Treatment Of IBD PDF

Treatment of IBD 11 & 12 ILOs At the end of this session, the student will be able to:  Enumerate the lines of treatment of IBD.  Appraise the indications, and route of administration for each therapy.  Discuss the monitoring plans and side effects for each line...

Treatment of IBD 11 & 12 ILOs At the end of this session, the student will be able to:  Enumerate the lines of treatment of IBD.  Appraise the indications, and route of administration for each therapy.  Discuss the monitoring plans and side effects for each line of therapy.  Identify the different management plans in all clinical types of IBD.  Explain the indications for the biological therapy.  Enumerate the different groups of biological therapy, their mechanism of action and side effects of them.  Appraise the monitoring protocol for biological therapy. Treatment of IBD The primary goal of medical therapy for IBD is directed toward the relief of clinical symptoms. For both Crohn disease and ulcerative colitis, medical therapy is generally considered as a two-step approach: (1) achieving remission from symptoms of active disease, and (2) maintaining remission. The clinical presentation dictates the choice of pharmaceutical agent. Patients with severe disease generally require more aggressive therapy than mild disease. Another important goal is to avoid complications as surgical resection or CRC, and to maintain patients in steroid free remission. A. Conventional therapy The term ‘conventional therapy’ has been widely used in the past to differentiate well-established traditional treatments (such as 5-aminosalicylates [5-ASA], corticosteroids, and thiopurine immunomodulators) from biologic therapies and other novel targeted small molecules. Page 1 of 8 1. 5-Aminosalicylates: ASA medications are the mainstay of therapy for mild to moderate ulcerative colitis, they have demonstrated efficacy in both the induction and maintenance of remission for ulcerative colitis. While in Crohn’s disease neither sulfasalazine nor other 5-ASA agents have been shown to be effective in maintaining clinical remission except in Crohn’s colitis. Sulfasalazine, the original drug in this class, consists of sulfapyridine attached to the 5-ASA moiety by azo bond which is released by the action of colonic bacteria releasing the 5.ASA moiety in the colon. Medications that contain two molecules of 5-ASA by a bond that cleaves at more than pH 7 selectively target the terminal ileum and colon. While the sulfa molecule carries a lot of side effects (nausea, vomiting, dyspepsia, headache, and malaise), the 5-ASA molecules are well tolerated and rarely induce side effects like interstitial nephritis, pneumonitis, pericarditis, and pancreatitis. 5.ASA can be given orally in divided doses or topically into the rectum in ulcerative proctitis. 5.ASA is proved to protect against CRC. Indications:  5-aminosalicylates is recommended at a dose of ≥2 g/ day to induce remission in patients with mildly-to moderately active UC.  Topical [rectal] 5-ASA at a dose of ≥1 g/d is recommended for the induction of remission in active distal colitis.  The use of oral 5-ASA [≥2 g/d] combined with topical [rectal] 5-ASA is suggested over oral 5-ASA monotherapy for induction of remission in adult patients with active UC of at least rectosigmoid extent.  Topical [rectal] steroids for the induction of remission in patients with active distal colitis is strongly recommended and it is suggested than topical steroid in the same situation.  Use of oral 5-ASA at a dose ≥2 g/day is strongly recommended for maintenance of remission in UC patients.  Topical [rectal] 5-ASA is suggested for the maintenance of remission in patients with distal UC.  Oral 5- ASA preparations have no significant advantage in maintaining remission in patients with CD.  Although controversial studies have found that it has been used for more than 10 years in some patients, might reduce hospital referral and steroid use and might reduce the recurrence after surgery in CD. Page 2 of 8 2. Corticosteroids: Act through impairment of T cell function and impairment of phagocytosis and chemotaxis and cytokine production. Oral and intravenous corticosteroids are effective in inducing clinical remission in both crohn’s disease and UC in moderate to severe disease. Oral prednisone (40–60 mg/day) is an effective dose either oral or intravenous. Once achieving response tapering dose should be started after 2 weeks with reduction of 5 mg / week. Although useful in achieving remission, steroids are not effective in maintaining it. Budesonide is an oral corticosteroid with significant first pass hepatic metabolism. As such, it offers therapy to the gut (typical dose 9 mg/day) with reduced systemic effect. Its predominant region of effect is the ileum and right colon. Its role is typically reserved for patients with mild to moderate ileocecal Crohn’s disease. Budesonide MMX is effective in left sided colitis as its main site of action is left side of the colon, it has less side effects than conventional steroid. Rectal budesonide enema is effective in distal colitis with little side effects. Common side effects of steroids are secondary DM, hypertension, acne, cushingoid face, hirsutism, myopathy, osteoporosis. 3. Immune suppressant agents: A. thiopurines: 6 mercaptopurines and Azathioprine are effective in maintaining remission in both moderate to severe Crohn’s disease and UC. Due to slow onset of action, it is not effective in induction phase of therapy. The dose is 2- 2.5mg/kg for azathioprine, 1- 1.5 mg/kg for 6 mercaptopurine. Common side effects include nausea, hepatitis, leucopenia, 1% increase in incidence of lymphoma, and increase non melanoma skin cancer. The drug is metabolized by enzyme thiopurine methyltransferase (TPMT). Mutation in the gene responsible for this enzyme carries high risk to develop leucopenia. So, it is essential to check the CBC every 1-2 weeks during the first 3 months, then every 2-3 months. Accumulation of toxic metabolite (6 MMP- 6. Methylmercaptopurine) induce liver toxicity so checking the metabolite level of the drugs should be done after 3-4 weeks to avoid liver toxicity. B. Methotrexate—Methotrexate is a folate antimetabolite that has been shown to be effective for achieving remission in Crohn’s disease only when delivered intramuscularly or subcutaneously (25 mg/week). It gives good response in ileocecal disease especially with arthritis as extraintestinal manifestation. The drug Page 3 of 8 is also effective at maintaining remission at lower doses (15 mg/week). Common toxicities include nausea, pancytopenia, pneumonitis, hepatitis, and hepatic fibrosis. It is also teratogenic and has never been used during pregnancy. 4. Antibiotics especially ciprofloxacin and metronidazole are effective in perianal Crohn’s disease. Metronidazole is the best in colonic and ileocolonic type. 5. Probiotics—Several recent studies have looked at the use of probiotics, specifically VSL #3, in both inducing and maintaining remission in mild to moderate ulcerative colitis as monotherapy or as an adjunct to 5-ASA and/or immunomodulator therapy. Limitations to the data include, varying dosages used in different studies. B. Biological therapy & small Molecule. Biological therapies have revolutionized the management of IBD. Monoclonal antibodies against tumor necrosis factor alpha (anti-TNF) have been the cornerstone of IBD therapy since the start of the century. In 1998, infliximab was the first biological medication approved for the use of Crohn's disease (CD), followed by adalimumab. Numerous studies have demonstrated their efficacy and cost effectiveness for the induction and maintenance of remission in CD and ulcerative colitis More targeted treatments for IBD interfere with two main pathways (namely cytokine signaling and immune cell trafficking) and are classified into biologics monoclonal antibodies and small molecule drugs. (Table 1). These therapies use monoclonal antibodies targeting tumor necrosis factor-α (TNF-α), integrins α4, and cytokine molecules such as the common p40 subunit of IL-12 and IL-23. Indications for biological therapy:  Steroid-refractory UC/CD  Steroid-dependent UC/CD  Immunomodulator-refractory UC/CD  Immunomodulator-intolerant UC/CD  Clinical predictors of a poor outcome at diagnosis  Fistulizing CD Page 4 of 8 1) Types of biological monoclonal Abs therapy in IBD A. Anti-TNF biologics: Mechanism of action:  Induction of antibody-dependent cell-mediated cytotoxicity,  Complement-dependent cytotoxicity and apoptosis,  Modulation of cellular populations, proliferation or cell activation, regulation of immune factors and cytokines, as well as modulation of angiogenesis, and the intestinal barrier function 1. Infliximab: Remicaid. It is a recombinant chimeric IgG1 monoclonal antibody. It is the first anti-TNF introduced since 1999. It is indicated in CD, UC, fistulizing CD, in children and during pregnancy. Dose 5mg/kg in week 0,2,6 as a bolus then every 8 weeks. Although losing response might occur and checking infliximab trough level and antibodies is essential before decision of dose adjustment or shifting to another type. 2. Adalimumab: Humira. Fully humanized IgG1 monclonal antibody, less antigenic than infliximab, used subcutaneously (induction 160 mg, 80 mg, 40 mg at week 0,2,6 than maintenance 40 mg every two weeks.). approved in adult and pediatric UC and CD. 3. Certolizumab pegol CIMZIA. Used only in Crohn’s disease, and given subcutaneously. 4. Golimumab: Simponi Used only in UC. It can be used as first biological or after failure of infliximab and adalimumab. Limitations and side effects of anti-TNF:  Primary non responders occur in 30% of cases after induction therapy, and require shifting to another class of therapy.  Secondary non responders who had initial response then loose it over time. the reason might be mechanistic failure, non-immune or immune mediated Page 5 of 8  pharmacokinetic failure. The drug trough level and antibodies are essential to detect the reason of failure and decide the medication should be used.  Increase the incidence of non-Hodgkin lymphoma and non-melanoma skin cancer. The risk is more especially if thiopurines used in combination with anti-TNF (combo therapy).  Opportunistic infection and reactivation of TB.  Cardiotoxicity, demyelination, and neurotoxicity.  Allergic reaction and lupus like reaction. B. Anti-Integrin Therapy: Anti-integrin drugs prevent the traffic of inflammatory cells that mediate the inflammatory process in IBD. 1. Vedolizumab : It is humanized immunoglobulin gastrointestinal (GI) monoclonal antibody to α4β7 integrin, approved for the treatment of moderate to severe UC and CD patients that did not respond to the antiTNF-α treatment. However, its efficacy may be greater in IBD patients naïve to anti-TNF-α therapy. As it is slower in action it is better for maintenance and co- induction with steroid or IV cyclosporine's. However, due to its high selectivity, vedolizumab is not effective to reduce extra-intestinal symptoms. 2. Natalizumab is an antibody directed against α4 integrin, designed to inhibit trafficking of leukocytes. Although effective for Crohn disease, its use is restricted due to an apparent associated risk for developing PML (progressive multifocal leukoencephalopathy). This risk is high in patients with JC virus antibodies. C- Anti-interleukin Therapy: Ustekinumab is a fully humanized IgG mAb that binds the shared p40 subunit of cytokines IL12 and IL-23, for the treatment of CD, UC, plaque psoriasis and psoriatic arthritis. Outcomes were worse in anti-TNF-α primary or secondary non- responders compared to those who had not failed anti-TNF-α. Small molecules: These drugs are small chemical structures with a short half-life and a relatively low cost. These molecules have less potency and half-life than biologics, a generally less specific mechanism of action and, a greater risk of unspecified side effects. However, an important advantage is their lack of immunogenicity. They include Jak inhibitors, modulators of sphingosine-1- phosphate receptors (lymphocyte trappers). Page 6 of 8  Janus kinase inhibitors—Tofacitinib is a nonbiologic small-molecule inhibitor of Janus kinase (JAK 1/3), which is involved through the JAK-STAT pathway in modulation of multiple interleukins. It is currently approved as second-line therapy for the treatment of moderate to severe ulcerative colitis (not Crohn disease) that has not responded to anti-TNF therapy. It has rapid oral absorption and lacks immunogenicity. Tofacitinib should not be prescribed to patients deemed at higher risk for thrombosis as it increases the risk of thrombosis events. It has a low risk of adverse events, including infections, except for herpes zoster.  Ozanimod: sphingosine 1-phosphate receptor modulators, once daily oral, approved for MS and for UC.  Additionally, other biologicals such as etrolizumab (monoclonal antibody against the B7 subunit of integrins α4β7 and αЕβ7) as well as guselkumab, mirikizumab and risankizumab, other monoclonal antibodies which binds to p19 subunit of interleukin 23 are emerging in the market. C. Surgery Ulcerative Colitis:  Surgery is indicated when (1) chronic intractable disease is not controlled with medication, or drug side effects are too severe; (2) patients with severe colitis require an urgent procedure; or (3) dysplasia or cancer is present.  Most patients needing surgery are candidates for an ileoanal pouch anastomosis (IPAA); the main considerations are age, gender, type of job, and lifestyle.  In most patients undergoing IPAA, a temporary diverting loop ileostomy is constructed to decrease the likelihood of pelvic sepsis.  Laparoscopic-assisted and open IPAA give equivalent results. Crohn’s Disease:  In general, surgery is indicated for complications (i.e., abscess, fistula, perforation, obstruction); considerations include symptom severity, medical treatment failure or side effects, and operative risk.  Most patients found to have Crohn disease at laparotomy for suspected appendicitis require early ileocolic resection.  Surgical procedures for treatment of fistula-in-ano include fistulotomy, long- term draining setons, endoanal flap closure, and ligation of intersphincteric fistula tract, if the rectal mucosa is normal.  Recent innovative therapy for anal fistula involves adhesive products, fibrin glue, and Bioprosthetic plugs of porcine collagen. Page 7 of 8 Table 1: Page 8 of 8