Immunomodulatory Agents for Treatment of Patients with Inflammatory Bowel Disease (Review safety of anti-TNF, Anti-Integrin, Anti IL-12/23, JAK Inhibition, Sphingosine 1-Phosphate Receptor Modulator, Azathioprine / 6-MP and Methotrexate)

Abstract

Purpose of the ReviewAs treatment options for Inflammatory Bowel Disease (IBD) expand each class of medication will have specific safety concerns and side-effect profiles that need to be considered for optimal treatment of patients. We will review the most recent safety data for the newly approved immunomodulator therapies for the treatment of IBD. Recent Findings There are a growing number of publications outlining safety concerns for medications used to treat IBD. We reviewed safety profile of anti-tumor necrosis factor antibodies (TNF) with specific attention to combination therapy (anti-TNF plus immunomodulator). Recent publications have demonstrated increased risk of serious infection and malignancy (lymphoma and overall cancer rates) in patients receiving anti-TNF combination therapy when compared with patients receiving anti-TNF monotherapy or immunomodulator monotherapy. Recent publications on Janus Kinase Inhibitors indicate an increased risk of infection, specifically Herpes Zoster, and increased risk of major cardiovascular events and venous thromboembolic events resulting in a black box warning for the medication. In contrast, anti-interleukin 12/23 agents and gut selective anti-integrin antibody agents have demonstrated a favorable side-effect profile with low rates of infection and malignancy. The latest class of medications to be approved, sphingosine 1-phosphate (S1P) receptor modulators, have cardiac and infectious precautions. Summary The field of IBD treatment is rapidly evolving with several mechanistic classes of medications now available. While corticosteroids continue to be associated with the greatest, overall, safety risks, each of the newer mechanistic classes have unique safety concerns. In the future, as we gain more experience with these agents, we will need to continue to evaluate the safety profile of our therapies used alone or in combination to make informed treatment decisions with our patients.

Managing IBD in patients with previous cancers

“…A large study of patients with previous cancer and RA, IBD or psoriasis involving over 11 000 patients with 31 000 person-years follow-up found no increased risk of cancer recurrence comparing anti-TNF, conventional immunosuppression and no immunosuppression other than an increase in NMSC in patients receiving thiopurines 57. As discussed previously, recent data do appear to be broadly supportive that anti-TNF therapy and the newer biologics do not appear to be associated with an increased risk of new or recurrent cancer in IBD 31. Evidence emerging since the ECCO drug holiday guidance suggests it may be unnecessarily conservative, especially when considering the risk of not treating IBD effectively.…”

“…When used in combination with thiopurines, there is an increased lymphoma risk,28 with hepatosplenic T-cell lymphoma distinctly associated with this combination 29. Initial reports of increased risk of melanoma have not been confirmed in meta-analysis,30 and overall malignancy does not appear to be associated with anti-TNF monotherapy 31…”

Plasmablastic lymphoma occurring in ulcerative colitis during treatment with immunosuppressive therapy

“…It is also suggested that among patients with a history of malignancy that do not respond to 5-aminosalicylic acid and local corticosteroids, the use of anti-TNF antagonists and systemic corticosteroids should be considered [ 36 ]. There are no reports showing that ustekinumab increased the risk of malignancy in IBD [ 37 ]. We considered that biologics may have an influence on the progression of lymphoma and cessation of azathiopurine and ustekinumab administration along with continued prednisolone administration can control UC.…”

Integrin Regulated Autoimmune Disorders: Understanding the Role of Mechanical Force in Autoimmunity

“…Natalizumab, vedolizumab, and lifitegrast are well-known anti-integrin therapeutics used in AD treatments such as Crohn's disease and MS (Park and Jeen, 2018;Slack et al, 2022). Unlike broad immune inhibitors such as corticosteroids and TNF inhibitors, anti-integrin therapeutics possess reduced risk factors (Sattler et al, 2021). Glucocorticoids, a class of corticosteroids, can act against autoimmune conditions by interfering with the function of L-selectin and LFA-1, thereby reducing the neutrophil transendothelial migration (Filep et al, 1997).…”