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Muller M, Broséus J, Feugier P, Thieblemont C, Beaugerie L, Danese S, Arnone D, Ndiaye NC, Kokten T, Houlgatte R, Peyrin-Biroulet L. Characteristics of Lymphoma in Patients with Inflammatory Bowel Disease: A Systematic Review. J Crohns Colitis 2021; 15:827-839. [PMID: 32949235 DOI: 10.1093/ecco-jcc/jjaa193] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Lymphoma is a dreaded complication of inflammatory bowel diseases [IBD]. Knowledge about lymphoma in patients with IBD is limited to epidemiological data and the description of risk factors. We performed a systematic review to describe the clinical characteristics and prognosis of lymphoma in patients with IBD. METHODS Electronic databases were searched up to June 1, 2020. All published clinical characteristics of lymphoma occurring in patients with IBD were collected. RESULTS Eleven studies were included. A total of 589 lymphomas were described in patients with IBD. As seen in de novo lymphoma, non-Hodgkin's lymphoma [NHL] was the most common histological subtype [83.9%]. Diffuse large B-cell lymphoma [DLBCL] and follicular lymphoma were the most well-represented NHL in patients with IBD [30% and 13% respectively]. Two main differences were observed in comparison with de novo lymphoma: primary intestinal lymphoma [PIL] represented a large proportion of lymphoma in patients with IBD [22-75%] whereas mucosa-associated lymphoid tissue [MALT] lymphoma was under-represented. Epstein-Barr virus [EBV]-positive status was observed in a large proportion of tumours [44-75%]. Survival data of lymphoma in patients with IBD were similar to those of de novo lymphoma. DISCUSSION This systematic review first highlights that PIL [especially DLBCL subtype] is significantly more frequent in patients with IBD and represents the most common entity. Conversely, MALT lymphoma is extremely rare in the IBD population. However, the overall quality of the evidence is low. Further studies are required to better define lymphoma characteristics in patients with IBD.
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Affiliation(s)
- Marie Muller
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Julien Broséus
- University of Lorraine, Inserm U1256 'Nutrition-Genetics and exposure to environmental risks-NGERE', Nancy, France.,University of Lorraine, CHRU-Nancy Hematology Laboratory, Laboratory department, Nancy, France
| | - Pierre Feugier
- University of Lorraine, Inserm U1256 'Nutrition-Genetics and exposure to environmental risks-NGERE', Nancy, France.,Department of Clinical Hematology, Nancy University Hospital, University of Lorraine, Nancy, France
| | | | - Laurent Beaugerie
- Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Department of Gastroenterology, Paris, France
| | - Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano Milan, Italy
| | - Djésia Arnone
- University of Lorraine, Inserm U1256 'Nutrition-Genetics and exposure to environmental risks-NGERE', Nancy, France
| | - Ndeye Coumba Ndiaye
- University of Lorraine, Inserm U1256 'Nutrition-Genetics and exposure to environmental risks-NGERE', Nancy, France
| | - Tunay Kokten
- University of Lorraine, Inserm U1256 'Nutrition-Genetics and exposure to environmental risks-NGERE', Nancy, France
| | - Rémi Houlgatte
- University of Lorraine, Inserm U1256 'Nutrition-Genetics and exposure to environmental risks-NGERE', Nancy, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France.,University of Lorraine, Inserm U1256 'Nutrition-Genetics and exposure to environmental risks-NGERE', Nancy, France
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Mark-Christensen A, Erichsen R, Veres K, Laurberg S, Sørensen HT. Extracolonic Cancer Risk After Total Colectomy for Inflammatory Bowel Disease: A Population-based Cohort Study. J Crohns Colitis 2020; 14:630-635. [PMID: 31811282 DOI: 10.1093/ecco-jcc/jjz199] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Patients with inflammatory bowel disease are at increased risk of extracolonic cancers. Little is known regarding this risk following total colectomy [TC]. METHODS Patients who underwent TC for inflammatory bowel disease in Denmark during 1977-2013 were identified from the Danish National Patient Registry. Incidence rates of extracolonic cancers were determined through record linkage to the Danish Cancer Registry and compared with expected incidence rates in the general population. Standardized incidence ratios [SIRs] were calculated as the observed vs expected cancer incidence. RESULTS In total, 4430 patients (3441 with ulcerative colitis [UC]; 989 with Crohn's disease [CD]) were followed for 54,183 person-years after TC. Following their surgery, 372 patients were diagnosed with extracolonic cancer compared to 331 expected [SIR = 1.1 (95% confidence interval {CI}: 1.0-1.2)]. The risk of extracolonic cancer overall was increased among patients with CD and TC (SIR = 1.5 [95% CI: 1.2-1.8]), but not among patients with UC and TC (SIR = 1.0 [95% CI: 0.9-1.2]). Patients with UC and TC had a higher risk of intestinal extracolonic cancer (SIR = 2.0 [95% CI: 1.4-2.7]). Patients with CD and TC had a higher risk of smoking-related cancers (SIR = 1.9 [95% CI: 1.2-2.9]), intestinal extracolonic cancer (SIR = 3.1 [95% CI: 1.6-5.5]) and immune-mediated cancers (SIR = 1.5 [95% CI: 1.0-2.1]). CONCLUSION Patients with CD and TC had a higher risk of extracolonic cancer overall compared to the general population, while patients with UC and TC did not. Site-specific cancer risk varied according to inflammatory bowel disease type.
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Affiliation(s)
- Anders Mark-Christensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark
- Department of Surgery, Section of Coloproctology, Aarhus University Hospital, Aarhus N, Denmark
| | - Rune Erichsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark
| | - Katalin Veres
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark
| | - Søren Laurberg
- Department of Surgery, Section of Coloproctology, Aarhus University Hospital, Aarhus N, Denmark
| | - Henrik Toft Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark
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Mansour R, Beattie M, Miller J, Haus C. Diffuse Large B-Cell Lymphoma Mimicking an Ulcerative Colitis Flare. ACG Case Rep J 2019; 6:1-3. [PMID: 31620491 PMCID: PMC6658017 DOI: 10.14309/crj.0000000000000031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 12/21/2018] [Indexed: 11/17/2022] Open
Abstract
We present a case of non-Hodgkin lymphoma of the rectum in a 41-year-old African American male with a 1 year history of ulcerative colitis and no previous immunomodulatory therapy. The patient presented with a 10-day history of hematochezia, for which endoscopy was performed with gross findings indicative of ulcerative colitis flare. Tissue biopsy, however, demonstrated significant lymphoid infiltrating regions with histologic findings suggestive of a diffuse large B-cell lymphoma. Non-Hodgkin's lymphoma accounts for less than 1% of all cases of colorectal cancer. Associated risk factors have been previously reported but, were absent in the patient's history. This suggests the possibility of distinct genetic abnormalities inherent to the tumor and/or an underlying germline mutation inherent to the patient that may have contributed to the premature development of diffuse large B-cell lymphoma.
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Affiliation(s)
- Ramy Mansour
- Department of Medical Education, Genesys Regional Medical Center, Grand Blanc, MI
| | - Michael Beattie
- Department of Medical Education, Genesys Regional Medical Center, Grand Blanc, MI
| | - Justin Miller
- Department of Medical Education, Genesys Regional Medical Center, Grand Blanc, MI
| | - Carolyn Haus
- Department of Pathology, Genesys Regional Medical Center, Grand Blanc, MI
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Bär F, Sina C, Fellermann K. Thiopurines in inflammatory bowel disease revisited. World J Gastroenterol 2013; 19:1699-1706. [PMID: 23555158 PMCID: PMC3607746 DOI: 10.3748/wjg.v19.i11.1699] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 11/15/2012] [Indexed: 02/06/2023] Open
Abstract
Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far, a definite cure of the disease is still out of scope. An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy. Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine, are widely used in the therapy of chronic active inflammatory bowel disease (IBD). Their steroid sparing potential and efficacy in remission maintenance are out of doubt. Unfortunately, untoward adverse events are frequently observed and may preclude further administration or be life threatening. This review will focus on new aspects of thiopurine therapy in IBD, its efficacy and safety.
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O'Connor A, Qasim A, O'Moráin CA. The long-term risk of continuous immunosuppression using thioguanides in inflammatory bowel disease. Ther Adv Chronic Dis 2012; 1:7-16. [PMID: 23251725 DOI: 10.1177/2040622310368736] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The efficacy of thiopurine treatment in the induction, and especially maintenance, of remission in inflammatory bowel disease is well proven; however, it is associated with side effects in both medium and long-term use. The potential harmful effects may be anticipated and minimised by due diligence prior to commencing these drugs followed by close monitoring of haematological and biochemical parameters once started. Careful clinical examination and history taking are also essential. Affected patients are expected to lead lives that include travel, employment and pregnancy - the implications of continued thiopurine therapy in such patients are discussed.
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Affiliation(s)
- Anthony O'Connor
- Dr Asghar Qasim Prof. Colm A. O'Moráin Department of Gastroenterology, Adelaide and Meath Hospital incorporating the National Children's Hospital/Trinity College Dublin, Belgard Road, Tallaght, Dublin 24, Ireland
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Molnár T, Farkas K, Nagy F, Szepes Z, Wittmann T. Lymphomas in two IBD patients treated with anti-TNF-α mono or combination therapy: is hepatosplenic lymphoma really the "old maid"? Inflamm Bowel Dis 2011; 17:2025-2026. [PMID: 21290481 DOI: 10.1002/ibd.21620] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 12/06/2010] [Indexed: 12/16/2022]
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Hepatosplenic T-cell lymphoma and inflammatory bowel disease. J Crohns Colitis 2010; 4:511-22. [PMID: 21122554 DOI: 10.1016/j.crohns.2010.05.006] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Revised: 05/19/2010] [Accepted: 05/19/2010] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This article reviews the current literature and knowledge about hepatosplenic T-cell lymphoma (HSTCL), providing an overview of the clinical features, a description of its pathology and immunophenotypic traits in relation to other lymphomas. In addition, we explore the history of reported cases of hepatosplenic T-cell lymphoma in relation to the possible existence of a causal relationship between infliximab use and HSTCL. The treatments for HSTCL will be briefly addressed. METHODS A comprehensive literature search using multiple databases was performed. Keyword search phrases including "lymphoma," "hepatosplenic T-cell lymphoma," "Inflammatory bowel disease," "6-mercaptopurine," and "infliximab" were used in various combinations. In addition references from published papers were reviewed as well. RESULTS There are over 200 reported cases of HSTCL. Only 22 cases of hepatosplenic T-cell lymphoma are associated with IBD treatment. Clinicians usually reserve immunomodulators and biologics for moderate to severe IBD cases. The ultimate goal of therapy is to control inflammation and therefore allow mucosal healing. IBD patients demonstrating mucosal healing are less likely to undergo surgery and experience complications related to their disease. We manipulate the immune system with corticosteroids, immunomodulators, and biologics, therefore causing bone marrow suppression. With bone marrow suppression, malignant degeneration may begin through selective uncontrolled cell proliferation, initiating HSTCL development in the genetically susceptible. CONCLUSION Hepatosplenic T-cell lymphoma is a rare disease, often with a poor outcome. With the increasing number of reported cases of HSTCL linked to the use of infliximab, adalimumab, and AZA/6-MP, there appears to be an undeniable association of HSTCL development with the use of these agents. This risk is unquantifiable. When considering the rarity of cases and the multiple complications with uncontrolled disease, however, the benefit of treatment far outweighs the risk.
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Smith MA, Irving PM, Marinaki AM, Sanderson JD. Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease. Aliment Pharmacol Ther 2010; 32:119-30. [PMID: 20412066 DOI: 10.1111/j.1365-2036.2010.04330.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Immunosuppression is a risk factor for carcinogenesis. Thiopurines specifically contribute to this. As thiopurines are used more aggressively in the treatment of IBD, it is likely that we will see more thiopurine-related malignancy. AIM To review the literature, exploring how immunosuppression, thiopurines specifically, might cause cancer and which malignancies occur in practice, placing specific emphasis on IBD cohorts. METHODS Search terms included 'malignancy' 'cancer' 'azathioprine' 'mercaptopurine' 'tioguanine (thioguanine)' 'thiopurine' and 'inflammatory bowel disease' 'Crohn's disease' 'ulcerative colitis'. We also searched for specific cancers (lymphoma, colorectal cancer, skin cancer, cervical cancer) and reviewed the reference lists of the articles detected. RESULTS Immunosuppression is associated with an increased risk of cancer. Thiopurines are associated with specific additional risks. In IBD cohorts, very few thiopurine-related malignancies have been reported. However, studies suggest a relative risk of 4-5 for lymphoma. This still translates into a low actual risk, (one extra lymphoma in every 300-1400 years of thiopurine treatment). CONCLUSIONS Whilst we must be aware of this risk and counsel our patients appropriately, thiopurines remain a mainstay of IBD therapy. We present practical advice aimed at minimizing our patients' risk of developing malignancy, whilst optimizing the benefits that thiopurines can provide.
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Affiliation(s)
- M A Smith
- Department of Gastroenterology Guy's & St. Thomas' NHS Foundation Trust, London, UK
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Abstract
The treatment of psoriasis has undergone a revolution with the advent of biologic therapies, including infliximab, etanercept, adalimumab, efalizumab, and alefacept. Biologics are generally safe and well tolerated. However, there has been concern over the risk of lymphoma with use of these agents because of their immunosuppressive properties. This review summarizes the current evidence in regards to lymphoma risk with biologic therapy obtained from case reports and case series, observational studies, clinical trials, and meta-analyses. The majority of data for T-cell inhibitors comes from case reports and relatively small, short-term clinical trials. In addition to published case reports and case series, TNF-alpha inhibitors have also been studied extensively in large cohort studies and meta-analyses of clinical trials derived primarily from the rheumatoid arthritis population. Current data are neither sufficient to completely rule out an increased risk of lymphoma associated with biologics, nor to firmly establish a causal relationship between biologics and lymphoma. Short- to intermediate-term treatment with biologics (e.g., up to 4 years) appears to be very safe with respect to lymphoma risk, especially with TNF-alpha inhibitors in which their potential risks appear to be well defined. Continued vigilance is warranted; however, in the appropriate patient, the risk-to-benefit profile of psoriasis treatment with respect to lymphoma risk appears highly favorable.
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Affiliation(s)
- Erica Dommasch
- Department of Dermatology at the University of Pennsylvania School of Medicine
| | - Joel M. Gelfand
- Department of Dermatology at the University of Pennsylvania School of Medicine
- Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine
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Schmidt LA, Lim MS. T cell lymphoproliferative disorders associated with anti-tumor necrosis factor alpha antibody therapy for ulcerative colitis: literature summary. J Hematop 2009; 2:121-6. [PMID: 19669196 PMCID: PMC2725290 DOI: 10.1007/s12308-009-0029-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2008] [Accepted: 02/09/2009] [Indexed: 12/19/2022] Open
Abstract
The enhanced risk of development of lymphoproliferative disorders in patients with inflammatory bowel disease has been attributed to immunosuppressive/immunomodulatory therapies. Infliximab is a chimeric monoclonal immunoglobulin G1 antibody directed against tumor necrosis factor alpha (TNF-α) that was approved by the Food and Drug Administration (FDA) in 1998 as an effective therapeutic agent against inflammatory bowel disease. Malignant lymphomas of both B and T cell lineage have been described in patients undergoing therapy involving TNF-α blockade. To date, eight cases of Epstein–Barr virus (EBV)-negative hepatosplenic T cell lymphoma associated with infliximab have been reported to the FDA’s Adverse Event Reporting System, as well as several other T cell lymphoproliferative disorders with aggressive clinical outcomes. We present the histologic, immunophenotypic, and molecular features of a T cell lymphoproliferative disorder involving the axillary lymph node of a 33-year-old male following infliximab treatment for ulcerative colitis. These EBV-negative lymphomas suggest that lymphoproliferative disorders following infliximab treatment for inflammatory bowel disease may involve EBV-independent immune dysregulation. The spectrum of lymphoproliferative disorders associated with infliximab and the potential mechanisms by which they occur are discussed.
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Affiliation(s)
- Lindsay A Schmidt
- Department of Pathology, M5240 Medical Science I, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109-0602 USA
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Shin US, Yu CS, Kim CW, Park JS, Jeong KY, Yoon SN, Lim SB, Song JS, Kim JC. Malignancy Associated with Inflammatory Bowel Disease. JOURNAL OF THE KOREAN SOCIETY OF COLOPROCTOLOGY 2009. [DOI: 10.3393/jksc.2009.25.3.150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Ui Sup Shin
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Chang Sik Yu
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Chan Wook Kim
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jin Seok Park
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kwang Yong Jeong
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sang Nam Yoon
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seok-byung Lim
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Joon Seon Song
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jin Cheon Kim
- Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Primary CD56+ NK/T-cell lymphoma of the rectum accompanied with refractory ulcerative colitis. J Gastroenterol 2008; 43:576-80. [PMID: 18648746 DOI: 10.1007/s00535-008-2192-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Accepted: 03/16/2008] [Indexed: 02/04/2023]
Abstract
A case of primary NK/T-cell lymphoma of the rectum accompanied with ulcerative colitis (UC) in a 73-year-old man is reported. He had a 6-year history of repeated admission to our hospital for UC. Total colonoscopy performed 4 months after resolution of refractory UC complicated by cytomegalovirus colitis showed a markedly submucosal tumor in the rectum, which was histologically diagnosed as malignant lymphoma. The findings of computed tomography of the chest and abdomen, gallium scintigraphy, abdominal ultrasonography, and upper gastrointestinal endoscopy showed no abnormal lesions. Therefore, based on a diagnosis of localized rectal lymphoma with UC, proctocolectomy was performed. The resected specimen showed three submucosal tumors in the rectum with local nodal involvement. Histologically, the tumors were characterized by diffusely infiltrating sheets of large atypical lymphoid cells, which were negative for CD4, CD8, and CD20 but were positive for CD56, CD3, and granzyme B. The presence of Epstein-Barr virus (EBV) infection in neoplastic cells was shown by in situ hybridization for EBV-encoded early small RNA1 (EBER-1). Based on these findings, the patient was diagnosed with primary CD56+ NK/T-cell lymphoma of the rectum (stage IIE). This is the first case report of primary rectal NK/T-cell lymphoma accompanied with UC.
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Abstract
Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeoxycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn's disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal-anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.
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Affiliation(s)
- Jianlin Xie
- GI Division, Mount Sinai School of Medicine, One Gustave Levy Place, New York City, NY 10029, USA
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Abstract
Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeoxycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn’s disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal-anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.
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Jones JL, Loftus EV. Lymphoma risk in inflammatory bowel disease: is it the disease or its treatment? Inflamm Bowel Dis 2007; 13:1299-307. [PMID: 17600819 DOI: 10.1002/ibd.20211] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
With the increasingly widespread use of immunosuppressive and biologic agents for the treatment of Crohn's disease and ulcerative colitis come concerns about potential long-term consequences of such therapies. Disentangling the potential confounding effects of the underlying disease, its extent, severity, duration, and behavior, and concomitant medical therapy has proven to be exceedingly difficult. Unlike the case in rheumatoid arthritis, the overwhelming preponderance of population-based evidence suggests that a diagnosis of inflammatory bowel disease (IBD) is not associated with an increased relative risk of lymphoma. However, well-designed studies that evaluate the potential modifying effect of IBD severity have yet to be performed. Although the results from hospital- and population-based studies have conflicted, the results of a recent meta-analysis suggest that patients receiving purine analogs for the treatment of IBD have a lymphoma risk approximately 4-fold higher than expected. Analyses of lymphoma risk in patients receiving biologic agents directed against tumor necrosis factor-alpha are confounded by concomitant use of immunosuppressive agents in most of these patients. Nevertheless, there may be a small but real risk of lymphoma associated with these therapies. Although the relative risk of lymphoma may be elevated in association with some of the medical therapies used in the treatment of IBD, this absolute risk is low. Weighing the potential risk of lymphoma associated with select medical therapies against the risk of undertreating IBD will help physicians and patients to make more informed decisions pertaining to the medical management of IBD.
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Affiliation(s)
- Jennifer L Jones
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
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Reynolds GJ, Annis KA, de Villiers WJS. Review article: multiple myeloma and inflammatory bowel disease. Dig Dis Sci 2007; 52:2022-8. [PMID: 17420948 DOI: 10.1007/s10620-006-9165-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2005] [Accepted: 11/27/2005] [Indexed: 01/30/2023]
Abstract
Since 1964 only nine cases of multiple myeloma occurring in the setting of inflammatory bowel disease have been reported. Although this occurrence may be a mere unfortunate coincidence, there are sound pathophysiological reasons for such an event. The possibility that chronic inflammatory conditions, immunomodulator therapy, and infliximab can predispose to multiple myeloma and lymphoma is reviewed. We discuss in detail the only reported case of multiple myeloma arising in the setting of infliximab treatment for Crohn's disease. It is highly probable that infliximab therapy had a causal role in our patient developing multiple myeloma. The pathogenesis of multiple myeloma arising in the setting of infliximab therapy may be related to decreased apoptosis of plasma cell populations. Since it is possible that a causal association exists between infliximab therapy and multiple myeloma, additional screening measures may be required in patients with Crohn's disease on infliximab.
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von Roon AC, Reese G, Teare J, Constantinides V, Darzi AW, Tekkis PP. The risk of cancer in patients with Crohn's disease. Dis Colon Rectum 2007; 50:839-55. [PMID: 17308939 DOI: 10.1007/s10350-006-0848-z] [Citation(s) in RCA: 193] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The risk of cancer in patients with Crohn's disease is not well defined. Using meta-analytical techniques, the present study was designed to quantify the risk of intestinal, extraintestinal, and hemopoietic malignancies in such patients. METHODS A literature search identified 34 studies of 60,122 patients with Crohn's disease. The incidence and relative risk of cancer were calculated for patients with Crohn's disease and compared with the baseline population of patients without Crohn's disease. Overall pooled estimates, with 95 percent confidence intervals, were obtained, using a random-effects model. RESULTS The relative risk of small bowel, colorectal, extraintestinal cancer, and lymphoma compared with the baseline population was 28.4 (95 percent confidence interval, 14.46-55.66), 2.4 (95 percent confidence interval, 1.56-4.36), 1.27 (95 percent confidence interval, 1.1-1.47), and 1.42 (95 percent confidence interval, 1.16-1.73), respectively. On subgroup analysis, patients with Crohn's disease had an increased risk of colon cancer (relative risk, 2.59; 95 percent confidence interval, 1.54-4.36) but not of rectal cancer (relative risk, 1.46; 95 percent confidence interval, 0.8-2.55). There was significant association between the anatomic location of the diseased bowel and the risk of cancer in that segment. The risk of small bowel cancer and colorectal cancer was found to be higher in North America and the United Kingdom than in Scandinavian countries with no evidence of temporal changes in the cancer incidence. CONCLUSIONS The present meta-analysis demonstrated an increased risk of small bowel, colon, extraintestinal cancers, and lymphoma in patients with Crohn's disease. Patients with extensive colonic disease that has been present from a young age should be candidates for endoscopic surveillance; however, further data are required to evaluate the risk of neoplasia over time.
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Affiliation(s)
- Alexander C von Roon
- Department of Biosurgery and Surgical Technology, Imperial College, St. Mary's Hospital, London, W2 1NY, UK
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Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: A review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 2007. [DOI: 10.1002/ibd.3780050209] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/19/2023]
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Jones OM, McCutcheon J, Herieka E, Fozard JB. High-grade lymphoma of the ileoanal pouch in an HIV-positive patient. Colorectal Dis 2007; 9:184-5. [PMID: 17223949 DOI: 10.1111/j.1463-1318.2006.00962.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Abstract
There has been a multitude of case reports, case series, hospital-based, and population-based studies that link CD to various types of cancers. When each of these studies is scrutinized, however, there is only enough evidence to support a link between colorectal adenocarcinoma, SBA, and squamous and adenocarcinomas that are associated with perianal fistulizing disease. All of the studies of large bowel adenocarcinoma or SBA follow patients in an era during which there were far fewer effective medicines to treat CD and surgery was more commonplace. The only surveillance study of patients who had extensive, long-duration Crohn's colitis showed a 22% risk for developing neoplasia (low-grade, high-grade, or cancer) after four surveillance examinations. Overall results from this study and the multitude of the other studies show that the risk for cancer in Crohn's colitis is equal to that in UC given equal extent and duration of disease. Patients who have Crohn's colitis that affects at least one third of the colon and with at least 8 years of disease should undergo screening and surveillance, just as in UC. Although the absolute risk for SBA in CD is low (2.2% at 25 years in one study), we should not rule out screening and surveying for this complication that is associated with significant morbidity and mortality in patients who have long-standing, extensive, small bowel disease. The risk for lymphoma and leukemia in CD is low, but immunomodulators and biologics may increase this risk. The evidence that links carcinoid tumors to CD is weak, and population-based studies need to be done. The study of cancers that are associated with CD is an evolving field that surely will change given that immunomodulators and biologics are being used with greater frequency.
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Affiliation(s)
- Sonia Friedman
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
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Melichar B, Bures J, Dedic K. Anorectal carcinoma after infliximab therapy in Crohn's disease: report of a case. Dis Colon Rectum 2006; 49:1228-33. [PMID: 16845561 DOI: 10.1007/s10350-006-0647-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Infliximab, monoclonal antibody against tumor necrosis factor alpha, is an effective agent in the therapy of Crohn's disease. Although therapy with infliximab is generally well tolerated, there is an obvious concern about the effect of this treatment on the incidence of cancer. We report a case of mucinous anorectal adenocarcinoma observed in a 39-year-old patient with long-standing Crohn's disease after therapy with two courses of infliximab. The carcinoma was discovered fortuitously after abdominoperineal resection. Despite clear margins, the tumor recurred in a few months and progressed during combination chemotherapy. Although there is currently no definitive proof of a causal link between infliximab therapy and cancer, the present observation and other reports in the literature should lead to a careful evaluation of the possibility of increased cancer risk in patients treated with this new agent.
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Affiliation(s)
- Bohuslav Melichar
- Department of Oncology and Radiotherapy, Charles University Medical School Teaching Hospital, Hradec Králové, Czech Republic.
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24
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Bai M, Katsanos KH, Economou M, Kamina S, Balli C, Briasoulis E, Kappas AM, Agnantis N, Tsianos EV. Rectal Epstein-Barr virus-positive Hodgkin's lymphoma in a patient with Crohn's disease: case report and review of the literature. Scand J Gastroenterol 2006; 41:866-9. [PMID: 16785203 DOI: 10.1080/00365520500529629] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We present the case of a 35-year-old man with Crohn's disease diagnosed at the age of 27, several months after an operation for small-bowel adenocarcinoma. Seven years after the adenocarcinoma diagnosis, the patient presented with severe continuous anal pain and diarrhea. In parallel with antibiotic administration, the patient was given treatment with Infliximab, but without clinical symptom amelioration. Sigmoidoscopy and subsequent biopsies from an ulcerated rectal area supported the diagnosis of Epstein-Barr virus-positive (EBV+) primary Hodgkin's lymphoma. Infliximab administration was immediately discontinued and the patient underwent oncological follow-up and began a course of chemotherapy. Only a few cases with primary gastrointestinal Hodgkin's lymphoma in Crohn's disease patients have so far been reported, including a variety of scenarios on the causal relationship including disease duration, presence of EBV, long-term immunosuppressive treatment and, recently, anti-TNFalpha administration.
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Affiliation(s)
- Maria Bai
- Department of Pathology, Medical School, University of Ioannina, GR-451 10 Ioannina, Greece
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Maykel JA, Hagerman G, Mellgren AF, Li SY, Alavi K, Baxter NN, Madoff RD. Crohn's colitis: the incidence of dysplasia and adenocarcinoma in surgical patients. Dis Colon Rectum 2006; 49:950-7. [PMID: 16729218 DOI: 10.1007/s10350-006-0555-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE Data supporting an increased risk of colorectal cancer in patients with Crohn's colitis are inconsistent. Despite this, clinical recommendations regarding colonoscopic screening and surveillance for patients with Crohn's colitis are extrapolated from chronic ulcerative colitis protocols. The primary aim of our study was to determine the incidence of dysplasia and carcinoma in pathology specimens of patients undergoing segmental or total colectomy for Crohn's disease of the large bowel. In addition, we sought to identify risk factors associated with the development of dysplasia and carcinoma. METHODS We performed a retrospective review of all patients operated on at our institution for Crohn's colitis between January 1992 and May 2004. Data were retrieved from patient charts, operative notes, and pathology reports. Logistic regression was used to model the probability of having dysplasia or adenocarcinoma. RESULTS Two hundred twenty-two patients (138 females) who underwent surgical resection for the treatment of Crohn's colitis were included in the study. Mean age at surgery was 41 (range, 15-82) years and the mean duration of disease was 10 (range, 0-53) years. There were five cases of dysplasia (2.3 percent) and six cases of adenocarcinoma (2.7 percent). Three patients with dysplasia and one with adenocarcinoma were diagnosed on preoperative colonoscopy; while the other cases were discovered incidentally on pathologic examination of resected specimens. Factors associated with the presence of dysplasia or adenocarcinoma included older age at diagnosis (38.2 vs. 30.3 years, P = 0.02), longer disease duration (16.0 vs. 10.1 years, P = 0.05), and disease extent (90 percent extensive vs. 59 percent limited, P = 0.05). CONCLUSIONS Patients with severe Crohn's colitis requiring surgery are at significant risk for developing dysplasia and adenocarcinoma, particularly when diagnosed at an older age, after longer disease duration, and with more extensive colon involvement.
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Affiliation(s)
- Justin A Maykel
- Department of Surgery, Section of Colon and Rectal Surgery, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, USA
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Daniel F, Damotte D, Moindrot H, Molina T, Berger A, Cellier C. A steroid-refractory ulcerative colitis revealing Epstein-Barr virus/cytomegalovirus-positive colonic lymphoma. Int J Colorectal Dis 2006; 21:288-90. [PMID: 15747126 DOI: 10.1007/s00384-004-0719-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/07/2004] [Indexed: 02/04/2023]
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Podolsky DK, Gonzalez RG, Hasserjian RP. Case records of the Massachusetts General Hospital. Case 8-2006. A 71-year-old woman with Crohn's disease and altered mental status. N Engl J Med 2006; 354:1178-84. [PMID: 16540619 DOI: 10.1056/nejmcpc059035] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
MESH Headings
- Aged
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/therapeutic use
- Brain/diagnostic imaging
- Brain/pathology
- Brain Neoplasms/diagnostic imaging
- Brain Neoplasms/etiology
- Brain Neoplasms/pathology
- Crohn Disease/complications
- Crohn Disease/drug therapy
- Diagnosis, Differential
- Epstein-Barr Virus Infections/etiology
- Fatal Outcome
- Female
- Groin
- Herpesvirus 4, Human/isolation & purification
- Humans
- Immunosuppressive Agents/adverse effects
- Immunosuppressive Agents/therapeutic use
- Infliximab
- Lymph Nodes/pathology
- Lymphoma, B-Cell/etiology
- Lymphoma, B-Cell/pathology
- Lymphoma, Large B-Cell, Diffuse/etiology
- Lymphoma, Large B-Cell, Diffuse/pathology
- Magnetic Resonance Imaging
- Mercaptopurine/adverse effects
- Mercaptopurine/therapeutic use
- Tomography, X-Ray Computed
- Unconsciousness/etiology
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Shibahara T, Miyazaki K, Sato D, Matsui H, Yanaka A, Nakahara A, Tanaka N. Rectal malignant lymphoma complicating ulcerative colitis treated with long-term cyclosporine A. J Gastroenterol Hepatol 2006; 21:336-8. [PMID: 16460502 DOI: 10.1111/j.1440-1746.2006.03988.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
MESH Headings
- Adult
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/drug therapy
- Cyclosporine/adverse effects
- Cyclosporine/therapeutic use
- Humans
- Immunosuppressive Agents/adverse effects
- Immunosuppressive Agents/therapeutic use
- Lymphoma, B-Cell/chemically induced
- Lymphoma, B-Cell/complications
- Lymphoma, B-Cell/diagnosis
- Lymphoma, Large B-Cell, Diffuse/chemically induced
- Lymphoma, Large B-Cell, Diffuse/complications
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Male
- Rectal Neoplasms/chemically induced
- Rectal Neoplasms/complications
- Rectal Neoplasms/diagnosis
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Kwon JH, Farrell RJ. The risk of lymphoma in the treatment of inflammatory bowel disease with immunosuppressive agents. Crit Rev Oncol Hematol 2005; 56:169-78. [PMID: 15979323 DOI: 10.1016/j.critrevonc.2005.02.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2004] [Revised: 01/30/2005] [Accepted: 02/10/2005] [Indexed: 01/12/2023] Open
Abstract
Immunosuppressive agents have become an established part of the therapeutic armamentarium for inflammatory bowel disease (IBD). However, when used in transplant recipients or for other indications, agents that suppress or modulate the immune system (immunomodulators) have been associated with an increased risk of lymphoma. Fortunately, in part because of the lower doses used in IBD patients, the risk of lymphoma in IBD patients appears to be significantly less than that associated with renal and hepatic transplant-related immunosuppression. Whether the risk of azathioprine or 6-mercaptopurine associated lymphoma in IBD is real or relates to the underlying disease remains unclear. The results of several recent large well designed population-based studies suggest that the lymphoma risk associated with azathioprine and 6-mercaptopurine therapy is likely to be of minimal clinical significance compared to the established and more frequent risks of myelosuppression and infection, and is far outweighed by the clinical benefit of immunomodulator therapy in IBD. While the issue of lymphoma risk is likely to become more relevant with the growing number of biologic and immunomodulators being tested in clinical trials for IBD, early post-marketing surveillance data on infliximab suggests that the lymphoma risk may not be any greater than that associated with azathioprine and 6-mercaptopurine.
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Affiliation(s)
- John H Kwon
- Center for Inflammatory Bowel Disease, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Dana 501, Boston, MA 02215, USA
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30
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Thayu M, Markowitz JE, Mamula P, Russo PA, Muinos WI, Baldassano RN. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease. J Pediatr Gastroenterol Nutr 2005; 40:220-2. [PMID: 15699701 DOI: 10.1097/00005176-200502000-00026] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Meena Thayu
- Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
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Farrell DJ, Birchley DW, Edwards CM. Histiocytic infiltration in ulcerative colitis, simulating malignancy. Histopathology 2004; 45:638-40. [PMID: 15569056 DOI: 10.1111/j.1365-2559.2004.01971.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- D J Farrell
- Department of Histopathology, Torbay Hospital, Torquay, UK
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Abstract
Etanercept is effective in the treatment of rheumatoid arthritis (RA)when used as monotherapy and in combination with methotrexate(MTX). Radiographic progression of disease was slowed significantly when the drug was used for a 24-month period and was statistically significantly better than MTX. In addition to its use in RA,etanercept is approved by the U.S. Food and Drug Administration for other rheumatologic conditions, including psoriatic arthritis,ankylosing spondylitis, and juvenile chronic arthritis.
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Affiliation(s)
- Mark C Genovese
- Division of Immunology and Rheumatology, Stanford University Medical Center, 1000 Welch Road, Suite 203, Palo Alto, CA 94304, USA.
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Reijasse D, Le Pendeven C, Cosnes J, Dehee A, Gendre JP, Nicolas JC, Beaugerie L. Epstein-Barr virus viral load in Crohn's disease: effect of immunosuppressive therapy. Inflamm Bowel Dis 2004; 10:85-90. [PMID: 15168806 DOI: 10.1097/00054725-200403000-00004] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND More than 80% of non-Hodgkin lymphomas (NHLs) occurring in transplant recipients on immunosuppressive therapy are associated with Epstein-Barr virus (EBV) infection. EBV viral load (EBV-VL) is predictive of NHL occurrence in this setting. The aim of this work was to determine EBV-VL in patients with Crohn's disease (CD), both according to disease activity and use of immunosuppressive therapy, including infliximab. METHODS Between December 1999 and July 2001, EBV-VL was determined 212 times by quantitative polymerase chain reaction (PCR) assay in 138 patients with CD and in 24 EBV-seropositive controls free of CD. RESULTS EBV-VL did not differ significantly between the controls and the patients with CD and was not influenced by CD activity or by immunosuppressive therapy, including recent infliximab infusion. High EBV-VL values were observed in two patients with severe uncontrolled CD, but returned to normal once the flare-up had been controlled (by immunosuppressive drugs in one case and by surgery in the other case). CONCLUSIONS EBV viral load is on the whole similar in patients with Crohn's disease and in EBV-seropositive controls. Infliximab infusion does not seem to increase significantly EBV-VL in the short-term. However, some patients with Crohn's disease have transient, very high EBV-VL values that are compatible with an increased risk of NHL in the transplant setting. The long-term clinical outcome of these patients must be determined.
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Affiliation(s)
- Didier Reijasse
- Department of Gastroenterology, Saint-Antoine University, Paris, France
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Jess T, Winther KV, Munkholm P, Langholz E, Binder V. Intestinal and extra-intestinal cancer in Crohn's disease: follow-up of a population-based cohort in Copenhagen County, Denmark. Aliment Pharmacol Ther 2004; 19:287-93. [PMID: 14984375 DOI: 10.1111/j.1365-2036.2004.01858.x] [Citation(s) in RCA: 109] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM To determine the long-term risk of intestinal and extra-intestinal malignancies in Crohn's disease patients in Copenhagen County, Denmark. METHODS In Copenhagen County, a strictly population-based cohort of 374 patients with Crohn's disease diagnosed between 1962 and 1987 was followed until 1997 in order to determine the long-term risk of intestinal and extra-intestinal malignancies. Information on cancer occurrence was provided by the Danish National Cancer Registry and confirmed by the examination of hospital files. The observed number of cases was compared with the expected number, calculated from individually computed person-years at risk and 1995 cancer incidence rates for the background population. RESULTS The risk of small bowel adenocarcinoma was significantly increased, independent of age and gender (standardized morbidity ratio, 66.7; 95% confidence interval, 18.1-170.7). The risk of colorectal cancer was not increased, either in the total group of patients or in patients with colonic Crohn's disease exclusively (standardized morbidity ratio, 1.64; 95% confidence interval, 0.20-5.92). Extra-intestinal cancer did not occur more frequently than expected. CONCLUSIONS This population-based study of patients with Crohn's disease revealed no increase in colorectal cancer risk, possibly due to maintenance treatment with 5-aminosalicylic acid preparations and surgery in treatment failure. In contrast, the risk of small bowel cancer was increased more than 60-fold, but the numbers were small. The risk of extra-intestinal cancer was not increased and no lymphomas were observed.
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Affiliation(s)
- T Jess
- Department of Medical Gastroenterology, Herlev Hospital, University of Copenhagen, Denmark.
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Warman JI, Korelitz BI, Fleisher MR, Janardhanam R. Cumulative experience with short- and long-term toxicity to 6-mercaptopurine in the treatment of Crohn's disease and ulcerative colitis. J Clin Gastroenterol 2003; 37:220-5. [PMID: 12960720 DOI: 10.1097/00004836-200309000-00006] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS The efficacy of 6-mercaptopurine (6-MP) in the treatment and long-term maintenance of remission of inflammatory bowel disease and prevention of recurrence after resection in Crohn's disease have been established. Concern about 6-MP toxicity remains, especially the development of neoplasm. The aim of this study is to determine the incidence of all short- and long-term toxicity by follow-up of all patients with inflammatory bowel disease treated with 6-MP over a 20-year period. MATERIALS AND METHODS We reviewed the office and hospital records and also determined the recent status of 410 patients with inflammatory bowel disease treated with 6-MP from 1980 to 1999. All toxicity was recorded. RESULTS There was a low incidence of early drug-related allergic reactions (3.9%) and pancreatitis (1.2%). Desensitization to either 6-MP or azathioprine is often successful with the same or the other drug. Significant leukopenia (<or=3500) was observed in 11.5%. In some cases, this was caused purposefully. Infectious complications occurred at different times during treatment with 6-MP in 14%, including pneumonia in 3.9% and herpes zoster in 3%. We now establish diabetes as a 6-MP-related complication. No significant difference in the incidence of neoplasm was seen from our earlier study or from patients not treated with 6-MP. We have now seen three lymphomas and two leukemias, again not greater in incidence than the overall inflammatory bowel disease population. CONCLUSIONS Our data support the long-term safety of 6-MP in the management of patients with inflammatory bowel disease. Earlier development of a neoplasm in a patient predisposed, without a change in incidence, remains possible.
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Affiliation(s)
- Jonathan I Warman
- Department of Medicine, Lenox Hill Hospital, New York, New York 10021, USA
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Abstract
A 32-year-old man with a 12-year history of Crohn's disease of the colon was found to have a 5-cm cecal mass on colonoscopy. Histology examination of the lesion revealed high-grade B-cell lymphoma of Burkitt's type. He was treated with chemotherapy and has done well in the past 12 months. Review of the literature reveals 30 cases of lymphoma in patients with a history of Crohn's disease.
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Affiliation(s)
- Calvin H Hall
- Section of Gastroenterology, Mercy Hospital and Medical Center, Chicago, Illinois, USA.
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Systemic consequences of intestinal inflammation. INFLAMMATORY BOWEL DISEASE: FROM BENCH TO BEDSIDE 2003. [PMCID: PMC7120497 DOI: 10.1007/0-387-25808-6_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Brown SL, Greene MH, Gershon SK, Edwards ET, Braun MM. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. ARTHRITIS AND RHEUMATISM 2002; 46:3151-8. [PMID: 12483718 DOI: 10.1002/art.10679] [Citation(s) in RCA: 429] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Etanercept and infliximab are tumor necrosis factor (TNF) antagonists that have been recently approved for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents. METHODS Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed. RESULTS We identified 26 cases of lymphoproliferative disorders following treatment with etanercept (18 cases) or infliximab (8 cases). The majority of cases (81%) were non-Hodgkin's lymphomas. The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short (median 8 weeks). In 2 instances (1 infliximab, 1 etanercept), lymphoma regression was observed following discontinuation of anti-TNF treatment, in the absence of specific cytotoxic therapy directed toward the lymphoma. CONCLUSION Although data from a case series such as this cannot establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease, the known predisposition of patients with RA and CD to lymphoma, the known excess of lymphoma in other immunosuppressed populations, and the known immunosuppressive effects of the anti-TNF drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association.
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Affiliation(s)
- S Lori Brown
- Center for Biologics Evaluation and Research, FDA, Rockville, Maryland 20852, USA
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Barthelmes L, Thomas KJ, Seale JRC. Prostatic involvement of a testicular lymphoma in a patient with myasthenia gravis on long-term azathioprine. Leuk Lymphoma 2002; 43:2425-6. [PMID: 12613537 DOI: 10.1080/1042819021000040189] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Side effects of long-term use of azathioprine in myasthenia gravis are infrequently reported. We present a patient who developed non-Hodgkin's lymphoma after eight years of azathioprine treatment for myasthenia gravis. He presented unusually with testicular lymphoma spreading to the prostate and the illness followed a particularly aggressive course.
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Affiliation(s)
- L Barthelmes
- Department of Urology, Alaw Unit, Ysbyty Gwynedd, Bangor LL 57 2 PW Wales, UK
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Barabino A, Torrente F, Ventura A, Cucchiara S, Castro M, Barbera C. Azathioprine in paediatric inflammatory bowel disease: an Italian multicentre survey. Aliment Pharmacol Ther 2002; 16:1125-30. [PMID: 12030954 DOI: 10.1046/j.1365-2036.2002.01269.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIM To assess the efficacy and safety of azathioprine in a paediatric population with inflammatory bowel disease. PATIENTS AND METHODS One hundred and twenty-three Italian children treated with azathioprine were studied retrospectively. The treatment duration and causes of its discontinuation, side-effects and variation in corticosteroid dose were assessed. RESULTS The mean age at inflammatory bowel disease diagnosis was 9.8 +/- 3.6 years, and at the start of azathioprine therapy 11.8 +/- 4.3 years. The mean duration of treatment was 19 +/- 16 months. Fifty patients (41%) stopped treatment due to surgery (12%), prolonged remission (11%), non-response (7%), severe side-effects (7%) and poor compliance (3%). Of the 73 patients (59%) remaining on azathioprine, 11 had never been treated with corticosteroids, 27 were able to stop them and 35 were still on a very low daily dose (91% < 0.3 mg/kg). The difference in the daily corticosteroid dose between the beginning of azathioprine treatment (1 +/- 0.6 mg/kg) and the conclusion of the study (0.18 +/- 0.16 mg/kg) was statistically significant. Side-effects were recorded in 48 of the 123 patients (39%), but only eight required discontinuation of azathioprine. CONCLUSIONS Azathioprine was efficacious in 70% of patients, but ineffective in 20% and induced severe toxicity in 7%. Corticosteroids were stopped or markedly reduced in 62% of patients, but they were never given in 9%.
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Affiliation(s)
- A Barabino
- Paediatric Gastroenterology, IRCCS G. Gaslini, Largo G. Gaslini 5, 16148 Genoa, Italy.
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Gisbert JP, Gomollón F, Maté J, Pajares JM. [Questions and answers on the role of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2002; 25:401-15. [PMID: 12069704 DOI: 10.1016/s0210-5705(02)70275-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- J P Gisbert
- Servicio de Aparato Digestivo, Hospital Universitario de la Princesa, Madrid, Spain.
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Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W, Rutgeerts P. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359:1541-9. [PMID: 12047962 DOI: 10.1016/s0140-6736(02)08512-4] [Citation(s) in RCA: 3020] [Impact Index Per Article: 131.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab. METHODS 573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat. FINDINGS 335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups. INTERPRETATION Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.
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Affiliation(s)
- Stephen B Hanauer
- Department of Gastroenterology and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, USA.
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Affiliation(s)
- Shigehiko Fujii
- Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan
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Dayharsh GA, Loftus EV, Sandborn WJ, Tremaine WJ, Zinsmeister AR, Witzig TE, Macon WR, Burgart LJ. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 2002; 122:72-7. [PMID: 11781282 DOI: 10.1053/gast.2002.30328] [Citation(s) in RCA: 211] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The use of azathioprine and 6-mercaptopurine for inflammatory bowel disease increased in the early 1990s. We sought to determine the effect of this change in therapy on the risk of lymphoma in patients with inflammatory bowel disease. METHODS All patients with inflammatory bowel disease at a single tertiary care medical center who developed lymphoma between 1985-2000 were identified and the pathologic features of the lymphoma including presence of Epstein- Barr virus were determined. The patients were divided into two 8-year periods (1985-1992, 1993-2000) corresponding with the introduction of azathioprine and 6-mercaptopurine in 1993. RESULTS Eighteen patients with lymphoma were identified, 6 between 1985-1992 and 12 between 1993-2000. Six of 18 lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine, all between 1993-2000. Seven patients developed Epstein-Barr virus-positive lymphoma (1 from 1985-1992, 6 from 1993-2000). Five of 7 Epstein-Barr virus-positive lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine compared with 1 of 11 Epstein-Barr virus-negative lymphomas (P = 0.01). Approximately 1200 patients with inflammatory bowel disease were treated with these agents between 1993-2000. CONCLUSIONS Treatment of inflammatory bowel disease with azathioprine or 6-mercaptopurine appears to be associated with a small increased risk of Epstein-Barr virus-positive lymphoma.
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Affiliation(s)
- Gerald A Dayharsh
- Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA
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Bebb JR, Logan RP. Review article: does the use of immunosuppressive therapy in inflammatory bowel disease increase the risk of developing lymphoma? Aliment Pharmacol Ther 2001; 15:1843-9. [PMID: 11736713 DOI: 10.1046/j.1365-2036.2001.01125.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
Recent case reports have raised concerns regarding the risks of non-Hodgkin's lymphoma in patients with inflammatory bowel disease treated with immunosuppressive agents. This evidence-based review examines this issue from data derived from the use of immunosuppression in other conditions (and inflammatory bowel disease). We conclude that, in transplant (cardiac and renal) recipients, immunosuppression increases the risk of non-Hodgkin's lymphoma. For non-transplant patients (with psoriasis and rheumatoid arthritis), debate remains as to whether the observed increase in the incidence of non-Hodgkin's lymphoma is due to drug or disease. For inflammatory bowel disease per se, population studies show no significant increase in the risk of non-Hodgkin's lymphoma, with a relative risk of 1.3 (95% confidence interval, 0.9-1.7) compared to expected rates, and several studies of immuno- suppression in inflammatory bowel disease do not appear to confirm a significant rate of lymphoma incidence. Reported cases of lymphoma from single centres should be viewed with caution as evidence of increased risk. If any association exists, it is likely to be of minimal clinical significance compared to the established and more frequent risks of myelosuppression and infection, and is unlikely to outweigh the benefit of immunosuppression in inflammatory bowel disease.
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Affiliation(s)
- J R Bebb
- Division of Gastroenterology, University Hospital, Nottingham, UK
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Abstract
BACKGROUND A proliferation of animal models has not only improved our understanding of inflammatory bowel disease, it has also formed the basis of new treatment strategies. METHODS A search was conducted using the National Library of Medicine for articles discussing immune therapies for inflammatory bowel disease. This was supplemented by findings from the authors' own laboratory. RESULTS An overview of the different animal models is presented. These models are used to highlight the recent human trials of immune therapies. Potential future therapies are also discussed. CONCLUSION Immune therapies have altered the management of patients with inflammatory bowel disease. In future they will influence not only the indications for surgery but also its timing and outcome.
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Affiliation(s)
- B Singh
- Nuffield Department of Surgery, John Radcliffe Hospital, Oxford, UK.
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Loftus EV, Sandborn WJ. Lymphoma risk in inflammatory bowel disease: influences of referral bias and therapy. Gastroenterology 2001; 121:1239-42. [PMID: 11677218 DOI: 10.1053/gast.2001.29271] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Aithal GP, Mansfield JC. Review article: the risk of lymphoma associated with inflammatory bowel disease and immunosuppressive treatment. Aliment Pharmacol Ther 2001; 15:1101-8. [PMID: 11472312 DOI: 10.1046/j.1365-2036.2001.01023.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lymphoma complicating inflammatory bowel disease is well described. Whether the risk of lymphoma is increased by immunosuppressive treatment with azathioprine, 6-mercaptopurine or infliximab is a common concern among patients and physicians considering using these agents. This review aims to quantify the lymphoma risk in inflammatory bowel disease and the added risk attributable to these treatments. The evidence from published cases is that lymphomas occur at sites of active inflammatory bowel disease more often than expected for this to be a chance association. Studies on inflammatory bowel disease populations are conflicting, with some follow-up studies from large inflammatory bowel disease clinics showing an increase in lymphoma incidence, while other population-based studies show little or no increase in risk of lymphoma. A small increase in lymphoma risk in inflammatory bowel disease, perhaps 2-3-fold, may be compatible with both sets of data. Studies of the risks associated with immuno- suppression are less satisfactory, with smaller numbers of patients and relatively short follow-up. The available evidence would support a further increase in lymphoma risk associated with immunosuppressive treatment in inflammatory bowel disease of around fivefold compared to no immunosuppressive use, and tenfold compared to the general population. The risks appear to be less than that associated with renal and hepatic transplant-related immunosuppression. Infliximab treatment is still too new to make a full assessment of its long-term safety, but post-marketing surveillance currently suggests that lymphoma risk may not be any greater than that associated with azathioprine and 6-mercaptopurine. Population-wide surveillance for lymphoma in inflammatory bowel disease would be required to narrow the confidence intervals on these estimates of lymphoma risk in inflammatory bowel disease and immunosuppressive treatment.
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Affiliation(s)
- G P Aithal
- Department of Gastroenterology, University of Newcastle, Newcastle upon Tyne, UK
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Abstract
Primary malignant lymphoma of the bowel is a rare complication of inflammatory bowel disease. The association of gastrointestinal lymphoma, inflammatory bowel disease and prior immunosuppression remains unclear. We report the first case of azathioprine-treated ulcerative colitis developing rectal lymphoma.
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MESH Headings
- Adult
- Azathioprine/therapeutic use
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/drug therapy
- Humans
- Immunosuppressive Agents/therapeutic use
- Lymphoma, Large B-Cell, Diffuse/complications
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Non-Hodgkin/complications
- Lymphoma, Non-Hodgkin/diagnosis
- Male
- Rectal Neoplasms/complications
- Rectal Neoplasms/diagnosis
- Rectal Neoplasms/pathology
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Affiliation(s)
- C W Tan
- Department of Gastroenterology, North Manchester General Hospital, Manchester, UK
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