Optimal Timing of Anti-TNF Therapy for Inflammatory Bowel Disease - European Medical Journal

Optimal Timing of Anti-TNF Therapy for Inflammatory Bowel Disease

6 Mins
Gastroenterology

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.

Inflammatory bowel disease (IBD) is a chronic inflammation primarily affecting the gut, with Crohn’s disease and ulcerative colitis representing the two main clinical forms. Over the past two decades, a greater understanding of the multiple signalling pathways involved in IBD has led to the development of biological therapies. These therapies have transformed the trajectory of IBD treatment.

It is important to note that, despite these advancements, there is no definitive cure. Some therapies may lead to adverse events, limiting their use, or result in an inadequate response in some patients.1 However, biological therapies have enabled the treat-to-target strategy, which aims to control inflammation and manage the disease, ultimately improving patient outcomes.1

Today, well-established biological therapeutic targets in the pathogenesis of Crohn’s disease and ulcerative colitis include anti-TNFs, such as adalimumab, infliximab, and golimumab. Additionally, anti-TNF biosimilars are also available for use.2 These anti-TNFs target TNF-α, a pro-inflammatory cytokine associated in both IBD and rheumatological conditions, downregulating the inflammatory cascade.

Several studies have demonstrated the efficacy and acceptable safety profiles,2 particularly for both steroid-sparing or, in the cases of unresponsive to conventional treatments, such as anti-inflammatory 5-aminosalicylates, corticosteroids, or immunomodulators.3,4 The availability of biosimilars has also led to a significant reduction in pharmacological expenditure, making anti-TNFs widely accessible.2

Despite considerable progress, there remains an area of unmet need, such as in cases where the therapeutic response is insufficient.2

Guidelines, while offering an evidence-based approach to integrating therapies into routine practice, are often unable to provide timely recommendations as new therapies emerge. Moreover, their incorporation of real-world evidence when making recommendations is also limited.5

In January 2024, a recent Delphi consensus paper presented key recommendations from gastroenterology experts for the early use of anti-TNF therapy in patients with IBD.6 This consensus provides valuable insights into the recommendations for initiating, optimising, and maintaining IBD treatment.6

CURRENT USE OF ANTI-TNFS FOR INFLAMMATORY BOWEL DISEASE

Anti-TNFs currently stand as the preferred first-line biological therapy for moderate-to-severe IBD, driven by the licensing of anti-TNF biosimilars and clinical experience. One challenge faced by healthcare professionals involves encouraging them to move away from habitual prescribing practices. 7 This challenge persists, despite emerging evidence supporting alternative treatment strategies, and the reduction in treatment costs due to increased competition and the introduction of biosimilars.7

Furthermore, guidelines regarding the introduction and monitoring of anti-TNF therapy in the context of IBD are limited. In Europe, the treatment approach for moderate-to-severe IBD in adults generally adheres to a “step-up” approach. This involves introducing biologics like anti-TNFs after the failure of first-line treatments, such as anti-inflammatory 5-aminosalicylates, corticosteroids, or immunomodulators.3,4 Conversely, in the USA, the guidelines for ulcerative colitis advocate for an early top-down approach.8

EXPERT CONSENSUS ON THE TIMING OF ANTI-TNF FOR INFLAMMATORY BOWEL DISEASE

Given the rapid evolution of IBD treatment options, including anti-TNF agents that improve deep clinical and endoscopic remission, criticism directed at current guidelines has arisen. This criticism deemed guidelines as insufficient in addressing the timing, optimisation, or maintenance of anti-TNF therapy for patients with Crohn’s disease and ulcerative colitis.6

A recent study, published in December 2023, which analysed real-world data from a large nationwide UK database, identified that current guidelines for treatment decisions – particularly considering primary versus non-primary non-response following failure to an anti-TNF, where patients experience failure due to delayed loss of response or intolerance – show superior outcomes when patients switch to a non-anti-TNF, rather than a second anti-TNF.7

The recent Delphi consensus, a process aimed at achieving agreement among experts in areas such as creating clinical guidelines, definitions, or recommendations, emphasises crucial gaps in international guidelines for IBD.6 While these guidelines typically focus on which drug therapy to use, they lack precise indications regarding the timing of use. As real-life experience with anti-TNF therapy grows, questions regarding the optimal timing of introduction, optimisation, and maintenance become increasingly critical.

For this consensus, a scientific board of gastroenterologists gathered expert opinions from 61 international healthcare professionals specialising in IBD management, following the Delphi method.6 The consensus identified agreement across 16 statements, with seven related to the introduction and optimisation of Crohn’s disease, four related to the introduction and optimisation in ulcerative colitis, and an additional five considering the maintenance across both diseases.6

Expert Consensus on Early Introduction of Anti-TNF

For Crohn’s disease, the experts unanimously agreed (defined as >85% of respondents indicating on a Likert scale from 1–9, where 9 equalled maximum agreement), that early introduction of anti-TNF (i.e., within less than 24 months), is the most effective therapy for complex perianal Crohn’s disease, and steroid refractoriness in both Crohn’s disease and ulcerative colitis.6 Early introduction is also advisable for severe rectal Crohn’s disease, severe colonic ulcerations, and extensive small bowel involvement.6 This agreement extended to the introduction of anti-TNF in the presence of axial spondyloarthritis or peripheral spondyloarthritis, and extra-intestinal manifestations refractory to conventional therapies, in both Crohn’s disease and ulcerative colitis.6

The Delphi consensus also agreed that in patients with IBD, reintroduction of anti-TNF therapy is acceptable after a drug holiday of less than 6 months, provided there is evidence of relapse in disease activity demonstrated by clinical or laboratory results.6 The experts also endorsed clinical and laboratory monitoring every 3 months.6 In cases where inflammatory markers persist or worsen, this monitoring triggers the optimisation of anti-TNF treatment for the maintenance of Crohn’s disease. 6 However, there was weak agreement concerning ulcerative colitis.6

Overall, the consensus among the expert panel is the early use of anti-TNF therapy for patients with Crohn’s disease and ulcerative colitis. This Delphi paper provides additional insights into the introduction, optimisation, and maintenance of treatment for patients with IBD.6 However, the panel had differing opinions on when to stop anti-TNF treatment, due to ongoing research on healing markers and their prognostic meaning, as well as the addition of immunomodulators.

Recognising the Impact of Anti-TNF on Rheumatic Extra-Intestinal Manifestations in Inflammatory Bowel Disease

Of note, extra-intestinal manifestations have gained recognition for their intricate relationship with IBD and other conditions, such as rheumatic manifestations. Hence, selecting the most suitable treatment for a particular patient can be challenging, particularly when extra-intestinal manifestations are present. However, given that biologics such as anti-TNFs target comparable immune pathways implicated in both IBD and rheumatological conditions, these therapies offer a comprehensive option for multimorbidity management. This is of importance, given that 20–40% of patients with IBD have rheumatic manifestations.9 A recent systematic review, published in September 2023, has highlighted the importance of holistic treatment approaches for managing complex medical scenarios, underscoring the efficacy of anti-TNF and other biologic agents in alleviating rheumatic symptoms in patients with IBD, and therefore transforming patient care.9

Use of Anti-TNF Biosimilars in Crohn’s Disease and Ulcerative Colitis

In recent times, the healthcare market has witnessed the approval of multiple anti-TNF biosimilars. These biosimilars offer cost-effective alternatives to reference products that have similar efficacy on IBD activity. The experts suggest that anti-TNF biosimilars are cost-effective for both ulcerative colitis and Crohn’s disease.6 They recommend the early use of anti-TNFs, and, given the cost-efficient profile of anti-TNF biosimilars, they provide an opportunity to increase access to biologic therapy.6 This makes them a first-line option for a significant proportion of patients with IBD, thus increasing the accessibility of this class of drugs.

Recent Insights on Anti-TNF Dosage and Timing During Pregnancy

Another perspective that the Delphi consensus did not address was the optimal timing for the last dose of anti-TNF agents in pregnant females with IBD, and the time it takes for anti-TNF agent-exposed infants to eliminate the agents from their bodies. Currently, there is limited scientific evidence on the dosage recommendations for pregnancy. However, a study published in August 2023 presented a pregnant macromolecule physiologically-based pharmacokinetic model to predict the amount of anti-TNF exposure in both the female and the fetus.10 This study provides a recommended dose and withdrawal timing during pregnancy, as well as vaccination timing based on the dosage regimen.10 Such research may help in the development of guidelines for the optimal dose and timing of dosing for anti-TNFs, such as infliximab, adalimumab, and golimumab, during pregnancy, as well as the recommended timing for vaccination. The findings of this study provide valuable insights into the development of a safe and effective clinical dosing regimen for pregnant females and their infants in the near future.10

IMPLICATIONS FOR FUTURE PRACTICES AND GUIDELINES FOR INFLAMMATORY BOWEL DISEASE

A recent review and position statement, published in November 2023, provides a detailed consideration of how to integrate current evidence, such as randomised clinical trials and real-world data, and how this aligns with the medial therapy positioning.5 The authors suggest that standard guidelines could use a “living guideline” approach, which optimises the process of standard guidelines, to allow for updates of individual recommendations as soon as evidence becomes available. This will provide relevant stakeholders and decision-makers with information in a more timely manner, especially in a world of rapidly evolving evidence and medical advances.5

It is expected that the future practices and guidelines for IBD will be more personalised and targeted, focusing on early intervention and optimised treatment. Early intervention emphasises the importance of selecting the most appropriate therapy early on, in order to avoid the use of steroids, or enable early steroid-sparing. These implications suggest a shift towards a more personalised, proactive, and evidence-based approach to IBD management. However, further research is needed to refine these practices and guidelines.1

References

  1. Bretto E et al. Inflammatory bowel disease: emerging therapies and future treatment strategies. Biomedicines. 2023;11(8):2249.
  2. Leone GM et al. Past, present and (foreseeable) future of biological anti-TNF alpha therapy.J Clin Med. 2023;12(4):1630.
  3. Torres J et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2020;14(1):4-22.
  4. Raine T et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis. 2022;16(1):2-17.
  5. Dulai PS et al. Integrating evidence to guide use of biologics and small molecules for inflammatory bowel diseases. 2023:S0016-5085(23)05228-9.
  6. Ardizzone S et al. Timing of proper introduction, optimization and maintenance of anti-TNF therapy in IBD: results from a Delphi consensus.Dig Liver Dis. 2024;56(1):98-105.
  7. Kapizioni C et al.; UK IBD BioResource Investigators.Biologic therapy for inflammatory bowel disease: real-world comparative effectiveness and impact of drug sequencing in 13,222 patients within the UK IBD BioResource. J Crohns Colitis. 2023:jjad203.
  8. Singh S et al.AGA technical review on the management of moderate to severe ulcerative colitis. 2020;158(5):1465-96.e17.
  9. Nag A et al. Role of biologic therapies in the rheumatic manifestations of inflammatory bowel disease: a systematic analysis. 2023;15(9):e45195.
  10. Chen J et al. Physiologically-based pharmacokinetic modeling of anti-tumor necrosis factor agents for inflammatory bowel disease patients to predict the withdrawal time in pregnancy and vaccine time in infants.Clin Pharmacol Ther. 2023;114(6):1254-63.

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