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Inflammatory bowel disease, or IBD, is a chronic, relapsing, remitting, dysregulated inflammation of the GI tract due  to genetic susceptibility, environmental influences, inflammatory catalysts, and microbiome-related factors.

The inflammatory cytokines tumor necrosis factor (TNF) and interleukin 12 and 23, cell adhesion molecules called integrins, and Janus kinases involved in cytokine signaling are key mediators of the inflammatory process of IBD. [Braga/p2/par 3]

In this video, we will review the pivotal role of TNF-alpha  in IBD and the therapeutic role of TNF-alpha inhibitors in its treatment.

In IBD, excessive TNF levels amplify the immune response, producing chronic inflammation in the GI tract , which results in the hallmark features of IBD.

Selectively inhibiting TNF-alpha can mitigate these inflammatory processes, minimizing continued damage and in fact potentially leading to mucosal healing.

Mechanism of Action of TNF-alpha Inhibitors in IBD

TNF-alpha inhibitors are antibody-based agents that bind to TNF-alpha, preventing it from interacting with receptors on the surfaces of immune cells.

The resulting interruption of the TNF-alpha signaling prevents the activation of immune cells – including macrophages and T cells – reducing their ability to produce and activate proinflammatory cytokines, interleukins, chemokines, and other mediators of immunity that contribute to inflammation when activated in excess.

Four monoclonal antibodies for TNF-alpha have been approved for patients with patients with IBD: infliximab, adalimumab, golimumab, and certolizumab pegol.

These agents differ in important ways.

Infliximab is a chimeric monoclonal antibody (25% murine, 75% human) indicated for adults and children with moderate to severe Crohn’s disease or ulcerative colitis who do not respond to conventional therapies  .

Adalimumab is a fully human monoclonal antibody indicated for adults and children with Crohn’s disease or ulcerative colitis, independent of response to conventional  therapies.

A second fully human monoclonal antibody, golimumab, is indicated for adults with moderate to severe ulcerative colitis who do not respond  adequately to, are unable to tolerate prior treatment, or require continuous steroid treatment.

The 4th agent, certolizumab pegol, is formulated from the Fab’ fragment of a fully human monoclonal antibody. The Fab’ fragment is responsible for the proinflammatory activity of TNF-alpha.

Certolizumab does not include the Fc antibody fragment responsible for the cytotoxic effects of TNF-alpha.

Certolizumab pegol is indicated for adults with moderate to severe Crohn’s   disease who do not respond to conventional therapies.

Infliximab is administered intravenously in a doctor’s office every 8 weeks after induction doses at Weeks  0, 2, and 6.

Adalimumab, golimumab, and certolizumab pegol can be self-administered subcutaneously every 2-4 weeks after 2 or 3 induction doses.

Many patients with ulcerative colitis or Crohn’s  disease achieve long-lasting relief or remission of symptoms on an anti–TNF-alpha agent.

In clinical trials, infliximab has proven highly  effective compared with placebo for induction of remission in patients with Crohn’s disease.

Infliximab and adalimumab have shown similar efficacy in maintaining remission, with lower risk reductions as both induction and maintenance therapy seen with certolizumab pegol. 

All 3 anti–TNF-alpha agents approved for the management of ulcerative colitis have shown efficacy for induction and maintenance of remission versus placebo.

As in Crohn’s disease, the highest remission  rates were seen with infliximab.

The efficacy results for anti–TNF-alpha drugs are not without caveats.

Up to two-thirds of patients treated successfully with anti–TNF-alpha drugs eventually develop immunogenicity that diminishes response over time.

Though highly effective, infliximab has been associated with the highest risk of antibodies against it forming.

Common adverse events with TNF-alpha inhibitors include reactions associated with immunosuppression, most notably an increased risk of infections.

Other common adverse reactions include headaches, rashes, and gastrointestinal symptoms.

Infusion-related reactions have been reported with infliximab, including vomiting  , fever, headache, and hypotension.

Injection site reactions have been reported with subcutaneous adalimumab, golimumab, and certolizumab pegol.

The package insert for each TNF-alpha inhibitor includes a black box warning for serious infections (TB, bacterial sepsis, invasive fungal infection, and opportunistic infections) and an increased risk of lymphoma and other malignancies.

Based on the most recent data, 2021 American Gastrointestinal Association (AGA) guidelines recommend infliximab and adalimumab (but not certolizumab pegol, despite its approval status) for inducing and maintaining remission in moderate to severe Crohn’s disease.

AGA guidelines also support an interleukin inhibitor or integrin receptor antagonist for induction but not for maintenance therapy.

Infliximab is the preferred anti–TNF agent in patients with active fistulas.

2020 AGA guidelines for the management of moderate to severe UC in adults recommend the anti-TNF-alpha drugs infliximab, adalimumab, or golimumab or an interleukin inhibitor 12/23 inhibitor – preferably with an immunomodulator.

Infliximab is a preferred anti–TNF-alpha drug in hospitalized patients with acute severe ulcerative colitis.

Efforts to optimize TNF-alpha inhibitor therapy in IBD include earlier intervention, therapeutic drug monitoring to facilitate timely treatment adjustments, and switching between TNF-alpha–blocking agents or drug classes in the face of primary nonresponse or loss of response over time.