Infliximab to Treat Crohn'S-like Inflammatory Bowel Disease in Chronic Granulomatous Disease

This study will determine if the drug infliximab is safe for treating inflammatory bowel disease (IBD) in patients with chronic granulomatous disease (CGD). IBD is an inflammation or irritation of the gut that leads to symptoms such as diarrhea, bloating and stomach cramps. CGD is an inherited disease affecting white blood cells called neutrophils in which patients are susceptible to repeated bacterial and fungal infections. They also have a higher incidence of some autoimmune diseases, such as IBD. Infliximab is approved to treat Crohn's disease, an IBD similar to that seen in patients with CGD. Patients 10 years of age and older with CGD and IBD may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, electrocardiogram (EKG), tuberculosis skin test (PPD skin testing), and stool test for the presence of infections. Additional tests may be done, including colonoscopy (procedure using a flexible tube through the rectum to examine the lining of the gut) and imaging studies such as an x-ray, chest CT scan (test using a special x-ray machine), MRI (test using a magnetic field and radio waves), and barium studies (study using a drinkable solution of barium to help enhance the x-ray pictures of the gut). Participants are divided into patients with IBD symptoms (Group 1) and patients without IBD symptoms (Group 2) for the following procedures: Group 1 Patients are evaluated every 6 months with a medical history and physical examination for signs and symptoms of IBD. Patients who are taking moderate to high doses of steroid medications have their medication slowly lowered (tapered) and are evaluated every 3 months for a total of 2 years. Patients in this group who start to develop IBD symptoms are moved to Group 2 for treatment with infliximab (see below). Group 2 Patients in Group 2 receive infliximab infusions at 2-week intervals for three doses. The drug is given over a 2-hour period through a catheter placed in a vein. Patients are evaluated with a medical history, physical exam, and blood tests the day of each dose. One week after the last dose, they have another evaluation, including a colonoscopy. Patients who respond well to infliximab may continue to receive the drug every 2 months for a total of 1 year, with evaluations at every dosing visit. At the end of the first year of receiving infliximab, all patients have follow-up evaluations every 6 months for a total of 2 years. Group 3 Subjects who volunteer to undergo colonoscopy and research biopsies that serve as controls for evaluation of the patient gut samples.

Sex

All

Minimum age

10 Years

* INCLUSION CRITERIA:

Group One

* Must have a confirmed CGD diagnosis
* Must have IBD documented by medical history or documented IBD endoscopically.
* Must not be pregnant or breastfeeding
* Must have a home physician
* Must be willing to submit samples for storage.

Group Two:

* Must have a confirmed CGD diagnosis
* Must have IBD documented by medical history or documented IBD endoscopically.
* Must be symptomatic
* Must have negative results on stool examination for culture of enteric pathogens, such as Salmonella, Shigella, Yersinia, Campylobacter, E. coli O157/H7, Clostridium difficile toxin assay, enteric parasites and their ova such as Cryptosporidia, Cyclospora, Microsporidia and Giardia (by stool enzyme immunoassay \[EIA\]) prior to the start of receiving TNF? inhibitors.
* Must not be pregnant or breastfeeding
* If of childbearing potential, one must agree to consistently use contraception, while on the study medication.
* Must have a recent chest CT (within 3 months) to confirm absence of tuberculosis (TB) infection
* Must have a home physician
* Must be willing to submit samples for storage.

Group Three:

* Must be willing to undergo upper and lower endoscopy and mucosal biopsies for research purpose
* Must be greater than or equal to 18 years old and weigh greater than or equal to 15 kg.
* Must not be pregnant
* Must be willing to submit samples for storage.

EXCLUSION CRITERIA:

Group One:

\- Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study.

Group Two:

* Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study
* Positive TB diagnosis
* Patients who are in the at-risk group for treatment such as history of tuberculosis, congestive cardiac failure or myocardial infarction within the last 12 months unstable angina, thrombocytopenia (platelet \< 100, 000), uncontrolled hypertension
* Acute systemic or intestinal infection(s)
* Evidence of Hepatitis B or C infection
* Signs and symptoms of hepatotoxicity
* Pregnant or breastfeeding
* History of cancer within the last 10 years
* The presence of certain types of acquired abnormalities of immunity such as HIV, cytotoxic chemotherapy for malignancy could be grounds for possible exclusion if, in the opinion of the investigator, the presence of such disease process interferes with evaluation of a co-existing abnormality of immunity that is a subject of study under this protocol.
* Co-existing Th2-type inflammatory disease
* Current active bowel obstruction, intestinal perforation, or significant GI hemorrhage.
* Live vaccine within 4 weeks prior to therapy or potential need for a live vaccine during the study.
* Unwillingness to undergo testing or procedures associated with this protocol.

Group Three:

* Acute systemic or intestinal infection requiring antibiotics
* Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study
* The presence of certain types of acquired abnormalities of immunity such as HIV, cytotoxic chemotherapy for malignancy could be grounds for possible exclusion if, in the opinion of the investigator, the presence of such disease process interferes with evaluation of a co-existing abnormality of immunity that is a subject of study under this protocol.
* Unwillingness to undergo testing or procedures associated with this protocol.

• BACKGROUNDVignais PV. The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci. 2002 Sep;59(9):1428-59. doi: 10.1007/s00018-002-8520-9. PMID 12440767
• BACKGROUNDSegal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). 2000 May;79(3):170-200. doi: 10.1097/00005792-200005000-00004. PMID 10844936
• BACKGROUNDWinkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, Dickler H. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000 May;79(3):155-69. doi: 10.1097/00005792-200005000-00003. PMID 10844935
• BACKGROUNDBuckner CM, Moir S, Kardava L, Ho J, Santich BH, Kim LJ, Funk EK, Nelson AK, Winckler B, Chairez CL, Theobald-Whiting NL, Anaya-O'Brien S, Alimchandani M, Quezado MM, Yao MD, Kovacs JA, Chun TW, Fauci AS, Malech HL, De Ravin SS. CXCR4/IgG-expressing plasma cells are associated with human gastrointestinal tissue inflammation. J Allergy Clin Immunol. 2014 Jun;133(6):1676-85.e5. doi: 10.1016/j.jaci.2013.10.050. Epub 2013 Dec 25. PMID 24373354