Derrick J. Stobaugh

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.

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.

Maternal and foetal adverse events with tumour necrosis factor-alpha inhibitors in inflammatory bowel disease.

Transplacental transfer of tumour necrosis factor‐alpha (TNF‐α) inhibitors has been shown in mothers receiving therapy for inflammatory bowel disease (IBD).

Alleged isotretinoin-associated inflammatory bowel disease: Disproportionate reporting by attorneys to the Food and Drug Administration Adverse Event Reporting System

BACKGROUND Some studies have purported to link isotretinoin prescribed for acne with the development of inflammatory bowel disease (IBD). OBJECTIVE We sought to identify existence of disproportionate attorney-initiated reporting of isotretinoin-associated IBD in the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS A total of 3,338,835 cases (2003-2011) were downloaded from the FAERS. These were queried for IBD cases reported with isotretinoin for a usage indication of acne while recording reporter category. Trends were analyzed over time for reports by attorneys for all medications compared with reports of IBD with isotretinoin. Signal inflation factor was calculated to determine the distortion of pharmacovigilance signals for IBD with isotretinoin. RESULTS There were 2214 cases of IBD resulting from isotretinoin. Attorneys reported 1944 (87.8%) cases whereas physicians reported 132 (6.0%) and consumers reported 112 (5.1%) cases (P value < .01). For the entire FAERS, only 87,905 of the total 2,451,314 (3.6%) reports for all drug reactions during the same time period were reported by attorneys (P value < .01). The signal inflation factor for IBD with isotretinoin for attorney-initiated reports was 5.82, signifying a clear distortion. LIMITATIONS The accuracy of reports was not ascertained. CONCLUSIONS Attorney-initiated reports inflate the pharmacovigilance signal of isotretinoin-associated IBD in the FAERS.

Ischemic Colitis with Type I Interferons Used in the Treatment of Hepatitis C and Multiple Sclerosis: An Evaluation from the Food and Drug Administration Adverse Event Reporting System and Review of the Literature:

OBJECTIVE To better characterize the association between type I interferons and ischemic colitis (IC) in patients with the hepatitis C virus (HCV) and multiple sclerosis (MS), by analyzing reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) and the published literature. DATA SOURCES A total of 2,562,390 reports of adverse events between January 2003 and June 2011 were downloaded from the FDA AERS. A literature review was performed on PubMed (January 1966–August 2012) using the MeSH terms interferon or interferon alfa or interferon beta and ischemic colitis separated by the Boolean operator “and” between the first 3 terms and the last term. Additional literature was identified by conducting a hand search of the reference list of the published literature identified in the initial search. STUDY SELECTION AND DATA EXTRACTION Cases were restricted to those with an indication of HCV or MS, a primary suspect drug of a type I interferon, and a reaction of IC. Full-length reports were requested and organized by type of interferon, age, sex, concomitant drugs, and comorbidities. The Naranjo prob a bility scale was used to define cases as definite, probable, possible, or doubtful drug-induced adverse events. DATA SYNTHESIS Type I interferons, including interferon alfa (IFN-α) and interferon beta (IFN-β), are approved for the treatment of HCV and MS. IFN-α has been shown to induce IC, but a relationship between type I interferons and IC has not been clarified in the medical literature. Fifty-six primary suspect reports of type I interferons associated with IC in patients with HCV or MS were identified from the FDA AERS. Seventeen cases were reported with IFN-α and 39 cases were reported with IFN-β. The majority of the cases were in females (80%) and those between the ages of 50 and 65 years (52%). The Naranjo probability scale identified 13 probable and 4 possible cases of IFN-α–induced IC, and 19 probable and 20 possible cases of IFN-β–induced IC. In the literature, 11 cases of IFN-α–induced IC were reported, while there were no reports with IFN-β. CONCLUSIONS Our study suggests a possible association between treatment with type I interferons and the development of IC. Further research to determine the mechanism of this association is warranted.

Hospitalizations for vaccine preventable pneumonias in patients with inflammatory bowel disease: a 6-year analysis of the Nationwide Inpatient Sample

Background Pneumonias are among the most common causes of hospitalization among inflammatory bowel disease (IBD) patients. Guidelines published in 2004 advocate vaccination against Streptococcus pneumoniae and influenza virus. We sought to examine trends in hospitalizations for vaccine preventable pneumonias among IBD patients since the availability of published guidelines, and to identify whether Haemophilus influenzae is a causative organism for pneumonia hospitalizations among IBD patients. Methods This cross-sectional study on the Nationwide Inpatient Sample was used to identify admissions for pneumonias in patients with IBD between 2004 and 2009. A multivariate logistic regression analysis was performed comparing IBD patients to controls, accounting for potential confounders. Results There were more admissions for S. pneumoniae pneumonia than influenza virus or H. influenzae (787, 393, and 183 respectively). Crohn’s disease (CD) as well as ulcerative colitis (UC) patients did not demonstrate increased adjusted odds of hospitalization for S. pneumoniae pneumonia (1.08; confidence interval [CI] 0.99–1.17 compared to 0.93; CI 0.82–1.06 respectively). Increased adjusted odds for hospitalization for pneumonias due to influenza virus were seen among UC patients in the bottom quartile of income (1.86; CI 1.46–2.37). Adjusted odds for H. influenzae pneumonia admission in patients with UC and CD patients were increased compared to controls (1.42; CI 1.13–1.79 and 1.28; CI 1.06–1.54, respectively). Conclusion The study identified lowest income UC patients as having higher adjusted odds, and these patients should be targeted for influenza virus vaccination. Additionally, H. influenzae may be another vaccine preventable cause for pneumonia among IBD patients.

Effect of Tumor Necrosis Factor–α Inhibitors on Drug-Induced Pancreatitis in Inflammatory Bowel Disease

Background: Mesalamine and thiopurines (6-mercaptopurine and azathioprine) have been shown to increase the risk of developing acute pancreatitis in inflammatory bowel disease (IBD) patients. Tumor necrosis factor-α (TNF-α) inhibitors have been shown to protect against pancreatitis in animal models. Objective: To determine the risk of pancreatitis when comparing thiopurine monotherapy, mesalamine monotherapy, and thiopurine and mesalamine dual therapy to identical treatments but with the addition of a TNF-α inhibitor. Methods: Using a case-control design, the Food and Drug Administration Adverse Event Reporting System was queried for cases of pancreatitis and control reactions in IBD patients on a thiopurine or mesalamine. The proportional reporting ratio method was used to compare the different therapy regimens with the same regimen combined with a TNF-α inhibitor. Results: In all, 549 cases and controls were identified. When comparing thiopurine monotherapy with thiopurines combined with a TNF-α inhibitor, the odds of pancreatitis were lower in those on combination therapy (odds ratio [OR] = 0.04; 95% CI = 0.01-0.12). A similar trend was seen when comparing mesalamine monotherapy to mesalamine combined with a TNF-α inhibitor (OR = 0.08; 95% CI = 0.04-0.14) and when comparing those on both a thiopurine and mesalamine with those on all 3 therapies (OR = 0.04; 95% CI = 0.01-0.16). Conclusions: Combination therapy with TNF-α inhibitors appears to be associated with a lower risk of pancreatitis in IBD patients on mesalamine, thiopurines, or a combination of both. Physicians should consider using TNF-α inhibitors in those with the greatest risk of pancreatitis, although prospective studies are needed.

Determinants of Palliative Care Utilization Among Patients Hospitalized With Metastatic Gastrointestinal Malignancies

Background: Gastrointestinal tract cancers account for a significant proportion of the national cancer burden. Aim: We sought to explore patient- and hospital-level determinants of palliative care utilization among patients hospitalized with metastatic gastrointestinal tract cancers using a national database. Methods: An analysis of the 2012 National Inpatient Sample was performed. International Classification of Diseases, Ninth Revision codes were used to identify hospital discharges associated with metastatic digestive tract cancers and patient/hospital covariates for inclusion in a logistic regression model. Total charges and length of stay were analyzed in a linear regression model. Results: Compared to males, females were more likely to receive inpatient palliative care (adjusted odds ratio [OR] 1.12, P = .002). No difference was seen between white and Asian patients (adjusted OR 1.2, P = .11) or Native Americans patients (adjusted OR 1.4, P = .22). However, relative to white patients, African Americans (adjusted OR 1.13, P = .02) and Hispanics (adjusted OR 1.25, P = .001) had significantly higher odds of inpatient palliative care. Medicare patients were least likely to receive palliative care compared to those with Medicaid or commercial payers. Length of stay during these hospitalizations was longer in African Americans (P = .0001), Asians (P = .0001), and Native Americans (P = .03) compared to white patients. No difference was seen when total charges were compared between white and African American patients (P = .08). Conversely, total charges were higher in Hispanics (P = .005) and Asians (P = .001) relative to white patients. Conclusion: Gender and racial differences exist in utilization of inpatient palliative care among patients hospitalized with metastatic gastrointestinal tract cancers.

African Americans Have Better Outcomes for Five Common Gastrointestinal Diagnoses in Hospitals With More Racially Diverse Patients

OBJECTIVES:We sought to characterize the relationship between hospital inpatient racial diversity and outcomes for African-American patients including rates of major complications or mortality during hospitalization for five common gastrointestinal diagnoses.METHODS:Using the 2012 National Inpatient Sample database, hospital inpatient racial diversity was defined as the percentage of African-American patients discharged from each hospital. Logistic regression was used to predict major complication rates or death, long length of stay, and high total charges. Control variables included age, gender, payer type, patient location, area-associated income quartile, hospital characteristics including size, urban vs. rural, teaching vs. nonteaching, region, and the interaction of the percentage of African Americans with patient race.RESULTS:There were 848,395 discharges across 3,392 hospitals. The patient population was on average 27% minority (s.d.±21%) with African Americans accounting for 14% of all patients. Overall, African-American patients had higher rates of major complications or death relative to white patients (adjusted odds ratio (aOR) 1.19; 95% confidence interval (CI) 1.16–1.23). However, when treated in hospitals with higher patient racial diversity, African-American patients experienced significantly lower rates of major complications or mortality (aOR 0.80; 95% CI 0.74–0.86).CONCLUSIONS:African Americans have better outcomes for five common gastrointestinal diagnoses when treated in hospitals with higher inpatient racial diversity. This has major ramifications on total hospital charges.

Su1160 Risk of Melanoma and Non-Melanoma Skin Cancers With Pharmacotherapy Among Inflammatory Bowel Disease Patients: An Analysis of the Food and Drug Administration Adverse Event Reporting System

Background: Natalizumab is a humanized monoclonal antibody to alpha-4 integrin that is approved by the Food and Drug Administration (FDA) for the induction of remission and maintenance of moderate to severe Crohns disease (CD). Progressive Multifocal Leukoencephalopathy (PML) secondary to an opportunistic infection with John Cunningham virus has been reported with natalizumab usage in CD. We sought to clarify the risk of other opportunistic infections in CD patients treated with natalizumab by analyzing reports to Adverse Event Reporting System (AERS) since its approval. Methods: The AERS is a publicly available database of voluntary reports for post marketing surveillance of all FDA approved drugs. 2,053,106 files between January 2008 and June 2011 were downloaded and analyzed using SPSS 20 (IBM Co. Armonk, NY, USA). They were queried for Primary Suspect (PS) reports of adverse events where natalizumab (or its trade names) was used for the treatment of Crohns disease. Control drugs (5-aminosalicylic acid and sulphasalazine, including trade names) served as a basis of comparison. Further queries for outcomes of viral, bacterial, fungal and parasitic infection as well as control reactions (syncope, hernia, deafness and vertigopredefined to have no association with natalizumab or control drugs) were performed using reactions terms from the Medical Dictionary for Regulatory Activities. Each report also had concomitant medications analyzed. Any patients reported who used a concomitant biologic medication (including a tumor necrosis factor α inhibitors) were excluded from analysis. Use of immunomodulators (methotrexate, azathioprine, and mercaptopurine) or systemic corticosteroids was noted. Odds ratios for the risk of opportunistic infections with natalizumab were calculated using the Fischers exact test. Results: 141 PS reports of infections were identified with natalizumab among CD patients, with a majority having a bacterial origin (115 reports, 82%). The reports demonstrated a female predominance (64.54%) with a mean age of 41 ±14 years. Similar usage of corticosteroids was seen among natalizumab cases and controls (14.18% versus 25.93%, p = 0.27) while a higher usage of immunomodulators was seen among control cases (0.71% versus 14.82%, p = 0.004). Significant odds of developing infections with natalizumab were seen only in the subcategory of bacterial infections (table 1). The majority of bacterial infections (figure 1) occurred in the respiratory system (33 reports, 29%) followed by 22 reports (19%) of disseminated infections. Conclusion: Risk of infections in patients receiving natalizumab for CD appears to be restricted to bacterial infections, with a female predominance and mainly affecting the respiratory system. Using this method, significant risk of other opportunistic infections was not found. Table 1: Reported risk of various infections in Crohns disease patients treated with Natalizumab