Systematic Review With Meta-analysis

The Effects of Immunomodulator or Biological Withdrawal From Mono- or Combination Therapy in Inflammatory Bowel Disease

Dóra Dohos; Lilla Hanák; Zsolt Szakács; Szabolcs Kiss; Andrea Párniczky; Bálint Erőss; Piroska Pázmány; Péter Hegyi; Patrícia Sarlós

Disclosures

Aliment Pharmacol Ther. 2021;53(2):220-233. 

In This Article

Abstract and Introduction

Abstract

Background: Withdrawal of treatment is a common therapeutic problem in patients with long-standing remission of inflammatory bowel disease.

Aims: To evaluate the relapse rate in patients with quiescent inflammatory bowel disease after cessation of biologic or immunomodulator therapy.

Methods: We searched five databases for studies evaluating disease relapse after withdrawal of monotherapy or a drug from combination therapy in Crohn's disease or ulcerative colitis. In meta-analysis, risk ratios (RR) were calculated with 95% confidence intervals (CI).

Results: Ten randomised controlled trials (587 patients) were included in the meta-analysis, and another nine studies in systematic review. Withdrawal of immunomodulator monotherapy resulted in a significantly higher risk of relapse within 24 months of follow-up compared to ongoing therapy in Crohn's disease, but not in ulcerative colitis (RR = 2.06, CI: 1.53–2.77 and RR = 1.39, CI: 0.85–2.26, respectively). Trial sequential analysis indicated that further studies with similar design are unlikely to change the significant association on relapse rates after withdrawing immunomodulator monotherapy in patients with Crohn's disease. Discontinuation of an immunomodulator from combination with biologics did not show a higher risk of relapse than continuation of both drugs (RR = 1.30, CI: 0.81–2.08). The relapse rate increased after withdrawal of biologic monotherapy, whereas contradictory results were observed after biologic withdrawal from combination regimens.

Conclusion: Continuing immunomodulator monotherapy should remain the preferred approach among patients with Crohn's disease, although long-term toxicity is a concern. Further randomised controlled trials are warranted in ulcerative colitis and on combination regimens including biologics.

Introduction

Inflammatory bowel disease (IBD)—comprising Crohn's disease (CD) and ulcerative colitis (UC), as the two main types—is chronic condition of the gastrointestinal tract with a relapsing and remitting pattern. CD is characterised by transmural inflammation and the chance of stricture development at any segment of the gastrointestinal tract.[1] CD is more likely to be associated with disease-related complications (eg abscesses, strictures) and extraintestinal manifestations than UC.[2] Although UC is a superficial mucosal inflammation of the colon, it can also cause several complications, such as fulminant colitis and increased risk of colorectal cancer.[3] The risk of surgery 1, 5 and 10 years after diagnosis of CD was 16.3%, 33.3% and 46.6%, while that in UC is 4.9%, 11.6% and 15.6% respectively.[4]

The therapeutic regimen of CD and UC bears several similarities. Medical treatments include 5-aminosalicylates for UC, and corticosteroids immunomodulators (IM, eg azathioprine, methotrexate or mercaptopurine) for both UC and CD. Biologic therapies have been available for more than 20 years to provide patients with moderate-to-severe disease with the best therapeutic option for the induction and maintenance of remission.[5,6] In clinical practice, three major classes of biologics are approved for IBD: tumour necrosis factor (TNF) alpha antagonists, integrin and interleukin-12/23 antagonists.[7] In addition to the assessment of the severity and activity of the disease, and to risk stratification, the optimal treatment decision involves individual and financial considerations.[8,9] The lifetime treatment strategy focuses not only on the induction and maintenance of remission but also on complete mucosal healing to prevent complications of the disease. Treatment with IMs and biologics improves the quality of life, reduces corticosteroid requirements and its consequences, but toxicity may occur.[10] When treated with IMs or biologics, moreover, with the combination of both agents, serious concern exists about opportunistic infections (eg tuberculosis, histoplasmosis). Studies of the CESAME cohort have highlighted the risks and consequences of IMs concerning the increased risk of lymphoproliferative, skin and urinary tract malignancies.[11–14]

Despite the consensus and guidelines for remission maintenance IBD therapies, our knowledge of withdrawing effective therapies in remission is uncertain.[15] Several rationales for stopping treatment exist, such as reducing total health care costs, adverse events (AE) or serious adverse events (SAE), and patient-specific factors are also considered (eg adherence to treatment, life events [pregnancy, breastfeeding], long-lasting remission).[7]

Recently, The European Crohn's and Colitis Organisation published a consensus on stopping treatment, called 'exit strategy'.[15] In UC patients with mild clinical course and complete mucosal healing, dose reduction in 5-aminosalicylates can be considered but 5-aminosalicylates should be continued in the long term to reduce the risk of relapse and colorectal cancer.[15] In the case of IM monotherapy in CD, an early cohort study found a similar relapse rate after 4 years in remission, regardless of whether IM therapy was continued or not.[16] In CD, recent randomised controlled trials (RCTs) and observational studies with different follow-up periods showed an increased relapse rate after IM withdrawal.[17–24] Unfortunately, fewer studies were performed in UC than in CD.[25,26] In three RCTs, IM withdrawal in CD patients treated in combination with biologic therapy resulted in a similar relapse rate compared to that of continued combination therapy.[27–29] In a recent meta-analysis, the overall risk of relapse after anti-TNF withdrawal was 30%-40% at 1 year, and 50% at 2 years, but there is a lack of controlled, high-quality studies in this area.[30]

The aims of the present study were to systematically review and meta-analyse the efficacy and safety of discontinuation of IMs or biologics in both UC and CD.

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