Cytokine Therapy for Crohn's Disease - KAfgan

Cytokine Therapy for Crohn's Disease - KAfgan - Cytokine...

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Unformatted text preview: Cytokine Therapies for Crohn’s Disease Disease Kashaf Sherafgan, MD PGY 2, Team 4 Surgery Conference Mount Sinai Hospital August 9th 2005 Case: JW Case: • • 20-year-old AA male HPI • • • • • Abdominal cramping N/V, diarrhea Anorexia & weight loss (50 lbs/6months) Headaches PMH – CD since 2000 refractory to medical PMH therapy Case, cont. Case, • • • • PHx: CD, appendectomy 1999 Family Hx: non contributory SHx: Denies ETOH, tobacco or SHx: recreational drug use recreational Medication: Remicade, mesalamine, Medication: budesonide, Mercaptopurine, Iron, Folic Acid Acid Case, cont. Case, • Physical Exam • • • • AVSS, NAD CTA b/l, RRR, S1 + S2 Abd: Soft, ND, mild tenderness RLQ, BS + nl Rectal exam: guaiac –ve, no evidence of Rectal perianal disease perianal Case, cont. Case, • Small bowel series (7/05) • Evidence of Crohn’s in ileocecal region • Mucosal edema of distal ileum and cecum • Marked dilation of ileum proximal to the abnormal Marked segment segment • Colonoscopy (7/05) • Obstructing pre-cecal mass that appeared to be of Obstructing inflammatory etiology • Hemorrhoids • • Surgery 8/4 – Extended ICR with LOA POD #5 – Tolerating PO, regular BF, awaiting DC Crohn’s Disease Crohn’s • • First documented by Morgagni in 1761 Crohn, Ginzburg and Oppenheimer in Crohn, 1932 provided the pathologic and clinical findings of this inflammatory disease in young adults disease Crohn’s Disease, cont. Crohn’s • • • Chronic, transmural inflammatory disease Chronic, of the GIT of unknown cause of Most commonly affects the small intestine Most and colon and Clinical manifestations • • • Abdominal pain Diarrhea Weight loss Crohn’s Disease, cont. Crohn’s • Complications • Intestinal obstruction • Localized perforation with fistula formation Localized • • Medical and surgical treatments are Medical palliative Operative therapy can provide effective Operative symptomatic relief symptomatic Gross Pathologic Features Gross • • • • Thickened grayish-pink or dull purple-red Thickened loops of bowel loops “Skip areas” “Fat wrapping” thickened, firm, rubbery and virtually thickened, incompressible bowel wall incompressible Gross Pathology, cont. Gross • • • • Internal fistulas Internal Thickened mesentery with enlarged LN Thickened “Transmural inflammation” “Cobblestone appearance” “Fat wrapping” and inflammation Microscopic Features Microscopic • • • Mucosal and submucosal edema Mucosal Chronic inflammatory infiltrate Chronic Noncaseating granulomas Noncaseating granulomas Noncaseating Clinical Manifestations Clinical • • • Abdominal pain Abdominal Diarrhea – 85% Diarrhea Systemic nonspecific symptoms • Low-grade fever • Weight loss • Loss of strength • Malaise Diagnosis Diagnosis • Barium contrast studies • • • • • • • Cobblestone appearance Kantor string sign Fistulous tracts Skip lesions CT scan Sigmoidoscopy or colonoscopy Serologic markers (pANCA, ASCA) String Sign CD with multiple fistulous tracks CT scan: marked thickening of the bowel CT Complications Complications • • • • • Obstruction Perforation Fistulas Fistulas Localized abscesses Toxic megacolon – marked colonic Toxic dilatation, abd tenderness, fever and leukocytosis leukocytosis Etiology Etiology • • Cause remains unknown Main theories • Infectious • Immunologic • Genetic • Other possibilities • • • Environmental and dietary factors Smoking Psychosocial factors Etiology, cont. Etiology, • Infectious • Mycobacterial infections, particularly M. Mycobacterial paratuberculosis and the measles virus paratuberculosis • First proposed as a cause for Crohn’s First disease was by Dalziel in 1913 disease Dalziel TK: Chronic interstitial enteritis. BMJ 2:1068, 1913 Etiology, cont. Etiology, • Immunologic • Humoral, as well as cell-mediated, immune Humoral, reactions directed against intestinal cells, suggesting an autoimmune phenomenon • Role of cytokines, such as IL-1, IL-2, IL-8 and Role TNF-α, as contributing factors • Remains controversial and may represent an Remains effect of the disease process rather than an actual cause actual Etiology, cont. Etiology, • Genetic • Single strongest risk factor is a relative w/ CD Single • NOD2 (IBD1, chromosome 16), an apoptosis regulatory protein, mediates the innate immune response • Allelic variants of NOD2 have a 40-fold RR of CD Allelic NOD2 • Other genomic regions include IBD2 on chromosome Other IBD2 12q and IBD3 on chromosome 6p IBD3 • < 100% concordance rate b/w monozygotic twins • Multiple causes (e.g. environmental factors) Pathogenesis of Crohn’s Disease Pathogenesis • • • • Two phases of inflammation Two • Inductive phase • Effector phase – chronic inflammation Both Th1 and Th2 pathways involved Traditionally results from a dysregulated Traditionally response by the acquired immune system response Recent evidence indicates that the innate Recent immune system may be equally important immune Common cellular pathways of activation Common Management Management • Medical therapy • • • Aminosalicylates (e.g., sulfasalazine, mesalamine) Corticosteroids Immunosuppressive agents (e.g., azathioprine, 6mercaptopurine, and methotrexate) • Antibiotics (metronidazole, ciprofloxacin, tetracycline, Antibiotics ampicillin, and clindamycin) ampicillin, • Infliximab (anti-TNF-α antibody) Infliximab • Surgery Anti–Interleukin-12 Antibody Anti–Interleukin-12 for Active Crohn’s Disease Mannon PJ et al Mannon New Engl J of Med 2004;35:2069 New Methods Methods • • • • • • Multisite Randomized Double-blind, placebo-controlled 79 patients October 2000 to January 2002 15 centers in the US, Germany and the 15 Netherlands Netherlands Methods, cont. Methods, • • • • Anti-IL-12 1 mg/kg or 3 mg/kg SQ weekly Anti-IL-12 x7 wks or placebo x7 Cohort 1 – One injection followed 4 wks Cohort later by one injection per week x6 wks later Cohort 2 – One injection per week x 7 wks Followed for 18 wks after the final injection Followed and were seen at 6, 12, and 18 wks and Methods, cont. Methods, • • Colonoscopy before the first injection and Colonoscopy 48 hrs after the final injection of study drug 48 Biopsy samples obtained w/in the same gut Biopsy regions from areas w/ endoscopically apparent inflammation or ulcer borders apparent Inclusion Criteria Inclusion • • At least 18 years old CDAI score of 220 to 450 w/in 2 weeks CDAI before beginning treatment before • Diarrhea, abdominal pain, extraintestinal Diarrhea, manifestations, hematocrit, weight loss, mass manifestations, • Eligible patients could continue to take Eligible concomitant medications concomitant Exclusion Criteria Exclusion • • • • • • • • • Medications: methotrexate, cyclosporine, Medications: tacrolimus, thalidomide, or mycophenolate tacrolimus, Steroids, NSAIDS, antibiotics Ostomy, short bowel, obstruction, stricture Probable requirement for intestinal surgery Probable C – diff colitis diff Cushing’s syndrome Active HBV, HCV, HIV, TB, Asthma History of cancer Pregnant or breast-feeding Assessments Assessments • • Safety Efficacy – Rates of response and remission • • • Response = Decrease in CDAI score > 100 Remission = CDAI < 150 Anti-drug antibodies Results Results • • Cohort 1 – No significant differences in response rates Cohort 2 • No statistical difference b/w placebo & 1 mg/kg antiIL-12 • 3 mg/kg of anti-IL-12 w/ higher response rates than mg/kg placebo administration (75% vs. 25%, P=0.03) placebo • At 18 weeks of FU, the difference in response rates was At no longer significant (69% vs. 25%, P=0.08) no • No statistical difference in remission rates (38% vs. No 0%, P=0.07) 0%, Results, cont. Results, • Decreases in the secretion of IL-12, INF-γ and TNF-α accompanied clinical and improvement in patients w/ anti IL-12 improvement Adverse Effects Adverse • • • • Local reactions at injection sites Transient and mild Required no treatment More frequent among patients who had a More response to anti–IL-12 than among patients who did not have a response (44 of 52 [85 %] vs. 7 of 11 [64 %]) %] Conclusions Conclusions • • Treatment with a monoclonal antibody Treatment against IL-12 may induce clinical responses against and remissions and This treatment is associated with decreases This in Th1-mediated inflammatory cytokines (IL-12, IFN-γ, TNF-α) at the site of disease (IL-12, at Conclusions, cont. Conclusions, • • • Incidence of infections not significantly Incidence increased in the anti–IL-12 group increased The risk of infection with longer-term use The remains to be established remains These preliminary data will help guide the These design of future studies to assess the efficacy of anti–IL-12 in Crohn’s disease efficacy References References • • • • Mannon PJ et al: Anti- IL- 12 antibody for active Mannon Crohn’s Disease NEJM 2004 Nov 11;351(20):2069-79 11;351(20):2069-79 Podolsky DK et al: Inflammatory bowel disease Podolsky NEJM 2002 Aug 8;347(6):417-29 NEJM Cominelli F et al: Cytokine-based therapies for Cominelli CD- new paradigms NEJM 2004 Nov 11; 351(20):2045-8 Sabiston Board Review ...
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