crohns disease

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Crohns Disease : 

Crohns Disease Rakesh Kumar.Adi M.D.,(D.M)

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Crohn's disease is a chronic, episodic, inflammatory condition of the gastrointestinal tract. It can affect any part of the gastrointestinal tract from mouth to anus .

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Described in 1932 by Crohn, Ginsburg, and Oppenheimer of Mount Sinai Hospital in New York. Terminal ileitis Regional enteritis Granulomatous enterocolitis

Epidemiology : 

Epidemiology White 43.6 per 100000 African-American 29.8 per 100000 Asian 5.6 per 100000 Hispanic 4.1 per 100000 Pediatrics 4.5 per 100000

Contd… : 

Contd… Most reports show a female-to-male 1.2:1 Incidence is bimodal with a peak in the 3rd dec and a smaller peak in the 7th decade. Racial and ethnic differences. It is more common in whites than in blacks, Jewish than in non-Jewish.

ETIOPATHOGENESIS : 

ETIOPATHOGENESIS

GENETICS : 

GENETICS First genetic susceptibility factor found: CARD15/NOD 2 gene mutations on Chrom 16 A toll-like receptor involved in sensing the bacterial environment Present in 20% Crohns patients, but not in UC Phenotypic link to ileal disease +/- fistulae

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Gene Chromosome SLC22A4 & SLC22A5 5 DLG5 10 PPARG 3

ENVIRONMENT : 

ENVIRONMENT Asso. with higher socio-economic status . Inc. risk of C.D. among women who use OCP. (NSAIDs) have been implicated as a potential precipitant of new cases, Increased intake of refined sugars and a paucity of fresh and vegetables in the diet . Crohn's disease is more prevalent among smokers, and smokers have more surgery for their disease .

Immune response : 

Immune response Crohn’s disease is a pre dominantly TH1- mediated process . C.D pts are characterized by enhanced recruitment and retention of effector macrophages, neutrophils and T cells into the inflamed intestine,

Pathogenesis : 

Pathogenesis

Pathology : 

Pathology The early features 1. The aphthous ulcer. 2. The granulomas (15% to 70% ) They are usually sparse, scattered, and not well formed. In contrast to tuberculosis, there is little or no central necrosis

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Late features larger ulcers with a stellate appearance . Linear or serpiginous ulcers may form when multiple ulcers fuse . The classic cobblestone appearance, Sinus tracts, and strictures . Morphologically characterized by transmural inf. and skip lesions .

Classification of C.D. : 

Classification of C.D. Based on anatomic location

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Based on behaviour of disease Stricturing disease. Penetrating disease. Inflammatory disease.

Classifications of Crohn’s disease Vienna Montreal : 

Classifications of Crohn’s disease Vienna Montreal

Clinical Features : 

Clinical Features Abdominal pain Diarrhea Fever Fatigue Rectal bleeding Weight loss Anorexia Nausea Physical examination Abdominal tenderness Palpable mass Guaiac-positive stool

Extraintestinal Manifestations : 

Extraintestinal Manifestations Upto 25% of pts C.D. Musculoskeletal Mucocutaneous Ocular Hepatobiliary Renal and Genitourinary Coagulation and Vascular

Investigation : 

Investigation Colonoscopy Barium study CT enteroclysis MR fistulogram Capsule endoscopy Serology

Goals of Treatment : 

Goals of Treatment Induce remission Maintain remission Prevent complications (e.g., fistulas) Improve quality of life Reduce or eliminate steroid use Avoid hospitalization and surgery Restore and maintain nutrition Hanauer S, et al. A J G. 2001;96:635.

TREATMENT : 

TREATMENT Dietary changes Lifestyle changes Drug therapies Surgery

DIETARY CHANGES : 

DIETARY CHANGES Taking specific nutritional supplements, Limiting dairy products, Eating low-fat foods, Avoiding foods high in undigestible fiber Eating smaller, more frequent meals.

LIFESTYLE CHANGES : 

LIFESTYLE CHANGES Exercise Adequate rest Stress reduction Avoid smoking

Drug Therapies : 

Drug Therapies 5-Aminosalicylates (5-ASA) Glucocorticoids (steroids) Antibiotics Immunosuppressants Biological Therapy

Aminosalicylates : 

Aminosalicylates Sulfasalazine (5-aminosalicylic acid and sulfapyridine as carrier substance) Mesalazine (5-ASA), e.g. Asacol, Pentasa Balsalazide (prodrug of 5-ASA) Olsalazine (5-ASA dimer cleaves in colon) Oral, rectal preparation

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USE Sulfasalazine 4 to 6 g/day is useful in the treatment of mild-to-moderate colonic Crohn's disease Maintaining remission.

Glucocorticoids : 

Glucocorticoids Inhibition of inflammatory pathways Budesonide Prednisolone. USE Moderate to severe disease Relapses Effective for the short-term control of symptoms of Crohn's disease but are neither effective nor safe for long-term maintenance of response.

Antibiotics : 

Antibiotics Metronidazole, ciprofloxacin Precise role in management is unclear Antibiotics are used to treat perineal disease, fistulas, and active Crohn's disease.

Immunosupressants : 

Immunosupressants Drugs include: Thiopurines Azathioprine 6-mercaptopurine Methotrexate Cyclosporin Interfere with inflammatory pathway Need close monitoring for toxicity

Thiopurines : 

Thiopurines Azathioprine, mercaptopurine Inhibit ribonucleotide synthesis Inducing T cell apoptosis Azathioprine metabolised to mercaptopurine and 6-thioguanine nucleotides Azathioprine 2 to 2.5 mg/kg/day 6-MP 1 to 1.5 mg/kg/day.

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Use Active and chronic disease Steroid sparing

methotrextrate : 

methotrextrate Inhibits dihydrofolate reductase Probably inhibition of cytokine and eicosanoid synthesis Use Relapsing or active CD refractory or intolerant to AZA or Mercaptopurine

Cyclosporin : 

Cyclosporin Preventing clonal expansion of T cell subsets Use Steroid sparing Active and chronic disease

Biological Therapy : 

Biological Therapy Infliximab Anti TNF-α monoclonal antibody It binds to membrane-bound TNF- α and neutralizes its activity & also reduces serum TNF- α levels

REMICADETM (infliximab)Mechanisms of Action : 

REMICADETM (infliximab)Mechanisms of Action

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Use Fistulizing CD Severe active CD refractory/intolerant of steroids or immunosuppression Side effects Disseminated tuberculosis ; Fungal infection Hypersensitivity reactions ; Demyelinating dis. Lymphoma ANA, ss DNA antibodies, lupus-like reaction

Other medications : 

Other medications Anti- diarrhoeals. Loperamide (Imodium) Laxatives ..senna, bisacodyl Pain relievers. acetaminophen . Iron supplements Nutrition

Working Definitions of C.D Activity : 

Working Definitions of C.D Activity Mild to moderate disease The patient is ambulatory and able to take oral alimentation. Tenderness, painful mass, obstruction, or weight loss of more than 10 percent. Moderate to severe disease Either the patient has failed treatment for mild to moderate disease OR including fever, significant weight loss, abdominal pain or tenderness, intermittent nausea and vomiting, or significant anemia.

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Severe fulminant disease Either the patient has persistent symptoms despite outpatient steroid therapy OR, high fever ,vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. Remission The patient is asymptomatic OR without inflammatory sequelae, including patients responding to acute medical intervention. Hanauer SB, Am J Gastroenterol 2001;96:635-43.

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Management of Fistulizing C.D

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Lifetime risk of fistula development in patients with Crohn’s disease 20-40% Development of fistula may precede or coincide with the diagnosis of CD Rate of recurrence 34-82%

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Infliximab Rutgeerts P et al. NEJM 1999;340:1398-405

Other anti-TNF-α therapies : 

Other anti-TNF-α therapies Thalidomide Destabilizes TNF-α mRNA Rapidly effective Pentoxiphylline Inhibits phosphodiesterase IV, limiting TNF-α transcription Disappointing clinical efficacy Etanercept Recombinant soluble TNF receptor ineffective CDP-571: More humanized anti-TNF-α antibody Adalimumab: Fully humanized anti-TNF-α antibody

CDAI : 

CDAI

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CDAI score Remission <150 Severe disease >450.

Surgery : 

Surgery INDICATIONS Stricture and obstruction unresponsive to medical therapy Refractory fistula Abscess Fulminant disease Colon dysplasia or cancer

Surgery : 

Surgery Types of surgery for CD include: Stricturoplasty Small bowel resection . Colectomy .

Natural history : 

Natural history The course is highly variable . In the first year after diagnosis, the cumulative relapse rate is high app 50%.

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Active disease in the preceding year yields a high likelihood of active disease in the next year. Conversely, a year in which symptoms are quiescent has an 80% probability of being followed by another year without exacerbation.

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Population-based studies from Scandinavia analysis has shown that 22% of pts remain in remission, 25% experience chronically active symptoms, 53% have a course that fluctuates between active and inactive disease. Over time, appr. 10% of patients may be disabled by their disease.

Colorectal cancer in CD : 

Colorectal cancer in CD Risk factors History of colonic (or ileocolonic) involvement long disease duration. The cancer risks in CD and UC are probably equivalent for similar extent and duration of disease. 22% developed dysplasia or cancer by the fourth surveillance exam after a negative screening colonoscopy.

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CHILDREN AND ADOLESCENTS Appr. 25% of new C.D. diagnoses are made in persons < 20 yrs of age Consequences disturbances in physical growth, sexual maturation psychosocial development.

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PREGNANCY depends on the status of the disease at conception. Among women with active disease at conception, the “one third rule” applies. Higher incidence of adverse pregnancy outcomes in patients with IBD Cornish, J. Gut. 2007 Jun;56(6):830-7.

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thanq

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