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Introduction Chronic granulomatous disease (CGD) is a rare immunodeficiency caused by mutations in the NADPH oxidase complex. Dysregulated immune function may cause inflammatory bowel disease (IBD). Patients with CGD-associated IBD may not respond to or may develop serious infections as a result of traditional IBD therapies such as vedolizumab and infliximab. Ustekinumab is approved for use in Crohn’s disease and ulcerative colitis however there is scarce data on its efficacy and safety in CGD. Aims To evaluate the efficacy and safety of ustekinumab for CGD-associated IBD. Methods A retrospective chart review was conducted on CGD patients followed at a single center who had consented to participate in a natural history study. Clinical, laboratory, and endoscopic data were extracted in those that had received ustekinumab for IBD. Results Eight patients were found. Four were male and four were female. Five were white, one was Asian, one was black, and one was mixed race. Median age at diagnosis of CGD was 3 years (IQR 8) and of IBD was 15.5 years (IQR 20). Median age at initiation of ustekinumab was 27.5 years (IQR 14) and median duration on ustekinumab was 10 months (IQR 7). Six had colonic disease, two had ileocolonic disease, and six had perianal disease. Six failed other biologics (n=5 for vedolizumab, n=1 for infliximab, n=1 for adalimumab). Six patients symptomatically improved whereas two had no improvement. Changes in hemoglobin and C-reactive protein were equivocal. Three patients had improved endoscopic findings, two had unimproved findings, and three patients lacked this data. Overall, four patients achieved clinical remission. However, none of the five patients with endoscopic reevaluation achieved endoscopic remission. Three patients discontinued therapy due to lack of response: two required surgery and one underwent stem cell transplant. Fungal pneumonia (n=2), otitis media (n=1), oral herpes simplex virus 1 (n=1), and viral gastroenteritis (n=1) were reported. One infusion reaction occurred. Discussion In our cohort of eight patients with CGD-associated IBD receiving ustekinumab, results were mixed with four patients experiencing some degree of clinical or endoscopic improvement including four who achieved clinical remission. Multiple CGD-related variables may account for the mixed laboratory findings. Four of the five patients with endoscopic reevaluation had pre-existing strictures that would be unlikely to reverse with medical therapy alone. Of these, two had otherwise resolved endoscopic inflammation. Only two patients had no endoscopic improvement. Two serious infections occurred however CGD confers increased infectious susceptibility and no infections lead to discontinuation of therapy. Given these promising results, further formalized study of ustekinumab in CGD-associated IBD is needed.

Chronic granulomatous disease (CGD) is a rare disorder caused by genetic mutations of the nicotinamide adenine dinucleotide phosphate oxidase complex (NADPH), occurring in approximately 1/200,000 individuals. These mutations decrease residual reactive oxygen species (ROS) levels, leading to dysregulated inflammation. Inflammatory manifestations can be widespread, including severe and recurrent infections. The gastrointestinal tract is the most commonly affected organ with resultant inflammatory bowel disease, termed CGD colitis. Manifestations include abdominal pain, diarrhea with or without blood, nausea/vomiting, obstructions, and fistulas which can occur in a perianal distribution. Patients are often misdiagnosed with Crohn’s disease or ulcerative colitis, especially in the absence of extensive infectious history. We aimed to characterize the small bowel involvement in CGD. Data is presented from a combined retrospective and ongoing prospective observational study of patients with genetically-confirmed CGD who underwent wireless video capsule endoscopy (VCE) at the National Institutes of Health Clinical Center (n = 8). VCEs were performed for clinical indications including abdominal pain (88%), diarrhea (75%), bloody stools (38%), and/or nausea/vomiting (25%). One patient (13%) underwent VCE for otherwise unexplained high inflammatory markers. Laboratory evaluation was significant for leukopenia/leukocytosis (75%), anemia (63%), and elevated C reactive-protein levels (63%). Seven patients (88%) had prior small bowel imaging, however none showed evidence of any abnormality in this organ. The most common VCE findings were ulcers and/or erosions (88%). Most patients also displayed other mucosal changes consistent with inflammation such as erythema and/or edema (88%). There was also evidence of blood or hematin on 63% of the endoscopies. While therapies for CGD colitis are targeted towards colonic involvement, our findings show that the vast majority of symptomatic patients also have active small bowel disease including ulcers, erosions, evidence of bleeding, and other signs of inflammation. These findings, however, are not specific to CGD. Given that certain biologic medications used for Crohn’s disease and ulcerative colitis have been shown to increase the risk of life-threatening infections in patients with CGD, it is important to keep other forms of IBD, especially CGD-related IBD, in mind when interpreting small bowel capsule endoscopy in patients with suspected IBD. Lastly, in patients with confirmed CGD colitis, small bowel disease should be rigorously investigated, and therapy should also seek to address small bowel involvement. Of note, our patients did not display any radiographic abnormalities of the small bowel. Due to our small sample size, we aim to study additional patients in the future to augment our data.