Inflammatory bowel disease. Kawa Obeid, PhD

Transcription

1 Inflammatory bowel disease Kawa Obeid, PhD 63

2 Introduction Inflammatory bowel disease (IBD) can be divided into two chronic inflammatory disorders of the gastro- intestinal tract, namely Crohn's disease (CD) and ulcerative colitis (UC). Crohn's disease affects any part of the gastro- intestinal tract whereas ulcerative colitis affects the colon and rectum only.

3 Aetiology The causes of both CD and UC are unknown. Infective, immunological, dietary and psychosomatic causes have been suggested, but until recently there has been no evidence for any of these.

4 Environmental Diet: fat intake, fast food ingestion, milk and fibre consumption. Smoking: Crohn's disease: 40% of patients are smokers. Stopping smoking can provoke the emergence of ulcerative colitis. Infection: Exposure to Mycobacterium paratuberculosis has been considered a causative agent of Crohn's disease. Ulcerative colitis may present after an episode of infective diarrhoea. Enteric microflora: Patients with IBD show a loss of immunological tolerance to intestinal microflora and consequently antibiotics often play a role in the treatment of IBD.

5 Environmental Drug: Non- steroidal anti- inflammatory drugs (NSAIDs) such as diclofenac have been reported to exacerbate IBD. Stress: Some patients find that stress triggers a relapse in their IBD and this has been reproduced in animal models. It is thought that stress activates inflammatory mediators.

6 Genetic 15% of first degree relatives have IBD. There is mounting evidence that Crohn's disease and ulcerative colitis result from an inappropriate response of the immune system in the mucosa of the gastro- intestinal tract to normal enteric flora.

7 Pathophysiology of IBD Trigger factors typically cause a severe, prolonged and inappropriate inflammatory response in the gastro- intestinal tract and the ongoing inflammatory reaction leads to an alteration in GIT architecture. Genetically susceptible individuals seem unable to downregulate immune or antigen non- specific inflammatory responses.

8 CD v UC

9 Location and distribution of ulcerative colitis and Crohn's disease

10 Clinical manifestation

11 Extra-intestinal complications of IBD Around 20 30% of patients with IBD will present with extra- intestinal manifestations. They are more commonly seen in patients where IBD affects the colon. Complications affect the joints, skin, bone, eyes, liver and biliary tree and are more common in active disease.

12 Investigations Differential diagnoses of IBD include carcinoma, infection, drug- induced colitis, ischaemia, radiation damage, irritable bowel syndrome and diverticulitis.

13 Endoscopy The key diagnostic investigation in IBD is lower gastro- intestinal tract endoscopy (sigmoidoscopy and colonoscopy), which allows direct visualisation of the large bowel and histopathological assessment from biopsies.. In patients with severe symptoms, it is sometimes necessary to delay a full colonoscopy because of the increased risk of perforation. Radiology Radiological imaging (Computed tomography (CT scan) and magnetic resonance imagery (MRI) is complementary to clinical and endoscopic assessment.

14 Laboratory findings Although not diagnostic, active disease is suggested in patients with raised inflammatory markers that include erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP) in addition to a low haemoglobin and raised platelet count. Vitamin B12 may be low in patients with chronic terminal ileal disease. Low red cell folate and serum albumin, magnesium, calcium, zinc and essential fatty acids also indicate chronic inflammation and malabsorption. Anti- Saccharomyces cer- evisiae antibodies (ASCA) are more likely to be present in Crohn's disease. Stool tests Red and white blood cells can be seen on microscopic examination of fresh stools. Microscopic identification of infective cells such as amoeba may also be visualised.

15 Management Nutritional therapy Nutritional therapy can be considered as an adjunctive or primary treatment. Patients with Crohn's disease are at particular risk of becoming malnourished and developing a variety of nutritional deficiencies Functional and structural damage to the small bowel can cause malabsorption problems and occasionally patients may require a low- lactose diet. Patients who have extensive small bowel resection may experience many nutritional deficiencies because of malabsorption. Iron depletion, hypoproteinemia, deficiencies in water- and fat- soluble vitamins. Where appropriate, and when enteral nutrition is not indicated or adequate, a total parenteral nutrition (TPN) regimen may be prescribed.

16 Drug treatment The main goals of drug treatment are to treat acute attacks, limit drug toxicity, modify the pattern of disease, avoid and/ or manage complications. The choice of drug and route of administration depends on the site, extent and severity of the disease together with the individual's treatment history. Drug therapy is often required for many years and patient preference, acceptability and possible side effects not only affect choice but will impact on medication adherence.

17 Corticosteroids, aminosalicylates and immunosuppressive agents (immunomodulators) such as azathioprine are the mainstays of treatment. Modern advances in treatment, such as the use of Human monoclonal antibody which modify the affected biochemical inflammatory pathways, now have a significant role in treatment of the disease. These are likely to be the main area of future development. Other drugs such as antibiotics, for example, metronidazole, are helpful in some cases, while colestyramine, thalidomide, sodium cromoglicate, bismuth and arsenical salts, nicotine, lidocaine, sucralfate, new steroid entities, cytoprotective agents, aloe vera, probiotics and fish oils are rarely used.

18 The route of administration is a particularly important factor in IBD. In contrast to most other conditions, minimal systemic absorption and maximal intestinal wall drug levels are required with oral therapy. Several delivery strategies have been used to achieve this including the chemical modification of drug molecules, delayed and controlled- release formulations and the use of bioadhesive particles. Proctitis is best treated with suppositories. Where inflammation affects the rectum and sigmoid colon (up to 15 20cm), foam enemas are preferred. In more extensive disease extending to the splenic flexure (30 60cm), liquid enemas are the agents of choice. Enemas or suppositories should be administered just before bedtime in a supine position as this allows a much longer retention time. Liquid enemas can be warmed and should be inserted while lying in the left lateral position.

19 Pharmacotherapy 1. Antidiarrhoeal agents, e.g. loperamide or codeine, may be needed to control florid symptoms, but should be used with caution because the resultant slower clearance of faecal residues may encourage the accumulation of pro- inflammatory agents and infectious agents.

20 2. Corticosteroids are the most effective agents and should be used to bring symptoms under control promptly in CD. Steroids, used intravenously in severe attacks (IV hydrocortisone or methylprednisolone therapy is used, e.g. up to 100 mg hydrocortisone 6- hourly) may be combined with aminosalicylates or, if the patient has been admitted in the previous 2 3 years with moderate to severe attacks, azathioprine. Oral prednisolone mg daily, reducing over 6 8 weeks, is widely used, with or without azathioprine or its metabolite, 6- mercaptopurine. Corticosteroid retention enemas are useful in CD only for rectal or distal colonic disease. In UC, corticosteroids are used to obtain remission in moderate to severe attacks or as an adjunct to aminosalicylates. Corticosteroid retention enemas is used routinely for UC and spare the systemic corticosteroid dose.

21 3. Immunosuppressants Azathioprine, or its metabolite 6- mercaptopurine, is used, especially in CD and moderate to severe UC for its steroid- sparing effect. It is ineffective as sole therapy in active disease as it takes several weeks to exert its effect. They are suitable for long- term maintenance therapy, but there is a high relapse rate on discontinuation. Methotrexate and IV ciclosporin have been used to manage disease resistant to steroids and other immunosuppressants. They are effective in producing remission but not for maintenance therapy.

22 4. Aminosalicylates These include sulfasalazine (SSZ), the original member of this group, which is a salt formed between sulfapyridine (SP) and 5- aminosalicylic acid (5- ASA); olsalazine (a dimer of 5- ASA); mesalazine (modified- release 5- ASA); and balsalazide (5- ASA linked by a diazo bond to 4- aminobenzoyl- beta- alanine, a carrier that has no pharmacological effect, unlike SP). SSZ is not absorbed in the small intestine, and the SP acts as a carrier to deliver 5- ASA to the colon, where the SSZ is split by bacterial action. The SP and some 5- ASA are subsequently absorbed, but about 50% of the 5- ASA remains in the colon to exert a local anti- inflammatory effect.

23 Oral mesalazine is specially formulated for large bowel release, in an attempt to avoid absorption of 5- ASA from the small intestine. It is licensed for the oral treatment of mild to moderate UC and to maintain remission. Olsalazine is similarly split by colonic bacteria to yield only 5- ASA and is licensed to treat mild UC and maintain remission. Balsalazide is a pro- drug of 5- ASA and resembles SSZ in drug delivery. The aminosalicylates are used primarily to induce and maintain remission in UC and for maintenance in CD.. SSZ is the only member of this group licensed for all severities of UC and for active CD, and also has a steroid- sparing effect. However, it has a limited place in the treatment of severe attacks, possibly because its hydrolysis to release 5- ASA is unpredictable in the diseased colon.

24 Few notes Side- effects. If the SP moiety in SSZ causes unacceptable side- effects, and this is more likely in slow acetylators, olsalazine, balsalazide or mesalazine may prove more suitable. However, 5- ASA also causes side- effects, e.g. nausea, headache, rash, and even diarrhoea and occa- sional exacerbation of colitis. SSZ causes a reversible oligospermia and so is unsuitable in men wishing to raise a family. There have also been occasional reports of nephrotoxicity with all aminosalicylates, which should be used cautiously in renal impairment and during pregnancy and breastfeeding. This is due to the absorption of 5- ASA, and mesalazine produces higher serum concentrations of 5- ASA than, olsalazine and balsalazie.

25 Few notes All aminosalicylates may cause blood dyscrasias, e.g. agranulocytosis, aplastic anaemia, leucopenia, neutropenia and thrombocytopenia. Patients should be advised to report any unexplained bruising, bleeding, sore throat, fever or malaise. If any of these occur the drug should be stopped and a full blood count done.

26 5. Biological agents Only one of these, infliximab, is currently used in IBD. human monoclonal antibody against the potent pro- inflammatory TNFalpha. It is used in severe active CD, especially if there is fistulation, and spares the corticosteroid dose. It is also licensed for moderate to severe UC. Recent trials have confirmed that infliximab is effective in UC. It produces about a 60% response rate at 8 weeks and about a 45% remission rate at 30 weeks. There is also significant mucosal healing and a steroid- sparing effect. Consequently, infliximab is likely to be especially beneficial in patients who are unresponsive to corticosteroids or are steroid- dependent, and in those who do not tolerate conventional immunosuppressive treatment. Adalimumab is a fully human anti- TNF anti- body that is currently licensed only for use in rheumatoid disease, but the licence is likely to be extended shortly for use in CD. a loading dose of 160 mg followed by 80 mg 2 weeks later, gives a remission rate of about 36% at 4 weeks. These doses are much larger than those used for RA. It appears to be effective in those who are not responding adequately to infliximab, but it is still antigenic. It has the advantage over infliximab that it is given by SC injection rather than by IV infusion. Certolizumab and natalizumab are under investigation

27 6. Antibiotics Metronidazole or tinidazole may be useful if there is bacterial overgrowth in the bowel or if septic complications occur, because anaerobes are often involved. Bowel perforation may lead to peritonitis and septicaemia, with an urgent need for surgery and parenteral antibiotics, after the identification of microbial sensitivities. Co- trimoxazole (trimethoprim plus sulfamethoxazole) has been used but is now appropriate only for infections of known sensitivity that are unresponsive to other agents. Continuing diarrhoea in well- treated patients is not necessarily due to infection, but may be due to failure of the diseased small bowel to reab- sorb bile salts. Treatment with the anion exchange resin colestyramine is then indicated.

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29 Diet In contrast to the management of acute episodes, a high- residue diet is preferred unless there is a possibility of bowel obstruction, e.g. as the result of stricture formation. A high carbohydrate, high- protein diet minimizes the possibility of nutritional deficiency due to chronic diarrhoea. Vitamin and mineral supplementation, especially iron, is often given. Avoiding milk or milk products may occasionally be useful in some patients, especially those with small- bowel CD.

30 Surgery Surgery is indicated if medical management fails, for the treatment of complications, e.g. toxic megacolon, perforation, obstruction, malignancy. In UC, colectomy is curative. Colectomy is also carried out as an elective procedure in patients who have had extensive UC for more than 10 years, or if they have ever had a pancolitis, to pre- empt possible malignancy. Surgery is avoided as far as possible in CD, because relapse is common (30% in 5 years, 50% in 10 years) and repeated surgery is debilitating and carries a relatively high cumulative mortality.

31 Prognosis Nearly all CD patients have chronic or recurrent disease, with at least one serious relapse. The probability of recurrence is greater if there was extensive initial disease. In UC, some patients have only a single attack, but many have mild disease, with proctitis only.

32 Thank you Kawa A. Obeid PhD Therapeutics