Inflammatory Bowel Disease DR Mokhtar.pptx

review in IBD

1. Prof Dr Abdelrahman Mokhtar presents Pharmacologic & non pharmacologic treatment of Inflammatory Bowel Disease 2019

2. IBD Therapies Aminosalicylates (5-ASA ) Antibiotics. Corticosteroids Immunomodulators (6 MP / AZA / MTX / calcinurine I ) Biologics Anti-TNF Anti-Integrin Anti IL-12 / IL-23

3. IBD Therapies Aminosalicylates (5-ASA) Corticosteroids Immunomodulators (6 MP / AZA / MTX / calcinurine I ) Biologics Anti-TNF Anti-Integrin Anti IL-12 / IL-23

4. Anti-inflammatory Drugs Aminosalicylates corticosteroids Acute maintenance acute

5. SULFASALAZINE Bacterial Flora (Colon) Bacterial azoreductase Sulfapyridine 5-aminosalicylic Acid Absorbed Acts through the lumen Systemic Adverse Effect Anti-inflammatory Effect

6. Aminosalicylates Local effect on mucosa in reducing inflammation Sulfasalazine contains sulfapyridine and 5-aminosalicylic acid 5-ASA. The 5-ASA accounts for its therapeutic benefits for IBD. Its exact mechanism of action is unknown, but topical application to the intestinal mucosa suppresses proinflammatory cytokines and other inflammatory mediators. When given orally, 5-ASA alone is absorbed before it reaches the lower GI tract where it is needed. When combined with sulfapyridine , 5-ASA reaches the colon. However, many people are unable to tolerate sulfapyridine . Newer preparations have been developed to deliver 5-ASA to the terminal ileum and colon olsalazine ( Dipentum ), mesalamine ( Pentasa ) and balsalazide ( Colazal ) These drugs are as effective as sulfasalazine and are better tolerated when administered orall y

7. Sulfasalazine Mesalamine Olsalazine Aminosalicylates

8. Sulfasalazine Oral use Mesalamine (5-aminosalicylic acid) { Asacol & Pentasa } timed released need PH >7. Oral delayed release capsules Enema Olsalazine . 5-ASA-n=n-5-ASA Bacterial flora breaks it into 5-ASA (COLON) Aminosalicylates

9. Mesalamine Available as Enteric-coated tablets (for ileal Crohn’s disease) Slow release tablets (for proximal bowel Crohn’s) Enemas, suppositories (for distal colonic disease) Used when sulphasalazine can not be tolerated

10. Indications Inducing remission in mild UC/CD (higher doses) Maintaining remission in UC Less effective for maintenance in CD

11. IBD Therapies Aminosalicylates (5-ASA ) Antibiotics. Corticosteroids Immunomodulators (6 MP / AZA / MTX / calcinurine I ) Biologics Anti-TNF Anti-Integrin Anti IL-12 / IL-23

12. Antimicrobials are used to treat CD, although no specific infectious agent has been discovered. Metronidazole ( Flagyl ), ciprofloxacin ( Cipro ) and clarithromycin( Biaxin ) have been used successfully with CD, but have not been shown to be as effective for UC.

13. IBD Therapies Aminosalicylates (5-ASA) Corticosteroids Immunomodulators (6 MP / AZA / MTX / calcinurine I ) Biologics Anti-TNF Anti-Integrin Anti IL-12 / IL-23

14. Corticosteroids: Prednisolone Hydrocortisone

15. USES Remission Induction No role in maintenance. Route of Administration Oral Intravenous Topical (Enema)

16. Indications Moderate to severe relapse UC & CD No role in maintenance therapy Combination oral and rectal Indications

17. Serious Side Effects of Prolonged GCS Therapy Sandborn W. Can J Gastroenterol . 2000;14( suppl C):17C-22C. *Overall GCS therapy (not only therapy for CD).

18. IBD Therapies Aminosalicylates (5-ASA) Corticosteroids Immunomodulators (6 MP / AZA / MTX / calcinurine I ) Biologics Anti-TNF Anti-Integrin Anti IL-12 / IL-23

19. Immunomodulator agents Thiopurines (Azathioprine & 6-mercaptopurine). Methotrexate. calcineurin inhibitors ( Cyclosporine & Tacrolimus ) Immune modifiers: uses • Can be used to reduce or eliminate corticosteroid dependence in patients with IBD. • Can be used in selected patients with IBD when 5-ASAs and corticosteroids are either ineffective or insufficient to control. • Can be used to maintain remission in CD and in UC when 5-ASAs fail. • Are an alternative treatment for CD relapses after corticosteroid therapy. • Can be used for corticosteroid dependence, to maintain remission and allow withdrawal of corticosteroids. • Either thiopurines or methotrexate can be used concurrently with biologic therapy to enhance effectiveness and reduce the likelihood of antibody formation.

20. Thiopurines Are given orally and take 3-6 months to exhibit full effectiveness. Azathioprine Inhibit ribonucleotide synthesis; induce T cell apoptosis by modulating cell (Rac1) signalling

21. Indications Steroid sparing agents Active disease CD/UC Maintenance of remission CD/UC Generally continue treatment x 3-4years

22. Caclineurine Inhibitors Ciclosporin MOA:inhibitor of calcineurin preventing clonal expansion of T cells In UC Use of CSA is limited to acute (corticosteroid-refractory) severe colitis. No value in CD Tacrolimus in CD.

23. Methotrexate MOA: inhibitor of dihyrofolate reductase; anti-inflammatory Inducing remission/preventing relapse in CD Refractory to or intolerant of Azathioprine

24. Safety and Toxicity Considerations 1. Feagan BG, et al. Cochrane Database Syst Rev. 2012;10:CD000544. 2. Gisbert JP, et al. Inflamm Bowel Dis. 2007;13(5):629-638. 3. World MJ, et al. Nephrol Dial Transplant. 1996;11(4):614-621. 4. Kotlyar D, et al, Clinical Gastroenterology and Hepatology. 2015;13:847–858. 5. Lichtenstein GR, et al. Am J Gastroenterol . 2009;104(2):465-483. 6. Methotrexate injection USP [package insert]. Lake Forest, IL: Hospira , Inc.; 2011. Mesalamine 1 5-ASA AZA/6-MP 4 MTX 5-6 Low incidence of adverse effects Diarrhea, headache, nausea most common Abdominal pain Dyspepsia Acute tolerance syndrome Nephrotoxicity Pancreatitis Incidence of kidney impairment occurs in less than 1 in 200 (<0.5%) patients treated with 5-ASA 2 Pancreatitis (4%) Allergy (2%) Bone marrow suppression (4%) Liver toxicity (9%) Serious infection ( 2%) Nausea/vomiting Bone marrow suppression Liver scarring Clinically important interstitial nephritis occurs in 1 in 500 patients―50% of cases occur in the first year, and others may occur many years later 3 Increased risk of lymphoma Nonmelanoma skin cancer Abnormal Pap smears Contraindicated if attempting pregnancy

25. IBD Therapies Aminosalicylates (5-ASA) Corticosteroids Immunomodulators (6 MP / AZA / MTX / calcinurine I ) Biologics Anti-TNF Anti-Integrin Anti IL-12 / IL-23

26. Biologics Infliximab ( Remicade ) is the first major biologic drug therapy ( immunomodulator ) to be approved for the treatment of IBD. Infliximab is a monoclonal antibody to the cytokine tumor necrosis factor. It is given IV to induce and maintain remission in patients with active CD and in patients with draining fistulas who do not respond to conventional drug therapy

27. Biologic therapy for IBD Certolizumab - Cimzia Adalimumab - Humira Golimumab - Simponi Infliximab - Remicade Anti-Integrin antibody: Natalizumab - Tysabri (PML –Progressive Multifocal Leucoencephalopathy ) Anti-Integrin antibody: Vedolizumab - Entyvio Anti IL-12 / IL-23 antibody: Ustekinumab – Stelara - moderate to severe CD .

28. Ongoing Therapeutic Monitoring TPMT, thiopurine methyltransferase; CBC, complete blood count; LFT, liver function tests; TB, tuberculosis;  TNF, tumor necrosis factor.

29. Treatment Concepts Treatment paradigms and therapeutic options for IBD have evolved rapidly over the past decade. 1) An increased emphasis on dual therapy to reduce immunogenicity, improve efficacy and preserve durability. 2) Emerging use of therapeutic drug monitoring to optimize response and guide management of loss of response. 3) Increased emphasis on mucosal healing as an important treatment goal as it correlates with surgical-free outcomes with minimal intestinal damage and patient disability. . Mucosal healing (i.e. absence of ulceration or erosion) is important in the clinical management of IBD—achieving mucosal healing has been unequivocally associated with better outcomes and has become an important treatment goal.

30. Disease status and drug therapy

31. Ulcerative Colitis- Management a) Topical aminosalicylate alone (suppository or enema b) ?ADD PO aminosalicylate to a topical aminosalicylate OR c) consider an PO aminosalicylate alone a) PO Aminosalicylate - High induction dose . b) ?ADD topical Aminosalicylate OR PO beclometasone dipropionate If no improvement 72 hrs despite IV Hydrocortisone OR Symptoms worsen to pancolitis: a) ADD IV Ciclosporin to IV steroids

32. Management of CD to induce remission oral high dose of 5-ASA +- oral corticosteroids reducing over 8/52 Azathioprine iv steroids/ metronidazole/elemental diet/surgery/infliximab

33. Maintaining remission +- Azathioprine (frequent relapses) Methotrexate (intolerant of azathioprine ) Infliximab infusions (8 weekly )

34. Crohn’s Disease Therapies Therapy is modified according to severity at presentation or failure at prior step Pentasa Biologics or Thiopurine + Corticosteroid Biologics + Thiopurine + Corticosteroid Disease Severity at Presentation Severe Moderate Mild Biologics or Thiopurine Pentasa Biologics Induction Maintenance For terminal ilium or colonic lesions only

35. Sequential Therapies for UC Therapy is stepped up according to severity at presentation or failure at prior step Aminosalicylate Aminosalicylate or Thiopurine + Corticosteroid Biologics + Thiopurine + Corticosteroid Disease Severity at Presentation Severe Moderate Mild Aminosalicylate or Thiopurine Aminosalicylate Biologics Induction Maintenance Colectomy

36. SURGICAL MANAGEMENT

37. Surgery in CD Surgical options are: — Drainage of abscesses — Segmental resection — Bowel-sparing stricturoplasty — Ileorectal or ileocolonic anastomosis — Ileocolic resection . — Temporary diverting ileostomy/colostomy in severe perianal fistula — Laparoscopic ileocecal resection

38. Surgery in UC — Total proctocolectomy plus permanent ileostomy . — Ileal pouch–anal anastomosis (IPAA). — Segmental resection can be considered for localized neoplasms in the elderly, or in patients with extensive comorbidity.

39. UC Indications for Surgery: Unresponsive to medical treatment Significantly affecting quality of life Growth retardation in Children Life-threatening complications... Bleeding Toxic Megacolon Impending perforation Carcinoma

40. Total Proctocolectomy -The colon and rectum are removed and the anus closed. The terminal ileum is brought out through the abdominal wall and a permanent ileostomy formed.  Ileorectal Anastomosis - The colon is resected, leaving a rectal stump. The terminal ileum is then anastomosed to this stump. This is an early alternative to total proctocolectomy , however, it has several problems. The remaining rectum is often still affected by the disease, and further treatment, even eventual resection, is often required. There is also a significant incidence of rectal cancer among clients who had this surgery.  Ileal Pouch-Anal Anastomosis - Also known as the J pouch; prevents the need for an ostomy and preserves the rectal sphincter muscle. The rectal mucosa is excised and the colon is removed. An ileoanal reservoir is then created in the anal canal, and a temporary loop ileostomy is formed. After healing has taken place, the ileostomy is reversed and stool drains into the reservoir, which is created by suturing two loops of bowel together.  Continental ileostomy or Kock Pouch - A procedure in which a reservoir or pouch is constructed from a loop of ileum. This allows stool to be stored intra-abdominally until it is drained through a nipple valve made from an intussucepted portion of ileum. This has advantages because the client does not need to wear an external pouch, has minimal skin problems, and usually has no leakage of stool or flatus. The client drains the pouch several times a day using a catheter, usually when a feeling of fullness occurs.

41. Lifestyle Modifications

42. Mediterranean Diet Primarily plant-based foods (fruits and vegetables, whole grains, legumes and nuts) Replace butter with healthier fats (olive oil) Herbs and spices instead of salt Limit red meat (beef and pork) to no more than a few times a month Fish, chicken, and turkey at least twice a week

43. Other Dietary Considerations Eat smaller, more frequent meals Drink plenty of fluids Consider multivitamin once daily Talk to a dietitian Probiotics once daily Dairy, gluten, excessive caffeine / carbonation can exacerbate symptoms

44. Lifestyle Changes Stress Management Exercise (20 minutes / day) Relaxation and breathing exercises (yoga and meditation) Smoking Cessation / avoid second hand smoke exposure Avoid unnecessary antibiotic exposure Utilize Patient Education Resources (CCFA )

45. Final Thoughts Early diagnosis / avoid treatment delays Treating IBD patients is a collaborative approach between primary care and GI and other specialists Increase patient satisfaction