T-cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study.

OBJECTIVES: The risk of non-Hodgkin's lymphoma (NHL) with tumor necrosis factor alpha (TNF-α) inhibitors is unclear, whether related to concomitant thiopurines usage or due to the underlying inflammatory disease. We sought to review all cases of T-cell NHL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors for all approved indications and examine the risk of T-cell NHL with TNF-α inhibitors in comparison with the use of thiopurines in inflammatory bowel disease (IBD). METHODS: The FDA Adverse Event Reporting System (AERS) was queried for all lymphomas following treatment with the following TNF-α inhibitors: infliximab, adalimumab, certolizumab, etanercept, and their trade names. Full reports for T-cell NHL cases were identified using the Freedom of Information Act. In addition, T-cell NHL reported in patients IBD with the use of the thiopurines-azathioprine, 6-mercaptopurine, and their trade names were also collected. A search of MEDLINE was performed for additional T-cell NHL with TNF-α inhibitors or thiopurines, not reported to the FDA but available in published literature. The histological subtypes of T-cell NHL reported with TNF-α inhibitors were compared with reported subtypes in Surveillance Epidemiology and End Results (SEER) -17 registry. Reported risk of T-cell NHL in IBD with TNF-α inhibitors, thiopurines, or concomitant use was calculated using Fisher's exact test using 5-aminosalicylates as control drugs. RESULTS: A total of 3,130,267 reports were downloaded from the FDA AERS (2003-2010). Ninety-one cases of T-cell NHL with TNF-α inhibitors were identified in the FDA AERS and nine additional cases were identified on MEDLINE search. A total of 38 patients had rheumatoid arthritis, 36 cases had Crohn's disease, 11 had psoriasis, 9 had ulcerative colitis, and 6 had ankylosing spondylitis. Sixty-eight of the cases (68%) involved exposure to both a TNF-α inhibitor and an immunomodulator (azathioprine, 6-mercaptopurine, methotrexate, leflunomide, or cyclosporine). Hepatosplenic T-cell lymphoma (HSTCL) was the most common reported subtype, whereas mycosis fungoides/Sezary syndrome and HSTCL were identified as more common with TNF-α-inhibitor exposure compared with SEER-17 registry. Nineteen cases of T-cell NHL with thiopurines were identified in the FDA AERS and one additional case on MEDLINE. Reported risk of T-cell NHL was higher with TNF-α inhibitor use in combination with thiopurines (95% confidence interval (CI) 4.98-354.09; P<0.0001) and thiopurines alone (95% CI 8.32-945.38; P<0.0001) but not with TNF-α inhibitor use alone (95% CI 0.13-10.61; P=1.00). CONCLUSIONS: Risk of T-cell NHL is increased with TNF-α inhibitor use in combination with thiopurines but not with TNF-α inhibitors alone.

Do gastroenterologists adhere to diagnostic and treatment guidelines for celiac disease?

AIM: Our group hypothesized that significant variation exists between suggested clinical guidelines, the clinical practices of practicing gastroenterologists and academic experts in celiac disease (CD). METHOD: We designed 4 CD vignettes comparing experts and practicing gastroenterologists. Practicing gastroenterologists (n=169) were surveyed during Digestive Disease Week 2009 and experts (n=22) answered e-mail surveys. Ratings for answers in each vignette was done using a 9-point RAND Appropriateness Scale (RAS) with endorsement defined as RAS score of 7 to 9. We also calculated the RAND "Disagreement Index" (DI) was calculated, with DI>1.0 indicated extreme variation. RESULTS: A total of 169 practicing gastroenterologists and 22 experts were included. Differences in all vignette answers were present. Differences were seen for use of IgA anti-endomysial antibodies (P=0.0241), human leukocyte antigen DQ2/8 testing (P=0.0325), gluten challenge (P<0.0001), and oat consumption (P<0.0001). There were differences in recommendations for biopsy review (P=0.0479) and management of dermatitis herpetiformis (P=0.0025). Experts consistently endorsed CD screening in patients with type 1 diabetes, Down and Turner syndromes, and relatives of CD patients compared with practicing physicians (P=0.0054, 0.0003, <0.0001, 0.0304). Experts endorsed CD screening for atypical presentations (delayed puberty, elevated transaminases, primary biliary cirrhosis, autoimmune hepatitis, and infertility). CONCLUSION: There is significant disagreement between nonexperts and experts in diagnosis and management of CD. Promotion of existing guidelines and further research is advised.

Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. The study of biologic and immunomodulator naive patients in Crohn's disease (SONIC), advocates combining infliximab with an immunomodulator in moderate-to-severe Crohn's disease. Unfortunately, combined immunosuppression increases risk for HSTCL. We herein review all cases of HSTCL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors. METHODS: Individual reports from the FDA Adverse Event Reporting System database for lymphomas from the biological agents - infliximab, adalimumab, certolizumab, natalizumab, and etanercept were downloaded and analyzed with Microsoft Access. Full reports for all identified HSTCL cases were obtained from the FDA. RESULTS: Twenty-five cases of HSTCL were identified. Twenty-two (88%) patients had inflammatory bowel disease and three had rheumatoid arthritis. Four cases (16%) were in women and four patients were above 65 years of age. Twenty-four cases (96%) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate). Two patients received adalimumab alone. CONCLUSION: HSTCL is no longer restricted to the previously identified risk group of young male patients, but can also occur in patients with rheumatoid arthritis, females and older adults receiving TNF-α inhibitors and immunomodulators. Improved disease outcomes using combination therapy should be tempered by the risk of developing HSTCL.