H.A. Kader, G. Telega, E. Rand, E.S. Maller and R.N. Baldassano
6-Mercaptopurine (6-MP) and azathiopurine (AZA) are used to treat severe cases of IBD. Common medical side effects include infection and leukopenia (8-15%), hepatitis (5-10%) and pancreatitis (3%). 6-MP is S-methylated to its effective 6-methylmercaptopurine metabolites by the enzyme thiopurine methyltransferase (TPMT). A competitive pathway also converts 6-MP to its cytotoxic 6-thioguanine nucleotides (6-TGNs) that are associated with bone marrow suppression (leukopenia, neutropenia, thrombocytopenia). Patients with decreased TPMT activity have increased levels of 6-TGN. TPMT levels have also been associated with specific genotypes. 89% of the general population is homozygous for TPMTH and have a TPMT level of 13.8-25.1 U/mL RBC.
To determine whether there is a relationship between the development of elevated aminotransferases, leukopenia or pancreatitis and the TPMT level in patients with IBD.
The medical records between 7/94 and 6/98 of patients with IBD were retrospectively reviewed for TPMT levels. All erythrocyte TPMT levels were determined at the MAYO Medical Laboratories. Determination of leukopenia (WBC<4000), elevated aminotransferases and pancreatitis was performed.
22 patients with IBD, mean age 13.7 years old, were treated with 6-MP or AZA and had TPMT levels obtained. 14 patients had Crohn's disease (CD) and 8 patients had ulcerative colitis (UC). AZA was used in 8 patients with CD and 2 with UC. 6-MP was used in 6 patients with CD and 6 with UC. The mean dose of 6-MP and AZA were 0.9 and 1.8 mg/kg/day, respectively. The TPMT levels ranged from 10.7 to 27.5 U/mL with a mean of 17.2 ( 3.2 U/mL. The mean TPMT level for patients who had transaminase elevations was 16.8 ( 1.4 U/mL and for leukopenia was 17.8 ( 1.0 U/mL which were similar to the mean TPMT level of the study population. For these patients with side effects, their mean dose of 6-MP/AZA was identical to that of all study patients. 1 patient, who's TPMT level was 15.1 U/mL, developed pancreatitis.
The TPMT level and dose of 6-MP/AZA were not predictive for the development of leukopenia, elevated transaminases or pancreatitis. Therefore, close monitoring of the WBC, ALT, and AST is indicated. Further studies of patients with IBD who have a low TPMT level, <5.0 U/mL, will be necessary to determine if this enzyme level is of clinical value. NASPGN Abstracts. <i/>J. of Pediatric Gastroenterology and Nutrition. October 1998.
M. Stephens, M. Shepanski, P. Mamula, J. Markowitz, L. Hurd and R. Baldassano
To determine the incidence of infusion reaction in a cohort of pediatric patients with inflammatory bowel disease (IBD) who receive infliximab.
A retrospective review of all infliximab infusions administered to patients at the IBD Center at The Children's Hospital of Philadelphia was undertaken. Data was obtained from a database and pharmacy records. Chart review and interviews with physicians, patients and families were used to obtain missing data.
A total of 291 infusions were administered to 66 patients (30 female and 36 male). The number of infusions each patient received ranged from 1 to 17. 10 (15%) of the 66 patients experienced infusion reactions including chest tightness, shortness of breath, hypoxemia, flushing, fever, headaches, nausea/vomiting, itching, and reduced blood pressure. 7 patients who had infusion reactions received repeat doses of infliximab (6 with premedication). 3 of these patients experienced infusion reactions and 4 tolerated repeat dosing without difficulty. 1 patient had 4 infusion reactions with repeated dosing. This patient received premedication with acetaminophen, diphenhydramine, corticosteroids and a slower infusion rate was used. subsequent reactions were mild. Another patient had anaphylaxis and required admission to the intensive care unit. A subsequent infusion at a slower rate with premedication was given without reaction. The dose was completed at the lower rate without further difficulty. In all cases, the infusion was suspended with the onset of symptoms, yet all but 1 case, the infusion was restarted and completed at a lower rate. Therapies employed for infusion reactions included diphenhydramine (n=8), acetaminophen (n=3), epinephrine (n=3), supplemental oxygen (n=1), inhaled bronchodilator (n=1). 2 patients received no medication and the infusion was completed at a lower rate. Out of the total 291 infusions, 16 (5%) infusion reactions occurred.
Infusion reactions to infliximab occur in children at a rate similar to that of adults. Infusion reaction (even when severe) does not preclude further use of infliximab.
Presented at Digestive Disease Week, May 19-23, 2002, San Francisco, California
Contact the Center for Pediatric Inflammatory Bowel Disease.