Controversies in the Management of Inflammatory Bowel Disease with Anti-TNF Therapies

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.

EXPLORING INFLAMMATORY BOWEL DISEASE

In 2023, the European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA) reported that inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, affects more than 3.4 million people in Europe, and potentially up to 10 million people worldwide.¹

Despite the ongoing quest for a cure for IBD, effective medical management can impact a patient’s quality of life (QoL) by alleviating symptoms. Treatment strategies typically involve tailoring therapies to meet specific targets, with therapy escalation in cases where these targets are not achieved.^2-5

Since their first release of IBD guidelines in 2006, the European Crohn’s and Colitis Organisation (ECCO) has provided evidence-based guidelines for healthcare professionals responsible for managing patients with IBD, establishing its position as the global reference for IBD management.^1-2

As we approach the United European Gastroenterology (UEG) 2023 Week, in Copenhagen, Denmark, in October 2023, this News Feature explores recent expert opinions on the use of anti-TNF agents, and anticipates forthcoming updates to the ECCO Treatment Guidelines for IBD.^2-4

THE ROLE OF ANTI-TNFS IN MANAGING INFLAMMATORY BOWEL DISEASE

In the treatment of IBD, standard guidelines recommend a range of first-line therapeutic approaches. These include anti-inflammatories, such as aminosalicylates, corticosteroids, and immunosuppressants; biological therapies, such as anti-TNFs (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab); anti-integrins; and antibiotics. These approaches aim to reduce inflammation, and help to maintain remission levels.^3,4

Anti-TNFs are monoclonal antibodies designed to target and inhibit TNF-mediated activation of proinflammatory pathways. This inhibition leads to a reduction in immune-mediated inflammation, thereby inducing and maintaining remission in patients with IBD. This approach can potentially lead to mucosal healing, thus altering the course of IBD, and significantly improving the QoL for these patients.⁶

For over two decades, anti-TNF agents have become the mainstay in the therapeutic treatment of IBD, particularly for moderate-to-severe IBD cases. They are used in both ‘step-up’ and ‘top-down’ approaches.^7,8 Furthermore, the arrival of anti-TNF biosimilars has expanded the availability of these treatments.⁹

However, it is essential to acknowledge that, while there are many treatment options, none serve as a universal remedy. Patients may experience relapses, and treatment failures can complicate the management of IBD. In cases where the condition proves unresponsive to medication, surgical intervention may become necessary.

CONTROVERSIES SURROUNDING ANTI-TNF THERAPIES

While anti-TNF therapies have proven to be effective and well-tolerated, they are not without their limitations. A significant challenge is that up to 40% of patients do not respond to the treatment, termed primary non-responders, and others may experience a loss of response over time, referred to as secondary responders.⁸ Importantly, if a patient stops responding to one biologic, the likelihood of a second one being effective is less likely.⁸

The use of anti-TNFs also raises safety concerns, including an increased risk of infection, potential associations with cancer, and risks during pregnancy.¹⁰ Consequently, guidelines recommend vaccination and screening for latent infections before initiating treatment to mitigate these risks.¹⁰

In response to these limitations and safety considerations, researchers are actively developing new therapeutic approaches, and exploring combination therapies with different mechanisms of action. Additionally, alternative treatments are being investigated for patients who do not respond to these drugs, and need to switch to a different class of medication. These developments have the potential to reshape the IBD landscape, as well as the published guidelines.¹¹

While anti-TNFs remain the preferred first-line biologic, recent ECCO guidelines recommend that physicians consider using ‘vedolizumab rather than adalimumab for the induction and maintenance of remission in patients with moderately-to-severely active ulcerative colitis.’³ Therefore, prescribing choices may evolve, particularly when comorbidities need to be taken into account.¹¹ Physicians may adapt their prescribing practices by considering known contraindications and precautions in light of these new recommendations.¹¹

CONSENSUS OUTCOMES OF CLINICAL CONTROVERSIES SURROUNDING ANTI-TNF THERAPIES

In September 2023, the outcomes of an international consensus meeting on ‘Difficult-to-treat inflammatory bowel disease’ were published.⁵ The consensus identified pertinent clinical controversies in the management of IBD with anti-TNF agents, specifically focusing on Crohn’s disease.⁵

The group defined difficult-to-treat IBD as ‘the failure of biologics and advanced small molecules with at least two different mechanisms of action, or postoperative recurrence of Crohn’s disease after two surgical resections in adults, or one in children.’⁵ Chronic antibiotic-refractory pouchitis, complex perianal disease, and comorbid psychosocial complications that impair disease management also qualified as difficult-to-treat IBD.⁵ The experts concluded that these criteria have the potential to standardise reporting, guide enrolment in clinical trials, and aid in identifying candidates for enhanced treatment strategies.⁵

At the ECCO Congress in Copenhagen, Denmark in March 2023, a Delphi consensus was presented on ‘Controversies in the management of anti-TNF therapy in Crohn’s disease patients’.¹² Nine gastroenterologists identified current relevant clinical controversies in the management of Crohn’s disease with anti-TNF therapies. The consensus aimed to consolidate experts’ perspectives when dealing with various clinical scenarios involving patients with Crohn’s disease on anti-TNF treatment. Additionally, the article highlighted the limited evidence available regarding the optimal positioning of agents as first- or second-line therapies, primarily due to the lack of robust head-to-head comparative data.¹²

The consensus identified statements related to the use of first-line non-anti-TNF biologic therapy, particularly in fragile patients with Crohn’s disease. It also addressed the role of HLA-DQA1*05 in daily practice, identifying that testing may help therapeutic decision-making. Furthermore, the consensus identified attitudes towards primary non-response and loss of response to anti-TNF therapy due to immunogenicity. It suggested that ustekinumab or vedolizumab could be viable options in refractory patients to anti-TNFs, especially when considering a change in the mechanism of action. Additional consensus statements covered topics such as anti-TNF drug monitoring during induction, and the consideration of combined therapy with an immunomodulator and anti-TNF monotherapy.

The aim of this consensus was to establish practical and feasible recommendations for the management of patients with moderate-to-severe Crohn’s disease using anti-TNF agents, while addressing the controversial areas of their treatment.¹²

UPCOMING CHANGES TO INFLAMMATORY BOWEL DISEASE TREATMENT GUIDELINES

ECCO is currently reviewing its IBD guidelines, and is expected to complete the process in 2024.^1,2 We anticipate further discussions on these updates and controversies surrounding anti-TNFs at UEG Week 2023, and beyond. The IBD treatment guidelines may incorporate the recent consensus outcomes into future updates.

Anti-TNF therapies have already transformed IBD care by shifting the focus from symptom control to achieving meaningful disease control, including mucosal healing, remission, and improved QoL. However, challenges persist, and ongoing research aims to enhance therapeutic strategies for patients living with IBD. Expert guidelines may consider the recent consensus recommendations for improving future IBD treatment. We eagerly await forthcoming updates, and will keep you informed.

References

1. European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA). What is IBD? Available at: https://efcca.org/content/what-ibd. Last accessed: 20 September 2023.
2. European Crohn’s and Colitis Organisation (ECCO). ECCO Guidelines. Available at: https://www.ecco-ibd.eu/publications/ecco-guidelines-science.html. Last accessed: 20 September 2023.
3. Raine T et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis. 2022;16(1):2-17.
4. Torres J et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2020;14(1):4-22.
5. Parigi et al. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023;8(9):853-9.
6. Fowler Braga SF, Clark KJ. Overview of TNF inhibitors for treating inflammatory bowel disease. US Pharm. 2021;46(5):34-7.
7. Chang S, Hudesman D. First-line biologics or small molecules in inflammatory bowel disease: a practical guide for the clinician. Curr Gastroenterol Rep. 2020;22(2):7.
8. Marsal J et al. Management of non-response and loss of response to anti-tumor necrosis factor therapy in inflammatory bowel disease. Front Med (Lausanne). 2022;9:897936.
9. Humphrey N. The rise of anti-TNF biosimilars: guidelines, real-world evidence, and challenges to acceptance. EMJ Gastroenterol. 2022;11(Suppl 7):2-10.
10. Humphrey N. Safety of anti-TNFs in patients with immune-mediated disease. EMJ Gastroenterol. 2022;1(Suppl 3):2-9.
11. Akbar A et al. Influence of comorbidities on treatment considerations for first-line biologic prescribing in patients with inflammatory bowel disease in the UK. Frontline Gastroenterol. 2022;13(6):490-6.
12. Gonzalez Lama Y et al. P654 controversies in the management of anti-TNF therapy in Crohn’s disease patients. A Delphi consensus. J Crohns Colitis. 2023;17(Suppl 1):i782-3.