Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease

Connell, William; Kamm, Michael A.; Dickson, Mark A.; Balkwill, Angela; Ritchie, Jean K.; Lennard-Jones, J E

doi:10.1016/s0140-6736(94)92150-4

Cited by 470 publications

(227 citation statements)

References 15 publications

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“…Azathioprine has been found eff ective in maintaining remission in controlled and uncontrolled drug withdrawal studies ( 231,232 ) and in a meta-analysis of seven placebo-controlled maintenance trials ( 233 ). Retrospective studies have shown the value of 6-MP and azathioprine in maintaining long-term remission ( 200,234 ), and it is generally well tolerated during long-term use ( 197,200,201,234 ). As with induction of remission in UC, there have been no studies comparing 6-MP with azathioprine.…”

Section: The Patient With Severe Colitis Refractory To Maximal Oral Tmentioning

confidence: 99%

“…However, experience with the thiopurines over the last four decades indicates that there is not an increased risk of the development of solid tumors (as discussed above) ( 201 ) or overall mortality ( 200,238 ). Conversely, a recent meta-analysis of six cohort studies calculated a fourfold increased risk of lymphoma among IBD patients treated with thiopurines, but it remains unclear whether this risk was due to the medications themselves or due to the underlying disease ( 176,180,239 ).…”

Section: The Patient With Severe Colitis Refractory To Maximal Oral Tmentioning

confidence: 99%

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Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee

Kornbluth

Sachar

2010

American Journal of Gastroenterology

1,140

977

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Guidelines for clinical practice are aimed to indicate preferred approaches to medical problems as established by scientifi cally valid research. Double-blind placebo controlled studies are preferable, but compassionate-use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. When only data that will not withstand objective scrutiny are available, a recommendation is identifi ed as a consensus of experts. Guidelines are applicable to all physicians who address the subject regardless of specialty training or interests and are aimed to indicate the preferable but not necessarily the only acceptable approach to a specifi c problem. Guidelines are intended to be fl exible and must be distinguished from standards of care, which are infl exible and rarely violated. Given the wide range of specifi cs in any healthcare problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. Guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the board of trustees. Each has been intensely reviewed and revised by the Committee, other experts in the fi eld, physicians who will use them, and specialists in the science of decision analysis. The recommendations of each guideline are therefore considered valid at the time of composition based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at a time established and indicated at publication to assure continued validity. The recommendations made are based on the level of evidence found. Grade A recommendations imply that there is consistent level 1 evidence (randomized controlled trials), grade B indicates that the evidence would be level 2 or 3, which are cohort studies or case -control studies. Grade C recommendations are based on level 4 studies, meaning case series or poor-quality cohort studies, and grade D recommendations are based on level 5 evidence, meaning expert opinion.

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Section: The Patient With Severe Colitis Refractory To Maximal Oral Tmentioning

confidence: 99%

Section: The Patient With Severe Colitis Refractory To Maximal Oral Tmentioning

confidence: 99%

Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee

Kornbluth

Sachar

2010

American Journal of Gastroenterology

1,140

977

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“…e risk of lymphoma related to purine analogs has been widely debated (15,17,216,217) . Aside from a potential risk of lymphoma (216) , neoplasia has not been observed with the use of purine analogs for in ammatory bowel disease (218,219) and it is accepted that the documented bene ts are most likely to o set a small increased risk (220) . Lymphomas that have occurred during thiopurine therapy have increasingly been recognized to be related to Epstein -Barr infections (216,217,221) .…”

Section: Maintenance Therapymentioning

confidence: 99%

Management of Crohn's Disease in Adults

2009

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Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifi cally valid research, derived from extensive review of published literature. When data that will withstand objective scrutiny are not available, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be fl exible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are infl exible and rarely violated. Given the wide range of choices in any health-care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. Expert opinion is solicited from the outset for the document. The quality of evidence upon which a specifi c recommendation is based is as follows: Grade A: Homogeneous evidence from multiple well-designed randomized (therapeutic) or cohort (descriptive) controlled trials, each involving a number of participants to be of suffi cient statistical power. Grade B: Evidence from at least one large well-designed clinical trial with or without randomization, from cohort or case -control analytic studies, or well-designed meta-analysis. Grade C: Evidence based on clinical experience, descriptive studies, or reports of expert committees. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fi elds. The fi nal recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientifi c developments at a later time.

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“…The fact that the highest mutation frequencies in Crohn's disease patients occurred in the two who had received azathioprine would be predicted from treatment with a known mutagen, and raises concerns that azathioprine therapy may add to the carcinogenic risk in inflammatory bowel disease. A recent retrospective study of Somatiic mubtio in HNPC OO-GT Wdhams et a 1,0 long-term neoplasia risk after azathioprine treatment in patients with Crohn's disease and ulcerative colitis (Connell et al, 1994) found a significant 2.5 fold increase in all neoplasms after more than 5 years of azathioprine, and a 17-fold increase in CRC, although this did not reach statistical significance (the absolute number of tumours was small). The same study compared the frequency of CRC in azathioprine-treated ulcerative colitis patients with matched patients who had not received the drug.…”

Section: Methodsmentioning

confidence: 95%

Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

Williams

Geraghty²,

Campbell³

et al. 1995

Br J Cancer

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S_mmimary Hereditary non-polyposis colorectal cancer (HNPCC) has recently been linked to germline defects of DNA repair genes. Colorectal tumours in HNPCC frequently show DNA microsatellite instability, but it is not certain whether this mutator phenotype occurs throughout the morphologically normal colonic mucosa. We have previously used the mPAS histochemical technique in human colorectal mucosa to identify a polymorphism for O-acetyltransferase activity that shows monogenic inheritance and to show that cryptrestricted loss of O-acetyltransferase activity in heterozygotes is due to somatic mutation. We have now used this histochemical technique to measure the somatic mutation frequency in the uninvolved colon of 12 heterozygous patients with HNPCC, 15 with ileocaecal Crohn's disease and 16 with sporadic colorectal cancer (CRC). HNPCC patients showed a significant increase in mutation frequency with age (Mann-Whitney U. P=0.02). In HNPCC patients aged <49 years the mean stem cell mutation frequency was significantly lower than in the slightly younger group of patients with Crohn's disease (0.8 ± 0.9 x 10-' vs 3.5 ± 3.3 x 10-4, P<0.01), probably reflecting an increased mutation rate relating to chronic mucosal damage in Crohn's disease. Although not statistically significant, the stem cell mutation frequency was slightly less in HNPCC patients >50 years than in sporadic CRC cases (4.9 ± 3.4 x 10-4vs 5.9 ± 3.6 x 10-4, P>0.5 al., 1993).The APC gene is thought to act as a tumour-suppressor gene and, although the function of its product is not established, there is evidence to suggest that it is involved in cell adhesion (Su et al., 1993). The four putative HNPCC genes so far identified, on the other hand, appear to be involved in DNA repair. Colorectal adenomas and carcinomas, and extracolonic carcinomas, of HNPCC patients show a high frequency of DNA microsatellite instability (Aaltonen et al., 1994), and human homologues of the prokaryotic DNA mismatch repair genes mutS and mutL map to the regions of chromosomes 2, 3 and 7 that have been shown by linkage studies to bear the HNPCC loci. Moreover, germline mutations of these repair genes occur in affected patients (Fishel et al., 1993;Leach et al., 1993;Bronner et al., 1994;Nicolaides et al., 1994). HNPCC patients might therefore be expected to show an increased frequency of somatic mutation in a wide range of other genes. Loss of heterozygosity for chromosomes 2 or 3 is not common in HNPCC tumours Lindblom et al., 1993) and it is not certain whether the gene is acting dominantly, conferring increased mutation in the normal colon as well as in tumours, or whether its action is confined to tumours. Evidence suggesting-the latter is derived from the fact that a lymphoblastoid cell line from an HNPCC-affected individual was proficient in mismatch repair and that normal tissue (of unspecified type) from HNPCC patients was not found to show microsatellite instability . However, the possibility that the inherited DNA defect is confined to tissues with an increased inci...

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Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease

Cited by 470 publications

References 15 publications

Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee

Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee

Management of Crohn's Disease in Adults

Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

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