Chronic Granulomatous Disease Managing GI Issues

Transcription

1 Chronic Granulomatous Disease Managing GI Issues N I C H O L A S H A R T O G, M D D i r e c t o r o f P e d i a t r i c / A d u l t P r i m a r y I m m u n o d e f i c i e n c y C l i n i c A s s i s t a n t P r o f e s s o r M i c h i g a n S t a t e U n i v e r s i t y C o l l e g e o f H u m a n M e d i c i n e S p e c t r u m H e a l t h / H e l e n D e v o s C h i l d r e n s H o s p i t a l

2 Disclosures H o r i z o n P h a r m a S p e a k i n g a n d c o n s u l t i n g

3 O v e r a l l Inflammatory manifestations are difficult to treat Inflammatory bowel disease, lung granulomas, genitourinary, ocular No specific recommendations exist for treatment of inflammatory bowel disease (IBD) in CGD involves immunosuppressing an immunodeficient patient

4 Colitis T r e a t m e n t o f i n f l a m m a t o r y b o w e l d i s e a s e ( I B D ) Mainstay of treatment is immunosuppression Corticosteroids and tumor necrosis factor (TNF) inhibition common

5 T N F - α i n h i b i t o r s i n C G D Works to dampen inflammatory response Leads to recurring problems with infection Time to first serious infection is 3-12 infusions Associated with deaths in 2 of 5 patients TNF-α inhibitors are profoundly dangerous and contraindicated in CGD

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7 O r a l G l u c o c o r t i c o i d s Often first line therapy for inflammatory manifestations Rapidly decrease symptoms and induce remission Burst and taper 1 mg/kg/day burst typical Looooooooong taper (often 3-6 months) Relapses common after cessation (up to 71%) One large cohort showed no steroid refractory cases

8 O r a l G l u c o c o r t i c o i d s Allows to control inflammation/symptoms while waiting for another medication to work Can remain on long term Some require long term low dose prednisone (5-10 mg daily) Significant long term side effects Infection, growth restriction, osteoporosis, weight gain, diabetes, adrenal suppression, mood disturbance, glaucoma, etc

9 S t e r o i d s p a r i n g a g e n t s Sulfasalazine and derivatives (mesalamine) 6-Mercaptopurine G-CSF case reports Thalidomide case reports Difficult to use in the US

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11 B i o l o g i c s Vedolizumab Α4β7 inhibitor

12 B i o l o g i c s Vedolizumab 2 series 6 patients and 2 patients All with improvement of symptoms and withdrawal of steroids Only 1 patient with infection pneumonia and inguinal adenopathy Retrospective cohort at NIH Promising results May be limited by loss of response over time

13 B i o l o g i c s Ustekinumab Anti-IL-23 approved for psoriasis and psoriatic arthritis

14 B i o l o g i c s Ustekinumab Case report of IL-23 blockade in CGD colitis Effective at treating colitis Returned on cessation of therapy Discontinued due to infection after 14 months

15 IL- 1 β i n h i b i t i o n Anakinra IL-1β is an inflammatory cytokine produced by inflammasome of innate immune system IL-1β blockade decreases inflammasome activation and restores autophagy in mice Autophagy normal process, maintains homeostasis by protein degredation and turnover of destroyed cell organelles for new cell formation Macrophages in CGD defect in autophagy inflammasome activation and IL-1β release Mixed results so far in human case series

16 m T O R i n h i b i t i o n Rapamycin (mtor inhibitor) shown to be autophagy inducer Shown in vitro to increase autophagy and decrease IL-1β release Rapamycin could be a new therapeutic option Some in vitro data that anakinra and rapamycin may work synergistically

17 S u r g e r y Occasionally needed Indications include: Small bowel obstruction Gastric outlet obstruction

18 D e f i n i t i v e t r e a t m e n t Prednisone dependent IBD is indication for HSCT in CGD Preferred to get inflammation under control prior to transplant Has been shown to induce complete remission of inflammatory manifestations

19 A r e w e c a u s i n g i t? Studies have shown colitis is unrelated/independent to bactrim, itraconazole or IFN-γ administration

20 T a k e h o m e Lesson learned from TNFα We are using immunosuppressants in immunodeficient patients Infections are very real risk Close monitoring necessary Close collaboration between gastroenterology and immunology necessary Oral corticosteroids work long term side effects Many options and more emerging options for treatment Difficult to treat HSCT and gene therapy are definitive treatments

21 Questions