Humberto Sifuentes

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-Hodgkins 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 Fishers 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 Crohns 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.

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-&agr; 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-&agr; inhibitors and immunomodulators. Improved disease outcomes using combination therapy should be tempered by the risk of developing HSTCL.

Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System

The association between inhibition of tumour necrosis factor alpha (TNF‐α) and new onset of neurological adverse events (AEs) is unclear.

The Metoclopramide Black Box Warning for Tardive Dyskinesia: Effect on Clinical Practice, Adverse Event Reporting, and Prescription Drug Lawsuits

OBJECTIVES:We examined the effects of the black box warning about the risk of tardive dyskinesia (TD) with chronic use of metoclopramide on management of gastroparesis within a single clinical practice, and on reporting of adverse events.METHODS:Medical records of gastroparesis patients were evaluated for physician management choices. The FDA Adverse Event Reporting System (FAERS) was analyzed for event reports, and for lawyer-initiated reports, with metoclopramide from 2004 to 2010. Google Scholar was searched for court opinions against metoclopramide manufacturers.RESULTS:Before the black box warning, 69.8% of patients received metoclopramide for gastroparesis, compared with 23.7% after the warning. Gastroenterologists prescribed domperidone more often after than before the warning. Metoclopramide prescriptions decreased after 2008. Adverse event reporting increased after the warning. Only 3.6% of all FAERS reports but 70% of TD reports were filed by lawyers, suggesting a distortion in signal. Forty-seven legal opinions were identified, 33 from 2009–2010.CONCLUSIONS:The black box warning for metoclopramide has decreased its usage and increased its rate of adverse event reporting. Lawyer-initiated reports of TD hinder pharmacovigilance.

Relationship between mesenteric abnormalities on computed tomography and malignancy: clinical findings and outcomes of 359 patients.

Background: Mesenteric abnormalities are detected on abdominal computed tomography (CT) performed for various indications. Goals: Determine the risk of malignancy on follow-up of patients with these abnormalities without a preexisting malignancy. Study: Data were collected on all patients at NorthShore University HealthSystem with abdominal CT scan reports of mesenteric abnormalities labeled as “panniculitis” from January 2005 to April 2010. Results: Three hundred fifty-nine patients were identified, 81 (22.6%) had a known malignancy at the time of the index abdominal CT scan. Nineteen (6.8%) of the 278 had a new diagnosis of malignancy on evaluation of the findings of the index CT scan. Among the 240 (86.33%) that did not have a notation of the abnormality in their medical record, 11 (4.58%) developed a malignancy during the study period. Sixty-eight of the 248 (24.46%) without a known malignancy had diseases associated with mesenteric abnormalities. The presence of these were associated with a reduction in the likelihood that the abnormalities are associated with new or delayed diagnosis of a malignancy (odds ratio, 0.197; 95% confidence interval, 0.0045-0.8501; P=0.013). Progression of underlying malignancy was unlikely in those where the mesenteric abnormalities did not worsen in appearance on follow-up CT scans (odds ratio, 0.03268; 95% confidence interval, 0.0028-0.3761; P=0.0061). Conclusions: In the presence of an underlying disease associated with these findings, the subsequent finding of a malignancy is less likely. In addition, neglect of these findings may result in delayed diagnosis of cancer.

Lubiprostone induced ischemic colitis.

Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding.

Risk of Gastrointestinal Bleeding with Dabigatran: A Head-to-Head Comparative Study with Rivaroxaban

Introduction: The risk of gastrointestinal (GI) bleeding of dabigatran and rivaroxaban is relatively unexplored. The aim of our study was to compare this risk in both drugs. Methods: We examined the medical records of patients on either dabigatran or rivaroxaban from October 2010 to April 2013 in two hospitals. Results: A total of 374 patients (147 rivaroxaban vs. 227 dabigatran) were identified. GI bleeding occurred in 5.3% in the dabigatran when compared to 4.8% in the rivaroxaban group (p = 0.8215). Multivariate analysis showed that the odds of GI bleeding while on dabigatran for ≤40 days when compared to ≥40 days was 8.3 (p < 0.0001). In the rivaroxaban group, patients who were on the drug for ≤40 days had a higher incidence of bleeding when compared to those >40 days (OR = 2.8, p = 0.023). Concomitant use of antiplatelets (single or dual) or non-steroidal anti-inflammatory drugs was not associated with increased bleeding in the dabigatran group; however, the use of dual antiplatelet agents with rivaroxaban was associated with an increased risk of GI bleeding (OR = 7.4, p = 0.0378). Prior GI bleeding had a higher risk of bleeding in the rivaroxaban group (OR = 15.5, p = 0.0002). Conclusion: Dabigatran was not associated with a higher incidence of GI bleeding. Both drugs had a higher bleeding risk in the first 40 days.

Ischemic colitis: A forgotten entity. Results of a retrospective study in 118 patients

The aim of our study was to document our 6‐year experiences in identifing the clinical characteristics, laboratory findings, risk factors and the outcomes of patients with ischemic colitis (IC) in a community hospital setting.

Gastrointestinal Bleeding with Dabigatran, a Comparative Study with Warfarin: A Multicenter Experience

BACKGROUND/AIMS The risk of gastrointestinal (GI) bleeding with dabigatran when compared to warfarin has been controversial in the literature. The aim of our study was to assess this risk with the use of dabigatran. METHODS We examined the medical records of patients who were started on dabigatran or warfarin from October 2010 to October 2012. The study was conducted in two hospitals. RESULTS A total of 417 patients were included (208 dabigatran vs. 209 warfarin). GI bleeding occurred in 10 patients (4.8%) in the dabigatran group compared to 21 patients (10.1%) in the warfarin group (p=0.0375). Multivariate analysis showed that patients who were on dabigatran for ≤ 100 days had a higher incidence of GI bleeding than those who were on it for >100 days (p=0.0007). The odds of GI bleeding in patients who were on dabigatran for ≤ 100 days was 8.2 times higher compared to those who were on the drug for >100 days. The incidence of GI bleeding in patients >65 years old was higher than in those <65 years old (p=0.0453, OR=3). History of previous GI bleeding was another risk factor for GI bleeding in the dabigatran group (p=0.036, OR=6.3). The lower GI tract was the most common site for GI bleeding in the dabigatran group (80.0% vs. 38.1%, p=0.014). CONCLUSIONS The risk of GI bleeding was lower with dabigatran. The risk factors for GI bleeding with dabigatran were the first 100 days, age >65 years, and a history of previous GI bleeding.

Colonoscopy — Indications and Contraindications

This chapter discusses some of the major indications and contraindications for colonoscopy. Advances in colonoscopic techniques have expanded the role of colonoscopy beyond conventional screening, surveillance, and diagnosis to various complex therapeutic and interventional utilities. Several guidelines with new information are being published and updated regularly in the field of colonoscopy and are currently used in clinical practice. However, there is still a lack of welldesigned randomized clinical trials investigating the role of colonoscopy in early diagnosis and treatment of various conditions and its impact on long-term survival and disease status. Nevertheless, retrospective observational studies and a few randomized clinical trials abundantly supply data supporting the role of colonoscopy in the diagnosis and management of colonic pathologies in the absence of comparable alternatives.