Ulcerative Colitis : UPDATED

2. Ulcerative Colitis : UPDATED By TARIK ZAHER , MD Assistant professor of Tropical Medicine , Zagazig University ,Egypt

3. EPIDEMIOLOGY • In general, there has been a distinct north-south gradient in risk. • In North America, incidence rates range from 6.0 to 15.6 cases per 100,000 person-years. • In contrast, studies have reported significantly lower incidence rates of 0.6 to 6 per 100,000 person-years in other parts of the world, including Asia, Africa, and Latin America.

4. The etiology of UC is currently unknown but is likely multifactorial; complex interaction of three elements: genetic susceptibility, host immunity, and environmental factors. ETIOLOGY AND PATHOGENESIS

5. GENETICS • Family history is one of the most important risk factors for developing the disease. • There are susceptibility genes for UC on chromosomes 1, 2, 3, 5, 6, 7, 10, 12, and 17. • The C3435T polymorphism for the human multidrug resistance 1 (MDR1) gene is linked to susceptibility for UC . • Several centers have reported an association between severe disease and a rare allele of HLA-DR1 (DRB1*0103).

6. ENVIRONMENTAL FACTORS • Several infectious organisms, including mycobacteria and viruses, have been implicated in the pathogenesis of IBD. • Three studies have identified more than 45,000 bacterial small-subunit (SSU) rRNA genes in UC patients. • A breakdown in the balance between protective and harmful intestinal bacteria, termed dysbiosis, can lead to disease. • Smoking ,intestinal parasites and appendectomy are protective.

7. IMMUNE FACTORS • Breaches in the well-regulated mucosal immune system lead to the chronic, uncontrolled mucosal inflammation observed in UC(increase TH1). • The concept that UC is an autoimmune disease is supported by its increased association with other autoimmune disorders, including thyroid disease, diabetes mellitus, and pernicious anemia. • Studies have suggested that pANCAmay be associated with a more-aggressive disease course. • A novel T-cell–mediated inflammatory pathway, which appears to be involved in the pathogenesis of both Crohn's disease and UC, has been discovered and centers on the Th17 cell lineage. • Th17 cells have been shown to produce a variety of cytokines, most notably IL-6 and IL-17. IL-17 is a potent proinflammatory cytokine that not only facilitates T-cell activation but also stimulates a variety of cells.

8. 45% of patients with UC have disease limited to the rectosigmoid, 35% have disease extending beyond the sigmoid but not involving the entire colon, and 20% of patients have pancolitis. PATHOLOGY

9. Macroscopically(ENDOSCOPIC) • The mucosa in UC appears hyperemic, edematous, and granular in mild disease. As disease progresses, the mucosa becomes hemorrhagic, with visible punctateulcers. These ulcers can enlarge and extend into the lamina propria. • Epithelial regeneration with recurrent attacks results in the formation of pseudopolyps. • Another characteristic appearance of long-standing disease is atrophic and featureless colonic mucosa.

10. Microscopically • Neutrophilic infiltration of colonic crypts gives rise to cryptitis and ultimately to crypt abscesses with neutrophilic accumulations in crypt lumens. This migration of neutrophils from the circulation into the lamina propria occurs in response to a variety of chemoattractants, including chemotactic peptides of colonic bacteria, IL-8, activated complement, platelet-activating factor, and leukotriene B4. • Chronic inflammatory infiltrate. • Inflammation in UC characteristically is confined to the mucosa.

11. Following the initial flare, 40% to 65% of patients have an intermittent course, and 5% to 10% of patients have a chronic continuous course.Up to 10% of patients have a severe first attack ultimately requiring colectomy. DIAGNOSIS

12. symptoms • Common symptoms include diarrhea, rectal bleeding, passage of mucus, tenesmus, urgency, and abdominal pain. In more-severe cases, fever and weight loss may be prominent.

13. SIGNS • Patients with mild or even moderately severe disease exhibit few abnormal physical signs. • Patients with severe attacks also might appear well, but most are ill with tachycardia, fever, orthostasis, and weight loss. • In fulminant colitis, the abdomen often becomes distended and firm, with absent bowel sounds and signs of peritoneal inflammation. • There may be aphthoid ulceration of the oral mucosa. Clubbing of the fingernails is a manifestation of chronic disease. Peripheral edema can occur secondary to hypoalbuminemia. • Signs of extraintestinal manifestations

14. LABORATORY FINDINGS • Hematologic changes, including anemia, leukocytosis, and thrombocytosis, reflect active disease. • Iron deficiency anemia may be present because of chronic blood loss. Anemia also may be present secondary to bone marrow suppression resulting from chronic inflammation or medications, including azathioprine, 6-mercaptopurine (6-MP), and sulfasalazine. • Serum inflammatory markers including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated in active disease.

15. ENDOSCOPY • Colonoscopy is not recommended in patients with severely active disease for fear of perforation; care must be taken to avoid excessive distention.

18. RADIOLOGY • A plain film can give considerable information with respect to the extent of disease. The presence of marked colonic dilatation suggests fulminant colitis or toxic megacolon. • Barium enema provides information on their location, length, and diameter and allows visualization of the entire colon when the presence of strictures precludes advancement of the colonoscope.

23. Truelove and Witts Classification of the Severity of Ulcerative Colitis Mild <4 stools/day, without or with only small amounts of bloodNo feverNo tachycardiaMild anemiaESR < 30 mm/hr Moderate Intermediate between mild and severe Severe >6 stools/day, with bloodFever > 37.5°CHeart rate > 90 beats/minAnemia with hemoglobin level < 75% of normalESR > 30 mm/hr

24. The goals of therapy of UC are to induce remission, to maintain remission, to maintain adequate nutrition, to minimize disease- and treatment-related complications, and to improve the patient's quality of life. TREATMENT:MEDICAL AND SURGICAL

26. Algorithm for the management of mildly to moderately active ulcerative colitis

28. Algorithm for the management of severely active ulcerative colitis

30. Induction Therapy for Ulcerative Colitis Based on Disease Severity Mild Disease 5-Aminosalicylates (Sulfasalazine , Olsalazine , Balsalazide , Mesalamine ):>2gm/d -Topical (distal colitis)-Oral (distal/extensive colitis)-CombinationModerate Disease 5-Aminosalicylates : -Topical (distal colitis) -Oral (distal/extensive colitis) - CombinationGlucocorticoids: -Topical (distal colitis): -Oral (distal/extensive colitis): 1 mg/kg /day predinisolon -CombinationAzathioprine or 6-mercaptopurine : 1 mg/kg /day Severe Disease IV glucocorticoids IV cyclosporine : 2 mg/kg/day(blood level 200 - 300 ng/ml) IV infliximab: 5 mg/kg/day ; 0,2,6 weeks

31. Maintenance Therapy for Ulcerative Colitis 5-Aminosalicylates -Topical (distal colitis)1.5 gm /day:-Oral (distal/extensive colitis)Azathioprine or 6-mercaptopurine:1mg/kg/day Infliximab:5mg/kg every 2 monthes

32. Side Effects of Sulfasalazine and 5-Aminosalicylates Dose-Related AlopeciaAnorexiaBack painFolatemalabsorption (with sulfasalazine)HeadacheNausea, vomiting, dyspepsia Non–Dose-Related Agranulocytosis, aplastic anemiaArthralgiaColitisFeverFibrosingalveolitis, pulmonary eosinophiliaHemolytic anemia (Heinz bodies)HepatitisHypersensitivity skin rashes (occasionally with photosensitivity)Male infertility (with sulfasalazine)PancreatitisPericarditis, myocarditis

33. Side Effects of Glucocorticoids AcneImpaired wound healingPurpura, ecchymoses, petechiaeStriaeAdrenal insufficiencyCushingoid appearanceDyspepsiaDysphagia/odynophagia (candidiasis)Numerous pathogens Growth retardationHyperglycemia, secondary diabetes mellitusHyperlipidemia, altered fat distributionHypertensionMyopathyOsteonecrosisOsteoporosisAnxiety, mood swingsDepressionInsomniaPsychosisCataractsGlaucoma

34. Side Effects of Azathioprine and 6-Mercaptopurine Abnormal liver biochemical test resultsBone marrow suppressionHypersensitivity reactions (fever, rash, arthralgia)InfectionsLymphomaNausea, abdominal pain, diarrheaPancreatitis

35. Side Effects of Cyclosporine AnaphylaxisDiarrheaElectrolyte abnormalitiesGingival hyperplasiaHeadacheHepatotoxicityHirsutismHypertensionInfectionsNausea, vomitingOpportunistic infectionsParesthesiaRenal insufficiencySeizureTremor Prophylaxis against Pneumocystis pneumonia (PCP) during therapy is required.

36. OTHERS • Antibiotics(metronidazole, ciprofloxacine, refaximin). • Probiotics(Lactobacillus or Bifidobacterium), Prebiotics(food constituents increasing,probioticsandSynbiotics( both). • Nicotine patches. • Heparin: anti-inflammatory. • Biological Therapy: -Anti-Tumor Necrosis Factor Antibodies: infliximab and adalimumab -Anti-Adhesion Molecules:Alicaforsen

37. OTHERS • Cytapheresis: decrease WBCs. • PeroxisomeProliferator Receptor Agonists(rosiglitazon) • Budesonide-MMX : decrease the rate of steroid side effects. • Tofacitinib:oral Janus kinase 3 (JAK3) inhibitor • Fish oil: protecting the integrity of colonic mucosa • Trichurissuis : increase TH2. • Daclizumab: humanized monoclonal antibody against the IL-2 receptor .

38. Anti-Tumor Necrosis Factor Antibodies 1- Risk of infection Serious infections have happened in patients Receiving TNFblocking; infections include tuberculosis (TB) and infections caused by viruses, fungi or bacteria that have spread throughout the body. 2- Risk of Cancer There have been cases of unusual cancers(lymphomas) in children and teenage patients using TNFblocking agents.

39. SURGICAL Indications for Surgery in Patients with Ulcerative Colitis -Colonic dysplasia or carcinoma-Colonic hemorrhage, uncontrollable-Colonic perforation-Growth retardation-Intolerable or unacceptable side effects of medical therapy-Medically refractory disease-Systemic complications that are recurrent or unmanageable-Toxic megacolon

41. SPECIFIC COMPLICATIONS

42. 1-TOXIC MEGACOLON Acute colonic dilatation with a transverse colon diameter of greater than 6 cm (on radiologic examination) and loss of haustration in a patient with a severe attack of colitis.

43. 2-STRICTURES • Colonic strictures complicate UC in approximately 5% of patients, most commonly in those with extensive and long-standing colitis. • Patients with colonic strictures usually present with alterations in bowel habits, both constipation and diarrhea. • One series reported malignancy in 24% of colonic strictures in patients with UC.

44. 3-DYSPLASIA AND COLORECTAL CANCER • In general, the risk of colorectal cancer may be estimated to increase within the range of 0.5% to 1.0% per year after 8 to 10 years of disease in patients with extensive UC. • Surveillance by colonoscopy every year after 8 years of UC ( biopsy every 10 cm).

48. 4-POUCHITIS • Pouchitis is said to occur when there is nonspecific inflammation of the ileal reservoir, resulting in variable clinical symptoms resembling those of UC. • The mainstay of therapy for pouchitis is antibiotics.

49. EXTRAINTESTINAL MANIFESTATIONS

50. Cutaneous/Oral Angular stomatitisAphthousstomatitisErythemanodosumOral ulcerationsPsoriasisPyodermagangrenosumPyostomatitisvegetansSweet's syndrome (acute febrile neutrophilicdermatosis)