Recent Perspectives of Anti-TNF Combination Therapy for Inflammatory Bowel Disease

Author: Hannah J. Moir

Support statement: The writing and publication of this news feature was supported by Viatris, who were not involved in the creation of this content.

Anti-TNF therapy is commonly used for moderate-to-severe inflammatory bowel disease (IBD) as a first-line biologic treatment in both ‘step-up’ and ‘top-down’ approaches, and is an important option in IBD management. However, some patients do not respond well to anti-TNFs, either as primary non-responders or due to secondary loss of response over time.

CURRENT PERSPECTIVES OF COMBINATION THERAPY IN INFLAMMATORY BOWEL DISEASE

Combination therapy with anti-TNFs for IBD has been proposed as being more effective than anti-TNF alone. Combination therapy consists of an anti-TNF such as infliximab or adalimumab, along with an immunomodulator such as methotrexate or thiopurines. Combination therapies have been shown to improve the pharmacokinetic profile by reducing immunogenicity (anti-drug antibodies) and improving anti-TNF drug concentrations, which have been associated with improved long-term clinical outcomes and reduced secondary loss of response.^1,2

In January 2024, the Crohn’s & Colitis Congress 2024 took place in Las Vegas, Nevada, USA. During the event, Chaaban et al.³ presented a study evaluating the use of combination therapy for ulcerative colitis in elderly patients aged 65 years or older. The study analysed network data comparing thiopurine monotherapy with combination therapy using anti-TNF in 2,597 elderly patients.³ The results indicated that patients receiving thiopurine monotherapy had a higher 10-year mortality (odds ratio: 1.67; p=0.002). On the other hand, patients receiving combination therapy had higher rates of steroid use (32.4% versus 24.3%; p=0.001) and colectomy (4.5% versus 1.2%; p<0.001).³ The study reported that combination therapy was used in those with more active disease indicators but was not associated with an increased risk of infection or mortality.³

THE SAFETY OF COMBINATION OF ANTI-TNFs WITH IMMUNOMODULATORS

On the other hand, it is important to note that long-term combination therapy use has a lower safety profile compared to monotherapy, where there have been reports of a greater risk of infection and neoplasms, including lymphoma and non-melanoma skin cancer.⁴ For patients initiating treatment with an anti-TNF in combination with an immunomodulator, discontinuation typically occurs within 6–12 months to mitigate the risk of immunomodulator-related adverse events.⁴

As such, it is important to consider the potential risks and benefits of combination therapy. This involves balancing the efficacy and remission rates with the potential adverse effects related to immunosuppression and associated medical costs. The risk-benefit ratio should therefore be considered on a case-by-case basis for each individual.

According to a recent meta-analysis published in January 2024, based on low-certainty evidence of randomised-control trials, patients with IBD who had sustained corticosteroid-free clinical remission for more than 6 months on combination therapy showed no difference in the risk of relapse between immunomodulator withdrawal (and continued anti-TNF monotherapy), compared with continued combination therapy.⁴ The risk of relapse was 16.8% for immunomodulator withdrawal, and 14.9% for continued combination therapy (risk ratio: 1.15; 95% confidence interval [CI]: 0.75–1.76).⁴ There was also no difference in the risk of serious adverse events with immunomodulator or anti-TNF withdrawal compared with continued combination therapy. However, anti-TNF withdrawal was associated with a 2.4-fold higher risk of relapse compared with the continuation of combination therapy, and thus appropriate counselling and monitoring strategies should be considered.⁴

The implications are that for those with IBD who have sustained corticosteroid-free clinical remission for more than 6 months on combination therapy, de-escalation with withdrawal of immunomodulators may be routinely considered. However, anti-TNF monitoring is warranted.^4,5

Before de-escalation, shared decision-making is crucial to consider the patient’s individual preference, risks, and benefits of de-escalation.⁵ Patients should also be counselled about the need for continued disease activity surveillance, close monitoring, and a rescue plan in case of relapse.⁵

COMBINATION THERAPY IN PAEDIATRIC INFLAMMATORY BOWEL DISEASE

Despite the demonstrated efficacy and safety of combination therapy with anti-TNFs in both adults and children with IBD, concerns over safety signals associated with combination anti-TNF with thiopurine have led some paediatric clinicians to consider alternative options.⁶

In March 2023, a large prospective multicentre, randomised, double-blind, placebo-controlled pragmatic trial was published.⁷ The study evaluated the efficacy and safety of anti-TNF combination therapy with low-dose methotrexate in paediatric patients with Crohn’s disease.⁷ The study demonstrated that combination therapy with adalimumab was more effective in increasing treatment efficacy with a two-fold reduction in treatment failure (hazard ratio: 0.40; 95% CI: 0.19–0.81) and a tolerable safety profile compared to infliximab, which observed no differences compared with monotherapy (hazard ratio: 0.93; 95% CI: 0.55–1.56).⁷

During the Crohn’s & Colitis Congress 2024, Iovino et al.⁸ presented a retrospective review of the de-escalation impact on clinical outcomes of 152 paediatric patients under 18 years of age with IBD who were initiated with combination therapy for an average duration of 106±56 weeks. According to the study, de-escalation may be safely considered in children on combination therapy.⁸ The study did not report an increased risk of worsening disease activity or laboratory values. However, for those with Crohn’s disease on infliximab in combination with thiopurines, de-escalation resulted in a significant increase in faecal calprotectin and decreased anti-TNF trough levels (p<0.05), although drug levels were still within the therapeutic range (>10 μg/mL).⁸

The study found that 18% of patients required subsequent escalation, resulting in lower anti-TNFs and higher C-reactive protein and erythrocyte sedimentation rates, compared to those who did not require adjustments. However, there were no cases of increased risk of worsening disease.⁸ The study also revealed that lower anti-TNF levels and higher inflammatory markers prior to de-escalation may be predictive markers for escalation in therapy after stopping an immunomodulator.⁸

Impact of Combination Therapy on Paediatric Growth

It is also important to note that IBD can affect the growth and development of children and adolescents, potentially limiting their full growth potential, particularly in terms of body weight.⁹ A recent population-based analysis of a paediatric IBD registry in Germany found that children diagnosed with IBD (i.e., those younger than 15 years of age) are likely to experience body weight and growth disturbances, with more than three-quarters having weights below the 50^th percentile of the child growth curve.⁹ Additionally, 50% of those with Crohn’s disease fall below the 16^th percentile.⁹

Anti-TNFs have been associated to improving the growth and nutritional status in children. At the Crohn’s & Colitis Congress 2024, Plott et al.¹⁰ presented the results of the multicentre COMBINE trial. The study examined the effect of anti-TNF (infliximab or adalimumab) combination therapy with oral methotrexate compared to anti-TNF monotherapy on growth development in children with Crohn’s disease.¹⁰ At the time of anti-TNF initiation, 26.6% and 27.7% of the cohort (N=199 children), had weight and height disturbance, respectively.¹⁰ After 12 months follow-up, the height disturbance reduced to 6.15%, and after 24 months, it was 0.90%.¹⁰ The weight disturbance reduced to 5.7% following 12 months, and after 24 months, it was 0.8%.¹⁰

These results demonstrate that anti-TNF therapy can improve growth disturbances.¹⁰ Plott indicated that counselling and initiation of anti-TNF at the time of diagnosis can not only provide disease control but also impact a child’s development, leading to improved self-esteem and wellbeing.¹⁰

ALTERNATIVE COMBINATION THERAPIES FOR INFLAMMATORY BOWEL DISEASE

There is emerging data considering the combination of two or more advanced therapies, such as biologics and small molecules, as an important area of future research.⁶ These combinations may be useful to treat luminal disease as well as coexisting extraintestinal manifestations.

Proof-of-concept data suggest that early combination treatment strategies may be beneficial for high-risk patients, such as those with refractory IBD who have failed multiple therapeutic options or those with very high-risk phenotypes and/or concomitant immune-mediated diseases.⁶ However, there remain many questions regarding currently off-label combination therapy, such as the mechanisms of action and heterogeneity, the combination approach and duration, as well as long-term safety signals of maintenance combination regimens.⁶

Therefore, there is a need for long-term evidence and potential risk associated with these combination approaches, to determine the effectiveness and safety of combination treatment strategies for IBD. Ultimately, the treatment decision should be individually tailored and personalised to the patient.

References

1. Noor NM.Combination therapies: the next major frontier in IBD management. Nat Rev Gastroenterol Hepatol. 2023;20(12):761.
2. Dai C et al. Combination therapy in inflammatory bowel disease: current evidence and perspectives.Int Immunopharmacol. 2023:114:109545.
3. Chaaban L et al. Lower mortality risk with combination therapy with anti-TNF therapy and thriopurine compared to thiopurine alone in elderly patients with UC. 2024;166(Suppl 3):S113-4.
4. Katibian DJ et al. Withdrawal of immunomodulators or TNF antagonists in patients with inflammatory bowel diseases in remission on combination therapy: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2024;22(1):22-33.e6.
5. Ahmed W et al. De-escalation of IBD combination therapy in patients with Crohn’s disease. 2023. Available at: https://www.gastroendonews.com/Inflammatory-Bowel-Disease/Article/06-23/De-escalation-of-IBD-Combination-Therapy-In-Patients-with-Crohn%E2%80%99s-Disease/70513. Last accessed: 13 February 2024.
6. Gallagher J et al. The future of advanced therapies for pediatric Crohn’s disease.Paediatr Drugs. 2023;25(6):621-33.
7. Kappelman MD et al. Comparative effectiveness of anti-TNF in combination with low-dose methotrexate vs anti-TNF monotherapy in pediatric Crohn’s disease: a pragmatic randomized trial. 2023;165(1):149-161.e7.
8. Iovino N et al. Assessing the clinical impacts of immunomodulatory withdrawal from anti-TNF combination therapy in pediatric inflammtory bowel disease. Gastroenterology. 2024;166(Suppl 3):S97-8.
9. Zhou X et al. Growth development of children and adolescents with inflammatory bowel disease in the period 2000–2014 based on data of the Saxon pediatric IBD registry: a population-based study. BMC Gastroenterol. 2024;24(1):25.
10. Plott N et al. Improvement in growth and nutrition status after anti-TNF therapy initiation among patients with pediatric Crohn’s disease: results from the COMBINE trial. Gastroenterology. 2024;166(Suppl 3):S98.