The role and advances of immunomodulator therapy for inflammatory bowel disease

Abstract

Immune modulating drugs such as thiopurines (azathioprine and 6-mercaptopurine) and methotrexate has been a mainstay for treatment of inflammatory bowel disease (IBD) for decades. However, despite widely used in IBD, questions still remain concerning the most rational treatment regimens of these agents. Results from a range of recent studies necessitate increased awareness on how to best use these potent drugs in the clinic. As controversy still remains regarding the most appropriate use of immunomodulators, this review is based on scrutinizing the current literature, with emphasis on randomized controlled trials and Cochrane reviews, focusing on aspects that can lead to optimal and evidence-based thiopurine and methotrexate treatment strategies in IBD.

Keywords:

• 6-mercaptopurine
• azathioprine
• Crohn’s disease
• inflammatory bowel disease
• methotrexate
• therapy
• ulcerative colitis

Author’s contributions

Nielsen O drafted the first manuscript version, and Coskun M, Steenholdt C and Rogler G critically revised it and helped creating the figures. All authors read and approved the final manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

Immunomodulators are widely used in the treatment of steroid-dependent or steroid-refractory inflammatory bowel disease (IBD) – both as monotherapy and in combination with biologic agents.

Based on the current review, it is concluded that in IBD:

• Thiopurines can be used to reduce relapse rates in quiescent Crohn’s disease or ulcerative colitis, but has no indication as first-line treatment of acute disease flares.

• Patients intolerant to thiopurine monotherapy may be considered for combination treatment with low-dose thiopurine combined with allopurinol, particularly among those who develop hepatotoxic side effects.

• Methotrexate administered intramuscularly/subcutaneously is effective at inducing remission (should be bridged by glucocorticoids) as well as preventing relapse in Crohn’s disease, and has no role in the treatment of disease flares.

• Depending on disease severity, steroid-refractory or steroid-dependent patients with IBD may favorably be treated with combination therapy of thiopurines (or possibly methotrexate) and a TNF inhibitor.

• Thiopurine treatment increases the risk of non-melanoma skin cancer and patients should be regularly monitored by dermatological specialists and advised to use sun protection.

• Prospective randomized controlled trials on the effects of concomitant treatment with thiopurines and TNF inhibitors at an early point versus sequential addition of thiopurines or biologics in patients experiencing a suboptimal benefit from monotherapy are discussed.

• The optimal length of treatment with immunomodulators taking into account risks of side effects needs to be identified.

• Algorithms for optimal individualized dosing of thiopurines, including combination with allopurinol from genetic and metabolite testing are warranted.

Notes