Intestinal Research

Review

IBD

Use of thiopurines in inflammatory bowel disease: an update: Arshdeep Singh, Ramit Mahajan, Saurabh Kedia, Amit Kumar Dutta, Abhinav Anand, Charles N. Bernstein, Devendra Desai, C. Ganesh Pai, Govind Makharia, Harsh Vardhan Tevethia, Joyce WY Mak, Kirandeep Kaur, Kiran Peddi, Mukesh Kumar Ranjan, Perttu Arkkila, Rakesh Kochhar, Rupa Banerjee, Saroj Kant Sinha, Siew Chien Ng, Stephen Hanauer, Suhang Verma, Usha Dutta, Vandana Midha, Varun Mehta, Vineet Ahuja, Ajit Sood; Intest Res 2022;20(1):11-30. Published online April 15, 2021; DOI: https://doi.org/10.5217/ir.2020.00155

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.

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Original Article

IBD

Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study: Ramit Mahajan, Arshdeep Singh, Saurabh Kedia, Kirandeep Kaur, Vandana Midha, Pabitra Sahu, Varun Mehta, Dharmatma Singh, Namita Bansal, Khushdeep Dharni, Sandeep Kaushal, Vineet Ahuja, Ajit Sood; Intest Res 2022;20(1):64-71. Published online February 3, 2021; DOI: https://doi.org/10.5217/ir.2020.00100

Abstract PDF PubReader ePub

Background/Aims
Infliximab (IFX) has been used to induce and maintain remission in patients with severe steroid-refractory ulcerative colitis (UC). Long-term use of biologics in developing countries is limited by high cost and frequent side effects. An optimal maintenance strategy in these patients needs to be established.
Methods
A retrospective analysis of maintenance of clinical remission with combination of azathioprine (AZA) and 5-aminosalicylates (5-ASA) in patients with severe steroidrefractory UC where IFX (5 mg/kg intravenously at weeks 0, 2, 6) had been used only as an induction therapy was done at 2 centers in India. Primary outcome was the proportion of patients maintaining corticosteroid-free sustained clinical remission (SCR) at the end of study period. Rates of relapse and cost of therapy were also analyzed.
Results
Of the 137 patients who received rescue IFX induction therapy, 77 (56.2%) achieved clinical remission (mean age 34.81 ± 13.32 years, 68.83% males, median follow-up 4 years, range 3 months to 6 years) and were included. Cumulative corticosteroid-free SCR was maintained in 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively. Sixty-seven relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, one required colectomy, whereas all other responded to repeat course(s) of corticosteroids. Annual per capita maintenance therapy with 5-ASA and AZA was cheaper by US$ 4,526 compared to maintaining remission with IFX.
Conclusions
Clinical remission achieved with IFX induction therapy in severe steroid-refractory UC can be sustained over long time with a combination of AZA and 5-ASA.

Citations

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Gastroenterology, Hepatology and Endoscopy Practice.2023; 3(4): 127. CrossRef
Advancements in the Management of Moderate-to-Severe Ulcerative Colitis: A Revised 2023 Korean Treatment Guidelines
Soo-Young Na
The Korean Journal of Medicine.2023; 98(5): 223. CrossRef
Effectiveness and Safety of Golimumab in Patients with Ulcerative Colitis: A Multicenter, Prospective, Postmarketing Surveillance Study
Jongwook Yu, Soo Jung Park, Hyung Wook Kim, Yun Jeong Lim, Jihye Park, Jae Myung Cha, Byong Duk Ye, Tae Oh Kim, Hyun-Soo Kim, Hyun Seok Lee, Su Young Jung, Youngdoe Kim, Chang Hwan Choi
Gut and Liver.2022; 16(5): 764. CrossRef
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Alexander Keith Turbayne, Miles Patrick Sparrow
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Identifying Care Challenges as Opportunities for Research and Education in Inflammatory Bowel Disease in South Asia
Madhura Balasubramaniam, Neilanjan Nandi, Tina Aswani-Omprakash, Shaji Sebastian, Vishal Sharma, Parakkal Deepak, Shrinivas Bishu, Neha D. Shah, Sumit Bhatia, Tauseef Ali, Sharan Khela, Kiran Peddi
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Yehyun Park, Chang Hwan Choi, Hyun Soo Kim, Hee Seok Moon, Do Hyun Kim, Jin Ju Kim, Dennis Teng, Dong Il Park
Intestinal Research.2022; 20(4): 452. CrossRef
Identifying Care Challenges as Opportunities for Research and Education in Inflammatory Bowel Disease in South Asia
Madhura Balasubramaniam, Neilanjan Nandi, Tina Aswani-Omprakash, Shaji Sebastian, Vishal Sharma, Parakkal Deepak, Shrinivas Bishu, Neha D. Shah, Sumit Bhatia, Tauseef Ali, Sharan Khela, Kiran Peddi
Clinical Gastroenterology and Hepatology.2022; 20(11): 2421. CrossRef
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Ji Young Chang, Jae Hee Cheon
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Case Report

IBD

Non-cirrhotic portal hypertension related to azathioprine therapy in a patient with Crohn’s disease: Jong Won Seo, Eun Soo Kim, Man-Hoon Han, Young Oh Kweon; Intest Res 2021;19(2):247-251. Published online July 2, 2020; DOI: https://doi.org/10.5217/ir.2020.00016

Abstract PDF PubReader ePub

Azathioprine is widely used for the treatment of Crohn’s disease (CD). Few cases from Western countries have reported idiopathic non-cirrhotic portal hypertension (NCPH) related to thiopurine therapy in patients with inflammatory bowel disease. Idiopathic NCPH is a rare hepatic condition with intrahepatic portal hypertension but no evidence of cirrhosis or chronic liver disease. Patients with idiopathic NCPH present with symptoms of portal hypertension such as thrombocytopenia, splenomegaly and esophageal varices. We report a case of idiopathic NCPH in a 51-year-old male patient with CD who had been taking azathioprine for 5 years. He was admitted due to esophageal variceal bleeding along with splenomegaly and thrombocytopenia. Evaluation of cirrhosis or chronic liver disease showed normal-range results as estimated by FibroScan evaluation, laboratory examination for autoimmune hepatitis or viral hepatitis, and liver biopsy. This case may suggest the need for careful monitoring for manifestations of portal hypertension in Asian patients with inflammatory bowel disease receiving thiopurine treatment.

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Review

Inflammatory bowel diseases

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease: Katsuyoshi Matsuoka; Intest Res 2020;18(3):275-281. Published online June 3, 2020; DOI: https://doi.org/10.5217/ir.2020.00002

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Thiopurine has been used to maintain remission and to reduce antidrug antibody formation in monoclonal antibody therapy in patients with inflammatory bowel disease (IBD). The use of thiopurine is limited by side effects such as leukopenia. Thiopurine S-methyltransferase (TPMT) variants are associated with thiopurine-induced leukopenia in Westerners, but the frequency of the risk alleles is low in Asians. Recently, a variant in the nudix hydrolase 15 (NUDT15) gene (R139C, c.415C > T) was reported to be associated with early severe leukopenia in Asians. NUDT15 is an enzyme that converts 6-thio-(deoxy)guanosine triphosphate (6-T(d)GTP) to 6-thio-(deoxy)guanosine monophosphate (6-T(d)GMTP). The R139C variant impairs the stability of the protein and increases incorporation of 6-TGTP and 6-TdGTP into RNA and DNA, respectively, resulting in leukopenia. The frequency of C/C, C/T, and T/T are approximately 80%, 20%, and 1%, respectively in East Asians. Early leukopenia occurred in less than 3% of patients with C/C and in around 20% of those with C/T, whereas it occurred in almost all patients with T/T. Patients homozygous for this variant also develop severe hair loss. The measurement of NUDT15 R139C can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of IBD.

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Case Report

Drug-induced eosinophilic pneumonia in a patient with Crohn's disease: diagnosis and treatment using fraction of exhaled nitric oxide: Jina Yeo, Hyun Sun Woo, Sang Min Lee, Yoon Jae Kim, Kwang An Kwon, Dong Kyun Park, Jung Ho Kim, Kyoung Oh Kim, Jun-Won Chung; Intest Res 2017;15(4):529-534. Published online October 23, 2017; DOI: https://doi.org/10.5217/ir.2017.15.4.529

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Oral 5-aminosalicylic acid agents (mesalazine and sulfasalazine) and azathioprine are the mainstays of treatment for inflammatory bowel disease. Reports of pulmonary toxicity induced by oral 5-aminosalicylic acid agents or azathioprine in patients with inflammatory bowel disease are very rare; to date, only 38 cases have been reported worldwide. We, herein, report a case involving a 26-year-old man who was diagnosed with eosinophilic pneumonia after using mesalazine and azathioprine for the treatment of Crohn's disease and recovered after treatment. We also found that the fraction of exhaled nitric oxide level was elevated in this patient. After treatment, the fraction of exhaled nitric oxide level decreased and the symptoms improved. The present case shows that fraction of exhaled nitric oxide is related to the disease activity and treatment effectiveness of druginduced eosinophilic pneumonia.

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