Eli D. Ehrenpreis

Thalidomide therapy for patients with refractory Crohn's disease: An open-label trial

BACKGROUND & AIMS Inhibition of tumor necrosis factor is a proposed mechanism for the anti-inflammatory properties of thalidomide. We performed an open-label trial of thalidomide in refractory Crohns disease. METHODS Twenty-two patients with refractory Crohns disease (Crohns Disease Activity Index [CDAI] > 200 and/or draining perianal disease) initiated therapy with thalidomide, 200 mg at bedtime (18 patients), or 300 mg at bedtime (4 patients). CDAI and goal interval scores (GIS) were assessed at weeks 0, 4, and 12. Clinical response for patients with luminal disease was defined as reduction in CDAI score of >150 points and for fistula patients was 2 scores of >/=1+ in 3 parameters of the GIS. Clinical remission was defined as a total CDAI < 150 (luminal patients) or >/=2+ for all parameters of the GIS (fistula patients). RESULTS Nine patients with luminal disease and 13 with fistulas (16 male, 6 female) were enrolled. The median CDAI score at entry was 371 (95-468). Sixteen patients completed 4 weeks of treatment (12 clinical responses, 4 clinical remissions). All 14 patients completing 12 weeks met criteria for clinical response. Nine achieved clinical remission (3 luminal, 6 fistula patients). The median CDAI score was 175 (30-468; P < 0.001 vs. baseline). CONCLUSIONS Thalidomide is efficacious in some patients with refractory Crohns disease.

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.

Acute pancreatitis in human immunodeficiency virus-infected patients: a review.

Acute pancreatitis is a clinical condition that develops when active pancreatic inflammation is induced by stimuli noxious to the pancreas. Patients infected with human immunodeficiency virus (HIV) often have histologic abnormalities of the pancreas, and acute pancreatitis is much more common in HIV-infected patients than in the general population. This article reviews the epidemiology and etiology of acute pancreatitis in HIV-infected patients. The clinical presentation and treatment of acute pancreatitis in HIV-infected patients are also reviewed.

D-xylose testing.

The literature on D-xylose testing has been reviewed, stressing advances in our understanding of absorption in general (including D-xylose absorption), the relationship of D-xylose testing to the development of excellent serologic tests for the diagnosis of celiac disease, the use of D-xylose testing in the evaluation of diarrhea in acquired immunodeficiency syndrome, new information on breath testing for the evaluation of malabsorption, and recent information on the understanding of D-xylose absorption compared with transcellular vs. paracellular transport. The authors suggest ways in which D-xylose testing might be employed in malabsorption or diarrhea evaluations, including some algorithms.

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.

A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of Retinol Palmitate (Vitamin A) for Symptomatic Chronic Radiation Proctopathy

PURPOSEThis study was designed to determine whether oral retinol palmitate (vitamin A) can reduce the symptoms of radiation proctopathy.METHODSA randomized, double-blind trial comparing retinol palmitate (10,000 IU by mouth for 90 days) to placebo was conducted. Eligible patients were more than six months postpelvic radiotherapy and had significant symptoms as measured with the Radiation Proctopathy System Assessments Scale. Nineteen patients were randomized in total: ten to retinol palmitate and nine to placebo. The Radiation Proctopathy System Assessments Scale scores before and every 30 days for 90 days were measured. Five placebo nonresponders were crossed over to the retinol palmitate for another 90 days. Response was defined as a reduction in two or more symptoms by at least two Radiation Proctopathy System Assessments Scale points.RESULTSSeven of ten retinol palmitate patients responded, whereas two of nine responded to placebo (P = 0.057). Mean pre-post-treatment change in Radiation Proctopathy System Assessments Scale (Δ Radiation Proctopathy System Assessments Scale) in the retinol palmitate group was 11 ± 5, whereas Δ Radiation Proctopathy System Assessments Scale in the placebo group was 2.5 ± 3.6 (P = 0.013, Mann-Whitney U test). Additionally, all five placebo nonresponders who were crossed over to treatment with retinal palmitate responded to treatment.CONCLUSIONSIn our trial, retinol palmitate significantly reduced rectal symptoms of radiation proctopathy, perhaps because of wound-healing effects. The current results can serve as the foundation for future trials examining retinol palmitate in the multi-institutional setting.

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.

Thalidomide treatment for refractory Crohn's disease: a review of the history, pharmacological mechanisms and clinical literature

Several recent case reports and clinical trials have demonstrated that thalidomide is emerging as an efficacious alternative in the treatment of selected patients with refractory Crohns disease. The effects of thalidomide are at least partly mediated by down-regulation of tumour necrosis factor (TNF)-α, a potent proinflammatory cytokine. However, thalidomide is also known to inhibit angiogenesis, and it has several other well-described immunomodulatory properties. Clinical studies have confirmed that previously refractory Crohns disease patients respond to thalidomide, and many enter clinical remission. Efficacy usually occurs within 4 weeks. Thalidomide also has steroid-sparing properties, and it is particularly useful in treating oral and fistulous complications of Crohns disease. Although it is usually tolerable, careful monitoring is recommended to prevent toxicities, such as birth defects and peripheral neuropathy. This review provides a detailed summary of the literature to date on the use of thalidomide treatment for Crohns disease. Special attention is directed towards its history, mechanisms, and proposed role. The recent development of thalidomide analogues is also discussed briefly.

Review article: current therapeutic options for radiation proctopathy.

Radiation proctopathy is a common unfortunate complication following radiation therapy of pelvic malignancies. Symptoms of chronic radiation procto‐ pathy include haematochezia, urgency, constipation, tenesmus, diarrhoea and rectal pain.

How Drugs are Developed and Approved by the FDA: Current Process and Future Directions

OBJECTIVES:This article provides an overview of FDAs regulatory processes for drug development and approval, and the estimated costs associated with the development of a drug, and also examines the issues and challenges facing the FDA in the near future.METHODS:A literature search was performed using MEDLINE to summarize the current FDA drug approval processes and future directions. MEDLINE was further utilized to search for all cost analysis studies performed to evaluate the pharmaceutical industry R&D productivity and drug development cost estimates.RESULTS:While the drug approval process remains at high risk and spans over multiple years, the FDA drug review and approval process has improved, with the median approval time for new molecular drugs been reduced from 19 months to 10 months. The overall cost to development of a drug remains quite high and has been estimated to range from