Biologics in Inflammatory Bowel Disease
Crohn’s Disease
First documented by Morgagni in 1761 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 grayish-pink or dull purplered loops of bowel “Skip areas” “Fat wrapping” thickened, firm, rubbery and virtually incompressible bowel wall
Gross Pathology, cont.
Internal fistulas Thickened mesentery with enlarged LN “Transmural inflammation” “Cobblestone 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-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, 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 cell-mediated, immune reactions directed against intestinal cells, suggesting an autoimmune phenomenon – Role of cytokines, such as IL-1, IL-2, IL-8 and TNF-α, as contributing factors – 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 40-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, mesalamine) – Corticosteroids – Immunosuppressive agents (e.g., azathioprine, 6mercaptopurine, and methotrexate) – Antibiotics (metronidazole, ciprofloxacin, tetracycline, ampicillin, and clindamycin) – Infliximab (anti-TNF-α antibody)
Surgery
Anti–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, placebo-controlled 79 patients October 2000 to January 2002 15 centers in the US, Germany and the Netherlands
Methods, cont.
Anti-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.
Colonoscopy before the first injection and 48 hrs after the final injection of study drug 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 breast-feeding
Assessments
Safety Efficacy – Rates of response and remission
– Response = Decrease in CDAI score > 100 – Remission = CDAI < 150
Anti-drug antibodies
Results
Cohort 1 – No significant differences in response rates Cohort 2 – No statistical difference b/w placebo & 1 mg/kg anti-IL-12 – 3 mg/kg of anti-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 IL-12, INF-γ and TNF-α accompanied clinical improvement in patients w/ anti IL-12
Adverse Effects
Local reactions at injection sites Transient and mild Required no treatment More frequent among patients who had a response to anti–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 IL-12 may induce clinical responses and remissions This treatment is associated with decreases in Th1-mediated inflammatory cytokines (IL-12, IFN-γ, TNF-α) at the site of disease
Conclusions, cont.
Incidence of infections not significantly increased in the anti–IL-12 group The risk of infection with longer-term use remains to be established These preliminary data will help guide the design of future studies to assess the efficacy of anti–IL-12 in Crohn’s disease
References
Mannon PJ et al: Anti- IL- 12 antibody for active Crohn’s Disease NEJM 2004 Nov 11;351(20):2069-79 Podolsky DK et al: Inflammatory bowel disease NEJM 2002 Aug 8;347(6):417-29 Cominelli F et al: Cytokine-based therapies for CD- new paradigms NEJM 2004 Nov 11; 351(20):2045-8 Sabiston Board Review