Risk of Lymphoma in Patients With Ulcerative Colitis Treated With Thiopurines: A Nationwide Retrospective Cohort Study

Khan, Nabeel; Abbas, Ali; Lichtenstein, Gary R.; Loftus, Edward V.; Bazzano, Lydia A.

doi:10.1053/j.gastro.2013.07.035

Cited by 193 publications

(129 citation statements)

References 47 publications

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“…Likewise, an immunomodulator holiday could be an effective method of returning the risk of lymphoproliferative disorders back to baseline. 78,79 This is by far the most extensive and comprehensive review of the literature on de-escalation strategies in patients with IBD to date, incorporating short-term and long-term results across different therapeutic strategies. However, this review has some limitations.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

et al. 2015

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Little is known about the optimal duration of therapy with an anti-tumor necrosis factor (TNF) agent and/or an immunomodulator for patients with inflammatory bowel disease (IBD). We performed a systematic search of the literature to identify studies reporting after de-escalation (drug cessation or dose reduction) of anti-TNF agents and/or immunomodulators in patients in remission from IBD. Studies were reviewed according to the type of IBD and drug. Rates of relapse, factors associated with relapse, and response to re-treatment were determined. Our search yielded 6315 unique citations; we analyzed findings from 69 studies (18 on de-escalation [drug cessation or dose reduction] of immunomodulator monotherapy, 8 on immunomodulator de-escalation from combination therapy, and 43 on de-escalation of anti-TNF agents, including 3 during pregnancy) comprising 4672 patients. Stopping immunomodulator monotherapy after a period of remission was associated with high rates of relapse in patients with Crohn's disease or ulcerative colitis (approximately 75% of patients experienced a relapse within 5 years after therapy was stopped). Most studies of patients with Crohn's disease who discontinued an immunomodulator after combination therapy found that rates of relapse did not differ from those of patients who continued taking the drug (55%-60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission 24 months later, but the proportion in remission decreased with time. Markers of disease activity, poor prognostic factors, and complicated or relapsing disease course were associated with future relapse. In conclusion, based on a systematic review, 50% or more of patients with IBD who cease therapy have a disease relapse. Further studies are required to accurately identify subgroups of patients who are good candidates for discontinuation of treatment. The decision to withdraw a drug should be made for each individual based on patient preference, disease markers, consequences of relapse, safety, and cost.Keywords : Crohn's Disease ; Ulcerative Colitis ; Patient Management ; Cessation.Abbreviations used in this paper : anti-TNF, anti-tumor necrosis factor therapy ; CD, Crohn's disease ; CRP, C-reactive protein ; FC, fecal calprotectin ; IBD, inflammatory bowel disease ; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses ; RCT, randomized controlled trial ; TNF, tumor necrosis factor ; UC, ulcerative colitis.Therapeutic strategies in inflammatory bowel disease (IBD) have evolved considerably in the past few decades. The acknowledgment that subclinical and undertreated inflammation can lead to poor outcomes has underpinned a shift in treatment goals from symptomatic control to sustained clinical and endoscopic remission.1 Treatment strategies have changed accordingly, including the ear...

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Section: Discussionmentioning

confidence: 99%

Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

et al. 2015

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“…AZA may therefore accelerate the natural decline of Vδ2 T cell tumor surveillance in CD patients more acutely in men than in women. Indeed, lymphoma risk in AZA-treated IBD has been reported to progressively increase with therapy duration (52), and older male patients are at the greatest risk of AZA-induced malignancy (53). Furthermore, HSTCL in AZA-treated CD is frequently of γδ T cell origin (49), and anti-TNF therapy reportedly increases the proliferation of γδ T cells in young, male CD patients (46).…”

Section: Discussionmentioning

confidence: 99%

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

McCarthy¹,

Hedin²,

Sanders³

et al. 2015

J. Clin. Invest.

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“…Thiopurines (azathioprine and mercaptopurine) have been incriminated for the development of basal cell and squamous cell skin cancers, lymphoproliferative disorders, and myelodysplastic syndromes [7,16,17,18,19,20,21,22,23,24,25]. Recent reports have also associated thiopurines with an increased risk of all-cause malignancies in IBD [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26].…”

Section: What Are the Potential Carcinogenic Properties Of Ims Used Imentioning

confidence: 99%

“…Recent reports have also associated thiopurines with an increased risk of all-cause malignancies in IBD [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Incorporation of 6-TGN nucleotides in the DNA and RNA is responsible for induction of both remission of disease and mutagenesis and cancer promotion.…”

Section: What Are the Potential Carcinogenic Properties Of Ims Used Imentioning

confidence: 99%

Previous Cancer and/or Lymphoma in Patients with Refractory IBD - Con: Anti-TNF or Conventional Immunosuppressive Treatment

Mantzaris¹

2014

Dig Dis

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Patients with IBD and prior cancer are at increased risk of developing recurrent or de novo cancer. Depending on the type of malignancy, risk factors include IBD itself, age, environmental factors, genetic susceptibility and exposure to immunosuppressants (IMS), namely thiopurines, methotrexate and anti-TNFα biologics. The procarcinogenic effect of IMS depends on the type of drug and length of exposure. Thiopurines increase the rates of nonmelanoma skin cancer and lymphomas. Methotrexate is less harmful, but data are scarce. Evidence favoring the ‘safety' of anti-TNF monotherapy is weak because most patients have been exposed to combinations of IMS prior to the development of malignancy. Anti-TNFα biologics may promote tumor proliferation and increase the risk of melanomas. Exclusion of these patients from trials with biologics, physician concerns or fear of incident cancers and medicolegal consequences, and patient concerns have led to a paucity of data regarding IMS treatment of patients with a prior malignancy. In the absence of guidelines, IMS should be avoided especially during the first 2 years after commencing cancer therapy. Depending on disease type, location and severity, 5-ASA, antibiotics, enteric nutrition, steroids alone or in combinations, seton placement, and ‘curative' or ‘diverting' surgery may allow for a crucial drug-holiday period before readministration of IMS. Preventive measures include smoking cessation, UV solar protection, annual skin examination and Pap test. If unavoidable, methotrexate should be the drug of first choice followed by anti-TNFα and then thiopurines. Patients should be managed on a case-by-case basis by a multidisciplinary team of experts.

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Risk of Lymphoma in Patients With Ulcerative Colitis Treated With Thiopurines: A Nationwide Retrospective Cohort Study

Cited by 193 publications

References 47 publications

Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

Previous Cancer and/or Lymphoma in Patients with Refractory IBD - Con: Anti-TNF or Conventional Immunosuppressive Treatment

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