Chrons

Cytokine Therapies for Crohn’s Disease

Kashaf Sherafgan, MD PGY 2, Team 4 Surgery Conference Mount Sinai Hospital August 9th 2005

Case: JW • 20 20--yearyear-old AA male • HPI • • • •

Abdominal cramping N/V, diarrhea Anorexia & weight loss (50 lbs/6months) Headaches

• PMH – CD since 2000 refractory to medical therapy

Case, cont.

• PHx: CD, appendectomy 1999 • Family Hx: non contributory • SHx: Denies ETOH, tobacco or recreational drug use • Medication: Remicade, mesalamine, budesonide, Mercaptopurine, Iron, Folic Acid

Case, cont.

• 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 perianal disease

Case, cont.

• 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 segment

• Colonoscopy (7/05) • Obstructing prepre-cecal mass that appeared to be of inflammatory etiology • Hemorrhoids

• Surgery 8/4 – Extended ICR with LOA • POD #5 – Tolerating PO, regular BF, awaiting DC

Crohn’s Disease • First documented by Morgagni in 1761 • Crohn Crohn,, Ginzburg and Oppenheimer in 1932 provided the pathologic and clinical findings of this inflammatory disease in young adults

Crohn’s Disease, cont.

• Chronic, transmural inflammatory disease of the GIT of unknown cause • Most commonly affects the small intestine and colon • Clinical manifestations • Abdominal pain • Diarrhea • Weight loss

Crohn’s Disease, cont.

• Complications • Intestinal obstruction • Localized perforation with fistula formation

• Medical and surgical treatments are palliative • Operative therapy can provide effective symptomatic relief

Gross Pathologic Features • Thickened grayishgrayish-pink or dull purple purple--red loops of bowel • “Skip areas” areas” • “Fat wrapping” wrapping” • thickened, firm, rubbery and virtually incompressible bowel wall

Gross Pathology, cont.

• • • •

Internal fistulas Thickened mesentery with enlarged LN “Transmural inflammation inflammation”” “Cobblestone appearance” appearance”

“Fat wrapping” and inflammation

Microscopic Features • Mucosal and submucosal edema • Chronic inflammatory infiltrate • Noncaseating granulomas

Noncaseating granulomas

Clinical Manifestations • Abdominal pain • Diarrhea – 85% • Systemic nonspecific symptoms • Low Low--grade fever • Weight loss • Loss of strength • Malaise

Diagnosis • Barium contrast studies • • • •

Cobblestone appearance Kantor string sign Fistulous tracts Skip lesions

• CT scan • Sigmoidoscopy or colonoscopy • Serologic markers (pANCA (pANCA,, ASCA)

String Sign

CD with multiple fistulous tracks

CT scan: marked thickening of the bowel

Complications • • • • •

Obstruction Perforation Fistulas Localized abscesses Toxic megacolon – marked colonic dilatation, abd tenderness, fever and leukocytosis

Etiology • Cause remains unknown • Main theories • Infectious • Immunologic • Genetic

• Other possibilities • Environmental and dietary factors • Smoking • Psychosocial factors

Etiology, cont.

• Infectious • Mycobacterial infections, particularly M. paratuberculosis and the measles virus • First proposed as a cause for Crohn’s disease was by Dalziel in 1913

Dalziel TK: Chronic interstitial enteritis. BMJ 2:1068, 1913

Etiology, cont.

• Immunologic • Humoral, as well as cellcell-mediated, immune reactions directed against intestinal cells, suggesting an autoimmune phenomenon • Role of cytokines, such as ILIL-1, ILIL-2, ILIL-8 and TNF--α, as contributing factors TNF • Remains controversial and may represent an effect of the disease process rather than an actual cause

Etiology, cont.

• Genetic • Single strongest risk factor is a relative w/ CD • NOD2 (IBD1, chromosome 16), an apoptosis regulatory protein, mediates the innate immune response • Allelic variants of NOD2 have a 4040-fold RR of CD • Other genomic regions include IBD2 on chromosome 12q and IBD3 on chromosome 6p • < 100% concordance rate b/w monozygotic twins

• Multiple causes (e.g. environmental factors)

Pathogenesis of Crohn’s Disease • Two phases of inflammation • Inductive phase • Effector phase – chronic inflammation • Both Th1 and Th2 pathways involved • Traditionally results from a dysregulated response by the acquired immune system • Recent evidence indicates that the innate immune system may be equally important

Common cellular pathways of activation

Management • Medical therapy • Aminosalicylates (e.g., sulfasalazine sulfasalazine,, mesalamine mesalamine)) • Corticosteroids • Immunosuppressive agents (e.g., azathioprine azathioprine,, 66mercaptopurine, and methotrexate) methotrexate) • Antibiotics (metronidazole (metronidazole,, ciprofloxacin, tetracycline, ampicillin,, and clindamycin ampicillin clindamycin)) • Infliximab (anti(anti-TNFTNF-α antibody)

• Surgery

Anti–InterleukinAnti– Interleukin-12 Antibody for Active Crohn’s Disease Mannon PJ et al New Engl J of Med 2004;35:2069

Methods • • • • • •

Multisite Randomized Double--blind, placeboDouble placebo-controlled 79 patients October 2000 to January 2002 15 centers in the US, Germany and the Netherlands

Methods, cont.

• AntiAnti-IL IL--12 1 mg/kg or 3 mg/kg SQ weekly x7 wks or placebo • Cohort 1 – One injection followed 4 wks later by one injection per week x6 wks • Cohort 2 – One injection per week x 7 wks • Followed for 18 wks after the final injection and were seen at 6, 12, and 18 wks

Methods, cont. â&#x20AC;˘ Colonoscopy before the first injection and 48 hrs after the final injection of study drug â&#x20AC;˘ Biopsy samples obtained w/in the same gut regions from areas w/ endoscopically apparent inflammation or ulcer borders

Inclusion Criteria • At least 18 years old • CDAI score of 220 to 450 w/in 2 weeks before beginning treatment • Diarrhea, abdominal pain, extraintestinal manifestations, hematocrit, weight loss, mass

• Eligible patients could continue to take concomitant medications

Exclusion Criteria • Medications: methotrexate, cyclosporine, tacrolimus, thalidomide, or mycophenolate • Steroids, NSAIDS, antibiotics • Ostomy, short bowel, obstruction, stricture • Probable requirement for intestinal surgery • C – diff colitis • Cushing’s syndrome • Active HBV, HCV, HIV, TB, Asthma • History of cancer • Pregnant or breastbreast-feeding

Assessments • Safety • Efficacy – Rates of response and remission • Response = Decrease in CDAI score > 100 • Remission = CDAI < 150

• Anti Anti--drug antibodies

Results • Cohort 1 – No significant differences in response rates • Cohort 2 • No statistical difference b/w placebo & 1 mg/kg antiantiILIL-12 • 3 mg/kg of antianti-IL IL--12 w/ higher response rates than placebo administration (75% vs. 25%, P=0.03) • At 18 weeks of FU, the difference in response rates was no longer significant (69% vs. 25%, P=0.08) • No statistical difference in remission rates (38% vs.

0%, P=0.07)

Results, cont.

• Decreases in the secretion of ILIL-12, INF INF--γ and TNFTNF-α accompanied clinical improvement in patients w/ anti ILIL-12

Adverse Effects • • • •

Local reactions at injection sites Transient and mild Required no treatment More frequent among patients who had a response to anti– anti–IL IL--12 than among patients who did not have a response (44 of 52 [85 %] vs. 7 of 11 [64 %])

Conclusions • Treatment with a monoclonal antibody against ILIL-12 may induce clinical responses and remissions • This treatment is associated with decreases in Th1Th1-mediated inflammatory cytokines (IL(IL-12, IFN IFN--γ, TNFTNF-α) at the site of disease

Conclusions, cont.

• Incidence of infections not significantly increased in the anti– anti–IL IL--12 group • The risk of infection with longerlonger-term use remains to be established • These preliminary data will help guide the design of future studies to assess the efficacy of anti– anti–IL IL--12 in Crohn’s disease

References • Mannon PJ et al: AntiAnti- ILIL- 12 antibody for active Crohn’s Disease NEJM 2004 Nov 11;351(20):2069--79 11;351(20):2069 • Podolsky DK et al: Inflammatory bowel disease NEJM 2002 Aug 8;347(6):4178;347(6):417-29 • Cominelli F et al: CytokineCytokine-based therapies for CDCD- new paradigms NEJM 2004 Nov 11; 351(20):2045--8 351(20):2045 • Sabiston Board Review