA is not used for this purpose. [3, 4]. Previous research has demonstrated that the use of these anti-TNF drugs can increase remission rates and reduce the need for hospitalization, surgery, and steroid use in UC [1, 2, 5, 6]. However, there are concerns about their potential adverse effects, such as serious opportunistic infections and malignancy [7–9].

Limited studies have compared the long-term efficacy and safety of IFX and ADA in biologic-naive patients with UC, and the results of these comparative studies have been variable [10, 11]. The aim of this study was to assess the long-term efficacy and safety of IFX compared to ADA in biologic-naive patients with UC.

Methods

Results

During the study period, a total of 475 patients with UC were followed for 7 years in our clinic. Anti-TNF treatment with either IFX or ADA was initiated in 112 of these patients, 26 of whom were excluded from the study (17 due to primary non-response or adverse events, 5 due to treatment duration of less than 3 months, 2 due to spondyloarthritis, and 2 due to pouchitis) (Fig. 1). The final study population consisted of 86 eligible patients with UC, including 41 treated with IFX (mean age at onset: 34.4 years, 61.0% male) and 45 treated with ADA (mean age at onset: 31.4 years, 60.0% male). The median disease duration was 7.2 years (interquartile range [IQR]: 8.0) for the IFX group and 8.1 years (IQR: 7.2) for the ADA group (p = 0.16). In IFX and ADA groups, active smoking was present in 12.2% and 11.1% (p = 0.40), family history of inflammatory bowel disease (IBD) was present in 17.1% and 11.1% (p = 0.45), and extra-intestinal manifestations were present in 48.8% and 53.3% respectively (p = 0.62). The duration of TNF antagonist treatment was 4.9 years (IQR: 7.1) for the IFX group and 6.9 years (IQR: 7.9) for the ADA group (p = 0.04). Both groups had similar disease extent, steroid dependence, and previous medical therapy, including mesalazine, sulfapyridine, thiopurines, or steroids. A total of 71 patients (82.6%) had prior experience with at least one immunomodulator (thiopurine or methotrexate) before starting anti-TNF agents. The IFX and ADA groups had similar rates of combination therapy with thiopurines (36.6% vs. 35.6%, p = 0.92). At baseline, the IFX group had lower hemoglobin and albumin levels, but higher C-reactive protein levels compared to the ADA group. However, the Mayo score at baseline was similar in both groups (p > 0.05) (Table 1).

In this study, the overall duration of anti-TNF use was longer in the ADA group (median 6.9 years) compared to the IFX group (median 4.9 years, p = 0.04). The steroid requirement was significantly higher in the ADA group (44.4%) compared to the IFX group (14.6%, p = 0.003). The rates of UC-related hospitalization (IFX 9.8% vs ADA 13.3%, p = 0.74) and colectomy (IFX 4.9% vs ADA 2.2%, p = 0.60) were similar between the IFX and ADA groups. Serious infections leading to treatment cessation were not significantly different between the two treatment groups (IFX 2.4% vs ADA 4.4%, p = 0.54) (Table 1). When the IFX and ADA monotherapy and combination treatments were compared in terms of treatment cessation led by steroid requirement, UC-related hospitalization, colectomy, and serious infections, no statistically significant differences were found (p > 0.05 for all parameters) (Table 2).

In the Kaplan-Meier analysis, the time until secondary LOR was longer in the IFX group, but the difference was not statistically significant (72.5% versus 46.7%, p = 0.057) (Fig. 2). When the monotherapies (p = 0.173) and combinations witht immunomodulators (p = 0.201) of both groups were compared, no statistically significant difference was observed time until secondary LOR (Fig. 3, 4). In the log-rank ttest, ADA group had a statistically higher need for steroids in both monotherapy and combination therapy groups (p = 0.012) whereas hospitalization and colectomy rates were statistically similar.

Discussion

While IFX and ADA are effective treatments for patients with moderate to severe UC who are refractory to 5-aminosalicylates, immunomodulators, and/or corticosteroids, there is a limited number of studies comparing their long-term efficacy and safety. In this study, we compared UC-related hospitalization, colectomy, steroid use, and serious infections leading to treatment cessation as long-term outcomes in both groups. The results demonstrated that there was no significant difference in terms of UC-related hospitalization, colectomy, and serious infection between the two groups. However, we observed that patients treated with IFX may have a lower need for corticosteroids compared to patients in the ADA group. These findings are consistent with the limited number of studies that also have compared the long-term efficacy and safety of different TNF antagonists [2, 13, 14].

Previous studies have also shown that patients using ADA are more likely to experience primary non-response compared to those using IFX, while both TNF antagonists have similar long-term efficacy and safety prodiles in primary response settings [8, 10].

Due to the lack of comparative head-to-head trials, the choice between different anti-TNF agents in UC remains unclear. While some studies have shown that IFX is more effective and tolerable than ADA in UC, others have not found any differences between the two groups. [11, 15, 16]. In our Kaplan-Meier analysis discontinuation of the drug due to secondary loss of response was statistically similar in both groups, but longer in the IFX group. This suggests that IFX may be more effective and tolerable. Targovnik and colleagues [17] reported treatment cessation rates of 66.0% and 41.3% in IFX-treated patients with UC after 1 and 5 years, respectively, without data for ADA. In this study, the treatment cessation rates were 44% in the IFX group and 26% in the ADA group after 5 years.

We compared the monotherapy of each TNF antagonist and their combination with an immunomodulator without any statistically significant differences in clinical outcomes. This finding differs from the data in the SUCCESS study, which showed that the combination therapy of IFX with thiopurines was associated with a greater likelihood of steroid-free remission compared to monotherapy[18]. Pouillon and colleagues also found that the use of concomitant immunomodulators did not affect clinical outcomes, similar to our study. This may partly be explained by the fact that the majority of patients in both groups were also receiving concomitant mesalazine, which may contribute to drug compliance [13, 16]. In our practice, we continued the combined immunomodulatory treatment with a TNF antagonist for at least 1 year in responding patients. However, our cohort database did not contain sufficient data on the duration of immunomodulator use.

One strength of this study was the extended duration of TNF antagonist use, which allowed for a thorough evaluation of long-term outcomes. Additionally, the homogeneity of demographic characteristics such as smoking status, disease location, disease behavior, baseline Mayo score, and prior treatment history helped to control for potential confounders that could affect clinical outcomes. However, the study also had some limitations, including its retrospective and observational design, which may have introduced bias. Additionally, the sample size was relatively small, which may limit the generalizability of the results. Another potential limitation is that we preferred the use of IFX in patients presenting with severe UC attacks who did not respond to steroids, which may have influenced the results. Overall, while this study provides valuable insights into the long-term effectiveness and safety of IFX and ADA in the treatment of UC, additional research with larger sample sizes and prospective designs is needed to further clarify the comparative efficacy of these TNF antagonists.

Conclusion

The results of this study suggest that IFX and ADA may be comparable in terms of clinical outcomes such as risk of UC-related hospitalization, colectomy, and serious infections in patients with UC who are new users of anti-TNF agents. However, the ADA group had a significantly higher steroid requirement compared to the infliximab group. When the monotherapy of each TNF antagonist and their immunomodulator combinations were compared, no differences in the clinical outcomes were observed. These findings suggest that both IFX and ADA may have similar long-term efficacy and safety when used as monotherapy or in combination with immunomodulators in the treatment of UC.

Declarations

Author Contributions:

Muhammed Bahaddin Durak: Investigation, data collection, writing-orginial draft preparation, reviewing and editing, visualization. Cem Simsek: Writing-orginial draft preparation, reviewing and editing. Ilhami Yuksel: Conceptualization, Methodology, Investigation, Supervision, writing- reviewing and editing

Acknowledgments:

None

Conflicts of Interest:

None

Disclosure of Financial Arrangements:

None

References

1. Rutgeerts, P., et al., Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med, 2005. 353(23): p. 2462-76. DOI: 10.1056/NEJMoa050516
2. Sandborn, W.J., et al., Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology, 2012. 142(2): p. 257-65 e1-3. DOI: 10.1053/j.gastro.2011.10.032
3. Baudet, A., et al., Severe ulcerative colitis: present medical treatment strategies. Expert Opin Pharmacother, 2008. 9(3): p. 447-57. DOI: 10.1517/14656566.9.3.447
4. Turner, D., et al., Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin Gastroenterol Hepatol, 2007. 5(1): p. 103-10. DOI: 10.1016/j.cgh.2006.09.033
5. Peyrin-Biroulet, L. and M. Lemann, Review article: remission rates achievable by current therapies for inflammatory bowel disease. Aliment Pharmacol Ther, 2011. 33(8): p. 870-9. DOI: 10.1111/j.1365-2036.2011.04599.x
6. Pouillon, L., P. Bossuyt, and L. Peyrin-Biroulet, Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease. Expert Opin Biol Ther, 2016. 16(10): p. 1277-90. DOI: 10.1080/14712598.2016.1203897
7. Marehbian, J., et al., Adverse events associated with common therapy regimens for moderate-to-severe Crohn's disease. Am J Gastroenterol, 2009. 104(10): p. 2524-33. DOI: 10.1038/ajg.2009.322
8. Singh, S., et al., Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol, 2014. 12(2): p. 210-8. DOI: 10.1016/j.cgh.2013.04.033
9. Wolfe, F. and K. Michaud, The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum, 2007. 56(5): p. 1433-9. DOI: 10.1002/art.22579
10. Ananthakrishnan, A.N., et al., Comparative Effectiveness of Infliximab and Adalimumab in Crohn's Disease and Ulcerative Colitis. Inflamm Bowel Dis, 2016. 22(4): p. 880-5. DOI: 10.1097/MIB.0000000000000754
11. Singh, S., et al., Comparison of Infliximab and Adalimumab in Biologic-Naive Patients With Ulcerative Colitis: A Nationwide Danish Cohort Study. Clin Gastroenterol Hepatol, 2017. 15(8): p. 1218-1225 e7. DOI: 10.1016/j.cgh.2016.11.024.
12. Satsangi, J., et al., The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut, 2006. 55(6): p. 749-53. DOI: 10.1136/gut.2005.082909.
13. Pouillon, L., et al., Treatment Persistence of Infliximab Versus Adalimumab in Ulcerative Colitis: A 16-Year Single-Center Experience. Inflamm Bowel Dis, 2019. 25(5): p. 945-954. DOI: 10.1093/ibd/izy322.
14. Singh, S., et al., Comparative effectiveness and safety of infliximab and adalimumab in patients with ulcerative colitis. Aliment Pharmacol Ther, 2016. 43(9): p. 994-1003. DOI: 10.1111/apt.13580.
15. Bonovas, S., et al., Systematic review with network meta-analysis: comparative assessment of tofacitinib and biological therapies for moderate-to-severe ulcerative colitis. Aliment Pharmacol Ther, 2018. 47(4): p. 454-465. DOI: 10.1111/apt.14449.
16. Singh, S., et al., Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Aliment Pharmacol Ther, 2018. 47(2): p. 162-175. DOI: 10.1111/apt.14422.
17. Targownik, L.E., et al., Factors Associated with Discontinuation of Anti-TNF Inhibitors Among Persons with IBD: A Population-Based Analysis. Inflamm Bowel Dis, 2017. 23(3): p. 409-420. DOI: 10.1097/mib.0000000000001025.
18. Panaccione, R., et al., Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology, 2014. 146(2): p. 392-400 e393. DOI: 10.1053/j.gastro.2013.10.052.

tables

Table 1. Demographic characteristics, disease location and behavior of patients with UC .

Table 2. Subgroup analyses of the treatment outcomes based on the combination (concomitant or addition) of IM within each group.