The role of 5-ASA in Inflammatory Bowel Disease
Transcription
The role of 5-ASA in Inflammatory Bowel Disease
Crohn’s and Colitis Foundation of Canada - CCFC & You Education Symposium Medications and IBD Dr. Alan Low, BSc.(Pharm.), Pharm. D., RPh., FCSHP, CCD Clinical Associate Professor, Faculty of Pharmaceutical Sciences, UBC Manager, Medical Affairs & Government Affairs, Servier Inflammatory Bowel Disease Inflammatory Bowel Disease (IBD) refers to a condition of chronic recurrent inflammation of the gastrointestinal tract of unclear cause. Clinical course of IBD is usually a course of active disease, often referred to as flares or recurrences, followed by periods of remission. Two major types of IBD are: – Ulcerative Colitis (UC) – Crohn's Disease (CD) Worldwide Incidence of IBD 9000 newly diagnosed cases annually – About 2-3 in 10,000 people – There are 200,000 people with IBD in Canada Peak onset: 15 to 25 years of age Second peak incidence: 50 to 65 years of age Clinical presentation varies widely for UC and CD Pinchbeck ER, Kirdelkis J, Thompson, ABR : Inflammatory Bowel Disease in North America. Clin Gastroenterology 10:505, 1988. Podolsky DK. Inflammatory bowel disease. NEJM 2002;347:417 Hanauer S. Inflammatory Bowel Disease. N Engl J Med. 1996;334(13):841-8 CCFC The Burden of Inflammatory Bowel Disease in (IBD)Canada, 2008 Causes of IBD Genetic Susceptibility Immune System Issues IBD Intestinal Microflora Environmental Triggers (Infection) Chronic Inflammation Mediator Imbalance Pro-inflammatory TNF IL-1β IL-12 / IL-18 IFNγ Anti-inflammatory IL-4 / IL-13 IL-1Ra TGFβ IL-10 PGE2 Environmental Triggers Antibiotics Infections IBD NSAIDs Diet Smoking Stress Natural Courses of UC Course Only one disease episode during study In remission at any given time Intermittent disease course Patients were followed for up to 25 years. Langholz E, et al. Gastroenterology. 1994;107:3-11 Patients (%) 23 40-50 77 Natural Courses of CD –The Facts Nearly 80% of patients require surgery within 20 years of onset1 Recurrence within 6 years of surgery: 90% endoscopic/radiologic, 58% symptomatic2 20% of patients treated with steroids fail to respond after 1 year 36% of patients are unable to discontinue steroids due to rapid recurrence3 1Mekhjian HS, et al. Gastroenterology. 77;898: 1979 2McLeod RS, et al. Gastroenterology. 113:1823; 1997 3Munkholm P, et al. Gut. 35:360; 1994 Toxic Megacolon Complication occurring in 1-2% of patients with UC and Crohn’s colitis – electrolyte imbalance, opiates, anticholinergics, laxatives, low protein intake leading to lumen edema Acute dilatation of the colon with associated infection Mortality rate up to 30% (perforation, peritonitis) Toxic Megacolon (con’t) Treatment – Medicines (IV steroids, IV antibiotics) – Surgery – Fluid and electrolytes replacement – Nutrition support – Bowel rest Avoid opiates, anticholinergics, and stimulant laxatives (eg. cascara, senna, bisacodyl, castor oil) Goals in Treating IBD Prompt diagnosis and treatment to manage symptoms of active disease Induction of complete remission Education on therapy and disease Individualized treatment options – treatment based on shared decisionmaking (minimize side-effects while maintaining efficacy and adherence) Improve quality of life Maintenance of remission Minimize steroid use IBD Therapy Therapeutic options for IBD Pharmacologic agents Anti-inflammatory Immunosuppressive Antimicrobial Biologics Psychological IBD Nutritional Surgery The Medications Drug Category Drugs Anti-inflammatory • Mesalamine (5-ASA) • Corticosteroids (prednisone, budesonide) Immunosuppressive • • • • • Antibicrobial • Metronidazole • Clarithromycin • Ciprofloxacin Probiotic • Many yogurts, supplements, milks, other Biologic • Infliximab • Adalimumab • Certolizumab Azathioprine 6-mercaptopurine, Methotrexate Cyclosporin Tacrolimus Therapeutic Options – Mild to Moderate Disease (acute therapy) Ulcerative Colitis (UC)* Crohn’s Disease (CD)* Pancolitis • Oral 5-ASA agents • Oral 5-ASA agents • Oral corticosteroids • Oral corticosteroids • Antibiotics for perianal disease/ fistulas Proctitis/distal colitis • Azathioprine for perianal disease/ fistulas • Oral and/or topical 5-ASA agents • Oral or topical steroid therapy *Therapies for UC and CD depend on disease severity and location; it is common to use more than one medication simultaneously to achieve the best clinical response. Patients in Endoscopic Remission at 6 Months Intention-to-Treat Analysis 80 70.1 % in Remission 70 60 48.3 50 40 30 20 10 0 5-ASA (Asacol) 1.6 g/d Placebo The Mesalamine Study Group. An Oral Preparation of Mesalamine as Long-Term Maintenance Therapy for Ulcerative Colitis. Ann Intern Med 1996:124:204-211. Adverse Events Most frequent – – – – – – Nausea Headache Vomiting Diarrhea Abdominal pain Flatulence (passing of gas) The Mesalamine Study Group. An Oral Preparation of Mesalamine as Long-Term Maintenance Therapy for Ulcerative Colitis. Ann Intern Med 1996:124:204-211. Therapeutic Options – Moderate to Severe Disease (acute therapy) Ulcerative Colitis (UC)* Crohn’s Disease (CD)* • IV corticosteroids or oral corticosteroids • Cyclosporine • IV corticosteroids or oral corticosteroids • Colectomy • Infliximab • Infliximab (for lumenal and fistulizing disease) • Adalimumab (for lumenal and fistulizing disease) • Certolizumab (for lumenal and fistulizing disease) • Tacrolimus *Therapies for UC and CD depend on disease severity and location; it is common to use more than one medication simultaneously to achieve the best clinical response. Dose Response to Mesalamine in Active Ulcerative Colitis % Patients in Remission/Improved * 80 70 60 50 * 40 * * 30 20 10 0 Placebo 1.6 gm 2.0 gm Mesalamine * Significantly different from placebo (two trials combined) 4.0 gm 4.8 gm Mechanism for Antibody Neutralization of TNF-α Macrophage or activated T-cell TNF TNF receptor Anti-TNF van Deventer S. Gut. 1997; 40:443-46 Scalion BJ. Cytokine. 1995: 7:251-59 Feldman M, et al. Advances in Immunology. 1997: 64:283-350 Target Cell Clinical Response and Remission in All Infliximab-treated Patients Response (%) 100 P<0.001 Placebo (n=25) 75 P<0.005 65 50 25 33 17 4 0 4-Week Clinical Response 4-Week Clinical Remission Clinical response defined as a 70-point decrease in CDAI score from baseline. Clinical remission defined as a CDAI score < 150. Targan, N Engl J Med, 1997 Infliximab 5, 10, and 20 mg/kg (n=83) Therapeutic Options – Maintenance Ulcerative Colitis (UC)* Crohn’s Disease (CD)* • Oral/topical 5-ASA agents • Oral 5-ASA agents • Immunomodulators • Immunomodulators oral azathioprine or mercaptopurine (steroiddependent or refractory patients) oral azathioprine or mercaptopurine (steroiddependent or refractory patients) • Methotrexate (if intolerant or not responding to immunomodulators) • Antibiotics (metronidazole, ciprofloxacin) • Infliximab / Adalimumab /Certolizumab • Methotrexate (if intolerant or not responding to immunomodulators) *Therapies for UC and CD depend on disease severity and location; it is common to use more than one medication simultaneously to achieve the best clinical response. Distal UC: Oral and Topical Mesalamine Therapy % of Patients Reporting No Rectal Bleeding Oral (2.4 g/d) 90 80 70 60 50 40 30 20 10 0 Rectal (4 g/d) Combined 90 90* 70 65 56 33 44 40 14 1 Week 33 36 27 18 2 Weeks *p < .002 vs oral alone, P=.04 vs topical alone Safdi M, et al. Am J Gastroenterol. 1997;92:1867-1871. 3 Weeks 6 Weeks Aminosalicylates in UC Summary of Maintenance Therapy Sulfasalazine 2 to 4 g or other 5–ASAs 1.6 to 4.8g/d – Study showed 4.8g/day better than 2.4g/day No comparative clinical data exist that show greater efficacy as a primary endpoint for any of the 5-ASAs for site-specific disease. 6MP/Azathioprine in corticosteroid-dependent patients but may need 4 to 6 months to take effect Steroids are not effective as maintenance therapy and should be avoided due to side effects Which 5-ASAs in IBD Indications for Aminosalicylates in IBD mildly to moderately active disease (induce remission) prevention of relapse (flares) How do physicians choose a 5-ASA: site of disease severity of attacks route of administration patient response frequency of relapse dose-related side effects compliance and cost issues dose-response effect 5-ASAs in IBD Mechanism of action topical not systemic anti-inflammatory effect Methods of delivery Azo bond – pH-dependent – two molecules split by colonic bacteria (e.g., sulfasalazine, Dipentum) resin-coated 5-ASA delays release until exposure to specific pH level (e.g., Asacol, mesalamine, sulfasalazine) Controlled-release – – encapsulated, ethylcellulose-coated 5-ASA microsphere released in small and large intestine (e.g., Pentasa) rectal suspensions and suppositories formulation stabilized with antioxidants 5-ASA Drug Delivery Systems Azulfidine® (sulfasalazine) Dipentum® (olsalazine) COOH NHSO2 N N N=N 5-ASA CH 5-ASA N=N 5-ASA Sulfapyridine Pentasa® (mesalamine) Asacol® (mesalamine) Rowasa® (mesalamine) Additional Formulations COOH 5-ASA 5-ASA 5-ASA Microspheres Eudragit S Inert carrier OH Ligumsky, et al. Gastroenterology. 1981;81:443. Stenson, et al. J Clin Invest. 1982;69:494. 5-ASAs in IBD Sulfasalazine Active compound (5-ASA) has local anti-inflammatory effects: Inhibits prostaglandins Inhibits leukotriene synthesis Acts as superoxide free radical scavenger Inactive carrier (sulfapyridine), linked by azo bond: delivers 5-ASA to colon associated with more adverse effects than 5-ASA 5-ASAs in IBD Sulfasalazine Adverse effects: primarily sulfa-related (e.g., impairs folic acid, headache, dizziness, nausea, fatigue, vomiting, arthralgia) (30% have difficulties) hematologic - blood related abnormalities unpredictable (e.g., skin rash, aplastic anemia, hemolytic anemia, agranulocytosis, altered sperm motility, bone marrow suppression, bronchospasm, nephrotic syndrome, etc.) 5-ASAs in IBD Benefits of pH-dependent 5-ASAs maximize release of mesalamine (5-ASA) at inflammation site Results in decreased systemic availability limit absorption in upper GI tract (depending upon pH release) fewer sulfa-related side effects (e.g., headache, fatigue, dizziness, diarrhea, abdominal pain, nausea, etc.) no reports of sperm abnormalities or infertility tolerated by 80-90% of sulfasalazine-intolerant or hypersensitive patients 5-ASAs in IBD Importance of Gastrointestinal pH levels: Drug release can be targeted for greater topical efficacy at disease site, e.g., 5-ASA release at pH 7.0 is roughly equivalent to terminal ileum pH is increasingly more alkaline (higher) in lower gut pH levels differ slightly among individuals pH levels of GI tract are affected by: – stress – diet – activity – concomitant drugs – concurrent medical conditions – disease severity – fluctuations by individual Location of Oral 5-ASA Release Stomach Jejunum Ileum Colon sulfasalazine Dipentum® (olsalazine) Asacol® (mesalamine) delayed-release tablets Pentasa® (mesalamine) controlled-release capsules Interchangeability of Products If need arises to interchange 5-ASA products – Discuss valid reason with patient – Inform patient, caregiver(s), physician(s) – Monitor for changes in response (ie. Change in disease activity, flare, etc) Osteoporosis in IBD Incidence 20% to 30% – Corticosteroid use, dose, and duration important – Other factors can increase risk (age, smoking, amenorrhea, exercise status, calcium, Vit D, etc.) Corticosteroid-associated bone loss occurs quickly (3 months of therapy or more) All people with IBD should considered risk assessment If high risk, consider calcium, vitamin D, and bisphosphonates [risedronate, alendronate, zoledronic acid], teriparatide, denosumab, raloxifene, hormone therapy Keep Up Your Bone Health Exercise: Weight-bearing, 4 times per week as deemed appropriate Calcium: 1000mg-1200mg daily (maximum of 500mg at once) from diet and supplement Vitamin D: 1000-2000 IU daily Fall Prevention: Balance, muscle strengthening, fix loose carpets Some Points to Consider Take medications at regular intervals as prescribed Recognize side effects and look at strategies to minimize Discuss issues and concerns with pharmacist, nurse or doctor Consult with a dietician – dietary advice – individualize food choices – nutritional supplements Other Considerations Watchouts: – Watch for signs of stress (consider relaxation techniques) – Keep a diary of symptoms and flares as well as any side effects (if side effects occur from sulfasalazine discuss 5-ASA with your doctor) – Avoid or minimize use of bowel active agents (eg. laxatives and antidiarrheals or Gravol) – Avoid drugs such as NSAIDs and triggers – Stop smoking (especially with Crohn’s) Other Considerations Watchouts: – Pay attention to chronic or long-term use of corticosteroids (eg. Prednisone). (Reduce or eliminate corticosteroids in consultation with doctor or gastroenterologist) Minimize use of corticosteroids (lowest dose, shortest time) – Maximize the potential of one treatment before moving on escalating to another treatment, optimize the dose Crohn’s and Colitis Foundation of Canada - CCFC & You Education Symposium Questions Dr. Alan Low