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. 2024 Jan;20(1 Suppl 1):3–4.

Anti-TNF

PMCID: PMC10910391  PMID: 38444831

Therapy for inflammatory bowel disease (IBD) requires the consideration of numer-us treatment parameters, including safety vs efficacy; the dose, timing, interval, and duration of administration of multiple drugs; and the costs associated with ongoing treatment.1 With so many variables to consider, optimizing therapy for patients with IBD can be challenging. Currently, 4 anti–tumor necrosis factor (TNF) biologic therapies are available for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC), including certolizumab pegol, adalimumab, golimumab, and infliximab (Figure 1). Despite the availability of traditional drugs and newer biologics, primary and secondary nonresponse remains a problem, as disease duration is associated with increased failure to respond to therapy.2,3 One approach to improve outcomes is prioritizing early initiation of anti-TNF therapy.4 When a patient presents with moderately to severely active CD, starting anti-TNF therapy as soon as possible yields superior disease control compared with initial treatment comprising 5-aminosalicylates, corticosteroids, and/or immunosuppressive therapy. Similarly, induction therapy with an anti-TNF biologic is more likely to achieve clinical remission in patients with early IBD than in patients with late IBD.5

Figure 1.

Figure 1.

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The 4 anti-TNF biologic therapies available for the treatment of Crohn’s disease and ulcerative colitis.

Fab, fragment, antigen binding; Fc, fragment, crystallizable; TNF, tumor necrosis factor.

Adapted from Rubin et al. Anti-TNF. Presented at the Advances in Inflammatory Bowel Disease Conference; Orlando, Florida; December 14-16, 2023.1

The development of antidrug antibodies presents a challenge to the use of biologic therapy. Episodic therapy increases the risk of developing antidrug antibodies and may be unintentional, owing to a loss of insurance coverage or the development of complications. Patients who achieve subtherapeutic serum levels of drugs and patients who experience complete drug clearance between doses are also at risk. Further, patients who have already developed anti-TNF antibodies are more likely to develop antibodies to a second anti-TNF therapy, and patients with a specific haplotype may be at higher risk as well.6,7 Other risk factors for the development of antidrug antibodies to monoclonal antibody therapy include male sex, increased body mass index, a high baseline level of C-reactive protein (CRP), smoking, and others.8-10

Patients with IBD and a high amount of visceral adipose tissue (VAT) have shown a reduced response to anti-TNF therapy.11,12 A prospective study evaluated 141 patients with IBD who were starting therapy with infliximab, vedolizumab, or ustekinumab vs 51 healthy controls.13 Patients with higher intra-abdominal VAT as a percentage of total body weight were less likely to achieve corticosteroid-free deep remission (P<.001) or endoscopic remission (P=.02) compared with patients who had a lower proportion of intra-abdominal VAT. Patients with a higher proportion of intra-abdominal VAT who failed to respond to treatment demonstrated a higher level of serum interleukin-6 (IL-6) and TNF at baseline compared with patients who exhibited a response or patients with a low proportion of intra-abdominal VAT. Increasing the dose level may improve outcomes; however, the data are equivocal.

Targeting TNF remains a mainstay of treatment for CD and UC, in particular for patients with fistulizing disease or extraintestinal manifestations. Advances in anti-TNF therapy include the availability of subcutaneous infliximab, which affords higher and more stable blood levels and another option for therapeutic delivery. Biosimilars to infliximab and adalimumab should eventually improve the pharmacoeconomics of advanced therapy for IBD.

– Stephen B. Hanauer, MD

Patients’ disease status should be routinely assessed by ultrasound, endoscopy, levels of CRP and fecal calprotectin, as well as serum levels of anti-TNF drug and antidrug antibodies.14 For patients who exhibit a partial or limited response to therapy, recapture of response may be possible by administration of a small loading dose, followed by decreasing the interval or increasing the drug dose. Other parameters to check include the presence of antidrug antibodies and the level of drug in the patient’s serum. Patients with a poor response and a therapeutic level of drug in the serum most likely require a different therapy, which may comprise changing to a different drug within the same class or switching to a drug with a different mechanism of action.

Therapeutic drug monitoring (TDM) is an active area of research for optimizing anti-TNF biologic therapy for patients with IBD. Some studies have suggested that proactive TDM and the associated dose adjustments may improve outcomes. For example, a retrospective observational study evaluated proactive TDM and adjusting the dose of infliximab to a target concentration in 48 patients with IBD who were in clinical remission.15 The initial trough concentration was undetectable in 15% of patients. After the first proactive measurement of drug level, the dose of infliximab was escalated in 12 patients (25%) and was decreased in 7 patients (15%) throughout the study. Patients with proactive dose adjustments based on proactive TDM were more likely to remain on infliximab compared with controls (HR, 0.3; 95% CI, 0.1-0.6; P=.0006). More recently, the NORDRUM B study evaluated the use of proactive TDM with infliximab during maintenance therapy.16 The parallel-group, open-label trial included 458 patients with CD, UC, and other diseases such as rheumatoid arthritis and psoriasis. Patients were evenly randomized to receive infliximab based on standard dosing or with dose adjustments based on proactive TDM. Patients had a mean age of 44.8 years and nearly one-half of patients were female. The trial met its primary endpoint, demonstrating sustained disease control without disease worsening in 167 patients (64%) in the proactive TDM arm vs 127 patients (56%) in the standard therapy arm, with an adjusted difference of 17.6% (95% CI, 9.0-26.2; P<.001) that favored proactive TDM and dose adjustment. The study showed a benefit with proactive TDM among patients with UC but not among patients with CD.

References

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