Immune-mediated colitis associated with ocrelizumab: A new safety risk.

BACKGROUND: An association between certain immunomodulatory therapies (rituximab, ipilimumab, and other immune checkpoint inhibitors) and inflammatory (non-ischemic and non-infectious) colitis in oncologic and non-oncologic patient populations is well documented in the medical literature. OBJECTIVE: The purpose of this case series is to describe adverse event reports of new onset, inflammatory colitis in association with ocrelizumab in patients with multiple sclerosis submitted to U.S. Food and Drug Administration (FDA) or published in the medical literature. METHODS: The FDA Adverse Event Reporting System (FAERS) and medical literature were searched. RESULTS: A review of postmarketing cases from FAERS and published medical literature identified 38 cases consistent with inflammatory, non-ischemic, and non-infectious colitis in association with ocrelizumab. The median time-to-onset was 8 months. Cases were reported using the following diagnostic terms: Crohn's disease (13), unspecified colitis (11), microscopic colitis (5), ulcerative colitis (5), medication-induced colitis (3), and autoimmune colitis (2). CONCLUSIONS: This case series highlights ocrelizumab induced immune-mediated colitis that can be clinically severe and potentially life-threatening. Based on the findings of this review, the ocrelizumab Prescribing Information was amended to include immune-mediated colitis in the Warnings and Precautions section.

Well-defined and reliable clinical outcome assessments for pediatric Crohn disease: a critical need for drug development.

OBJECTIVES: The aim of the present study was to identify areas for further development of clinical outcome assessment (COA) in pediatric Crohn disease (CD). METHODS: The study analyzed the measurement properties of all existing COA tools for pediatric CD in literature and published registration trials of approved drugs for pediatric CD based on criteria described in Food and Drug Administration guidance for patient-reported outcome (PRO) development. RESULTS: The Pediatric Crohn's Disease Activity Index (PCDAI) and its derivatives (abbreviated, short, modified, and weighted PCDAIs) were reviewed. The Crohn's Disease Activity Index (CDAI) and Harvey-Bradshaw index (HBI), designed for adult patients, have been adapted for use in a few pediatric CD studies. The use of PCDAI as an endpoint in Remicade and Humira trials led to the Food and Drug Administration-approved indication in pediatric CD. Common issues in measurement properties of COA tools included the absence of direct patient or caregivers' input to generate the items measuring signs and symptoms; absence of evidence demonstrating correlation with clinically relevant inflammation observed with endoscopic measures; lack of standardization in measurement, age-appropriate interviewer script, and response rating criteria for the physician interviewer. CONCLUSIONS: Available evidence indicates that CDAI, HBI, and 5 versions of the PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials intended to support approval of products intended to treat pediatric CD. In order to facilitate pediatric drug development, a well-defined, reliable, sensitive, and globally recognized PRO that measures signs and symptoms in children with CD and that can be used in conjunction with endoscopy-based endpoints and/or biomarkers is sorely needed.

Identifying predictive factors for posttransplant lymphoproliferative disease in pediatric solid organ transplant recipients with Epstein-Barr virus viremia.

Epstein-Barr virus (EBV) viremia (EV) in pediatric solid organ transplant (SOT) recipients is a significant risk factor for posttransplant lymphoproliferative disease (PTLD) but not all patients with EV develop PTLD. We identify predictive factors for PTLD in patients with EV. We conducted a retrospective chart review of all pediatric SOT recipients (0 to 21 y) at a single institution between 2001 and 2009. A total of 350 pediatric patients received a SOT and 90 (25.7%) developed EV. Of EV patients, 28 (31%) developed PTLD. The median age at transplant was 11.5 months in the PTLD group and 21.5 months in the EV-only group (P=0.003). Twenty-three (37%) EV-only patients had immunosuppression increased before EV, compared with 28 (100%) of PTLD patients (P<0.001). The median peak EBV level was 3212 EBV copies/10 lymphocytes for EV-only and 8392.5 EBV copies/10 lymphocytes for PTLD (P=0.005). All patients who developed PTLD had ≥1 clinical symptoms. Younger age at transplant, increased immunosuppression before EV, higher peak EBV level, and presence of clinical symptoms have predictive value in the development of PTLD in SOT patients with EV.

Off-label use of medicine in pediatrics: focus on gastrointestinal diseases.

PURPOSE OF REVIEW: To provide current information on off-label medication use in pediatric gastroenterology, including a discussion on US legislative efforts to address the issue. RECENT FINDINGS: Medications used to treat pediatric gastrointestinal illnesses are frequently prescribed off-label. Acid suppressors, antiemetics, laxatives, and antitumor necrosis factor therapies are types of medications frequently used off-label in the pediatric gastroenterology arena. Pediatric studies conducted under US Federal laws are generating much-needed data on the safety and effectiveness of medications used to treat pediatric patients. Moreover, a new US law, the Food and Drug Administration Safety and Innovation Act, may further the development of pediatric medications in part by requiring pediatric-specific study plans earlier in the overall drug development process. As of today, there still are gaps in our knowledge about these medications, including for the treatment of pediatric gastroenterology diseases. SUMMARY: Medications are widely used off-label in pediatrics, including medications intended to treat gastrointestinal diseases, such as antitumor necrosis factor and laxatives. Although legislation is helping to generate and make available important information about pediatric medications, most still do not contain pediatric data. Therefore, providers need to understand the potential risks and benefits of prescribing off-label products to pediatric patients.

Graft rejection in pediatric liver transplant patients with Epstein-Barr viremia and post-transplant lymphoproliferative disease.

Treatment of primary EV and PTLD in pediatric LT recipients (pLT) involves IS reduction/cessation. Retrospective review of pLT at our institution from 2001-2009 was conducted to characterize risk factors for GR after EV/ PTLD. Of 184 pLT, EV occurred in 61 (33%) at mean 16.5 m (0-82) and PTLD in 18 (9.8%) at mean 17.7 m (3-78) post-LT. Median age at pLT was 11 m (1-245 m) and follow-up six yr. For EV, 86% underwent IS reduction and 51% received antivirals. GR occurred in 12 (27.9%) with EV and 15 (83.3%) after PTLD diagnosis (relative risk of GR for PTLD 2.98). GR treated with methylprednisolone bolus in half and/or oral IS in half. Following GR therapy, four had PTLD relapses, no graft loss and one EV patient required re-transplantation. GR history before EV was a risk factor for GR after EV (p = 0.024). GR at any point after pLT was a risk factor for PTLD (p = 0.001). Children with EV and GR prior to EV should be monitored closely for GR after IS reduction and GR is a significant risk factor for PTLD. Most children with PTLD eventually developed GR.

Recurrent intrahepatic pigmented stones after liver transplantation in a patient with hemoglobin SC disease: case report and review of the literature.

Patients with hemoglobinopathies may have hepatic involvement, which if severe, can lead to chronic liver disease and a need for liver transplant. Here, we present a case of a 16-yr-old female adolescent who presented to our center with hemoglobin SC disease, obstructive jaundice because of pigmented intrahepatic biliary stones, and progressive liver disease. She underwent a successful liver transplant but a few years later, she developed recurrent cholangitis and graft dysfunction because of recurrent intrahepatic biliary stones. Recurrent formation of intrahepatic stones after liver transplant is a rare and severe complication in patients with hemoglobinopathies. We recommend hypertransfusion therapy and surveillance imaging studies after liver transplant for early detection and prevention of this complication.

Analysis of current treatments used in clinical practice in a pediatric summer camp population for children with inflammatory bowel disease.

BACKGROUND: Many treatment options exist for children with inflammatory bowel disease (IBD), yet the lack of clinical guidelines for management has lead to great variation in care. The purpose of this project was to evaluate current treatment modalities in children from the Northeast US who applied to the 2010 session of Camp Oasis, a Crohn's and Colitis Foundation of America (CCFA)-sponsored camp for children ages 8-17 with medically stable IBD. METHODS: Patient demographics, medical history, and current medications were entered into the camp database. The subjects were divided into two groups; Crohn's disease (CD) or ulcerative colitis/indeterminate colitis (UC/IC). In all, 164 applicants were included, 121 (74%) with CD and 43 (26%) with UC/IC. RESULTS: There were no significant differences between the two groups with respect to median age at the time of camp, median age at diagnosis, or median length of illness. Of the 121 applicants with CD, 13 (10.7%) were on an antibiotic, 56 (46.3%) were on a 5-aminosalicylate (5-ASA), 10 (8.3%) were on corticosteroids, 57 (47.1%) were on immunomodulators, and 44 (36.4%) were on a biologic agent. Six (5%) were on both an immunomodulator and a biologic agent. Of the 43 subjects with UC/IC, 27 (62.7%) were on a 5-ASA, two (4.7%) were on corticosteroids, 13 (30.2%) were on an immunomodulator, and four (9.3%) were on a biologic agent. The groups were similar with regard to surgery (20.7% for CD and 18.6% for UC/IC). CONCLUSIONS: Identifying current treatment patterns may serve to highlight variations in care among this pediatric IBD population.