Recommended drug therapy for inflammatory bowel disease

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1 Drug review IBD Recommended drug therapy for inflammatory bowel disease SPL Kirstin Taylor BSc, MRCP and Mark Wilkinson BSc, MD, FRCP Inflammatory bowel disease is a chronic condition of unclear aetiology that can greatly impact on the lives of those affected. Our Drug review discusses the currently available treatments and their properties, followed by sources of further information. nflammatory bowel disease (IBD) is a nonspecific term referring to a group of chronic diseases of the intestine. The two main IBD conditions seen are ulcerative colitis (UC) and Crohn s disease (). UC is restricted to the colon and causes continuous inflammation (see Figure 1) that extends a variable distance from the rectum, which is always involved. Inflammation is limited to the rectum in 30 per cent of cases (proctitis), involves the left colon in 40 per cent of cases, and is extensive or pancolonic in the remaining 30 per cent. can affect any part of the GI tract from the mouth to the anus but the terminal ileum is the most commonly involved site. Unlike UC, the inflammation is patchy; however, purely colonic may be difficult to distinguish from UC. Involvement of the upper GI I 28 Prescriber 5 February 2012 tract occurs in up to 10 per cent of patients with and usually represents an aggressive disease course. True oral (orofacial granulomatosis) is rare and should be managed in conjunction with specialist oral surgeons. can progress from a purely inflammatory type through stenosis and scarring to penetrating (fistulising) disease, and one of the aims of medical therapy is to delay or halt this progression. Inflammation in UC is superficial while that in is transmural (involving all layers of the bowel wall). While UC and are said to be distinct clinically and histologically, sometimes there is difficulty in making this distinction and per cent of patients are said to have IBD unclassified. The cause of IBD is not known, but the widely accepted theory is that environmental/microbial facwww.prescriber.co.uk

2 tors trigger the disease in genetically susceptible individuals. GPs are frequently confronted with new patients who present with initial symptoms suggestive of IBD and this article will discuss the currently available treatments. Drugs available to treat UC and Once the diagnosis has been established, treatment of IBD is required to bring the disease into remission as rapidly as possible to improve symptoms and quality of life as well as maintaining the disease in cortico - steroid-free remission, and ideally inducing healing of the mucosa. Treatment of IBD will depend on the clinical presentation, severity and disease extent (see Table 1). There are a number of first-line medications available and they can be grouped into the aminosalicylates (5-ASAs), corticosteroids, other immunosuppressive agents and antibacterials. In the last few years, newer biological therapies have been developed, including antagonists of the proinflammatory cytokine tumour necrosis factor (TNF-alpha); these include infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (unlicensed). Figure 1. UC is restricted to the colon; the 5-ASA drugs are effective for the acute treatment of mild-to-moderate UC and maintaining remission Aminosalicylates The 5-ASA drugs are commonly used, and are effective for the acute treatment of mild-to-moderate UC and in maintaining remission in UC. They are used in higher doses, sometimes co-prescribed with cortico - steroids, to bring an acute flare under control. Initially published trials of 5-ASAs showed efficacy for ileal and colonic, and they became a popular choice for treating mild disease. However, two meta-analyses of the placebo-controlled trials in 1,2 have not shown evidence of clinically relevant benefit. The European Crohn s and Colitis Organisation guidance 3 on the management of states at this stage mesalazine should be considered clinically no more effective than placebo for active ileal or colonic Crohn s disease. This is echoed by the British Society of Gastroenterology guidance. 4 However, some evidence suggests that 5-ASA therapy could help prevent recurrence following surgery. 5 The 5-ASAs act as mucosal anti-inflammatories, although the exact mode of action is not clear. Inhibition of local proinflammator y pathways is thought to play a role. A number of 5-ASA preparations are available on the UK market (see Table 2). Sulfasalazine is the oldest and least expensive, and consists of a sulfa pyridine carrier molecule linked via an azo bond to salicylate. In the colon, the bond is cleaved by colonic bacteria releasing the inert carrier molecule and the active salicylate. It is not as commonly prescribed today because of the possibility of side-effects associated with sulfapyridine. 5-ASA agents include mesalazine, balsalazide (Colazide) and olsalazine (Dipentum). The preparations of mesalazine consist of either the drug being contained within a ph-dependent resin film or in microspheres enclosed within an ethylcellulose semipermeable membrane. This is to prevent drug absorption and degradation in the proximal small bowel and Figure 2. most commonly involves the terminal ileum but can affect any part of the GI tract; corticosteroids are highly effective for inducing remission in acute flares SPL SPL Prescriber 5 February

3 IBD subtype Active, left-sided or extensive UC Recommended treatment mesalazine 2 4.8g daily balsalazide 6.75g daily consider olsalazine 1.5 3g daily for patients with left-sided disease or intolerance of other 5-ASAs consider sulfasalazine 2 4g daily if co-existent reactive arthropathy prednisolone 40mg daily if a prompt response is required or if 5-ASA unsuccessful; reduce gradually over 8 weeks azathioprine 2.0mg/kg/day or mercaptopurine 1 1.5mg/kg/day if unable to wean from steroids consider topical agents (either steroids or mesalazine) if patients have troublesome rectal symptoms, mesalazine is usually more effective ciclosporin (or infliximab) may be effective for severe, steroid-refractory UC Active, distal UC topical mesalazine 1g daily (in appropriate form for extent of disease) combined with oral mesalazine 2 4g daily, olsalazine 1.5 3g daily or balsalazide 6.75g daily consider sulfasalazine 2 4g daily if co-existent reactive arthropathy topical corticosteroids less effective than topical mesalazine; consider if patient intolerant of topical mesalazine if above does not control symptoms consider prednisolone 40mg daily; reduce gradually over 8 weeks Active ileal/ileocolonic budesonide 9mg daily if ileal/right colonic disease if above does not control symptoms, consider prednisolone 40mg daily; reduce gradually over 8 weeks consider azathioprine 2 2.5mg/kg/day or mercaptopurine 1 1.5mg/kg/day in active as adjunctive therapy and as a steroid-sparing agent; consider methotrexate 25mg/week intravenous steroids (hydrocortisone 400mg/day or methylprednisolone 60mg/day; avoid if evidence of infection or likely requirement for surgery) infliximab or adalimumab if above fail Fistulating and perianal metronidazole 400mg 3 times daily and/or ciprofloxacin 500mg twice daily in simple perianal fistulae azathioprine 2 2.5mg/kg/day or mercaptopurine 1 1.5mg/kg/day Table 1. Subtypes of IBD and their recommended management (adapted from the British Society of Gastroenterology guidelines 2011) allows the drug to be released in the distal small bowel and colon. Different brands of mesalazine have different bioavailabilities and these preparations should not be considered interchangeable. A multimatrix system (MMX) formulation of mesalazine (Mezavant XL) is also available, in which the drug is bound within a polymeric matrix inside a ph-dependent gel. This permits once-daily dosing that is helpful in improving medication adherence. Recent trials using other mesalazine preparations (Pentasa, Asacol, Salofalk) have shown similar efficacies for once daily vs split dosing. Balsalazide is a prodrug of mesalazine, and olsalazine is a dimer of 5-ASA linked by an azo bond, which is cleaved by colonic bacteria. In addition to oral formulations, mesalazine is also available in suppositor y and enema forms, which can be useful in patients with IBD limited to the left colon. Combined treatment with oral and topical preparations in patients with mild or moderate extensive colitis is superior to oral therapy alone. 6 Side-effects Important side-effects of the 5-ASAs include the rare but serious possibility of blood dyscrasias (see Table 3); patients should be warned to tell their doctor if they develop a sore throat, bruising, fevers or a rash and to have a full blood count (FBC) checked. Other side-effects include headaches, hepatitis, pancreatitis, renal impairment and worsening of the symptoms of colitis, in which case the drugs should be stopped. Pancreatitis and 30 Prescriber 5 February

4 Sulfasalazine Mesalazine Olsalazine Balsalazide Form sulfa carrier and 5-ASA coated with 5-ASA dimer prodrug of 5-ASA 5-ASA ph resin or semipermeable membrane Mode of action colonic bacteria delivery characteristics of colonic bacteria colonic bacteria breakdown releasing mesalazine preparations breakdown breakdown releasing active salicylate and vary; refer to BNF/ releasing active active salicylate inert sulfa carrier pharmaceutical literature salicylate Use UC UC UC UC especially if reactive arthropathy Table 2. Form, mode of action and use of 5-ASA drugs in UC interstitial nephritis appear significantly more common with mesalazine than the other 5-ASAs, 7 and renal function in patients who receive 5-ASAs should be evaluated and monitored at least once a year. In addition, olsalazine may cause water y diarrhoea. However, the popular use of 5-ASAs is due to the overall low incidence of side-effects and good safety record. It should be noted that an alteration in gut ph may inhibit mesalazine release, so co-prescription of lactulose should be avoided. Mesalazine may also increase the risk of haematological toxicity when co-prescribed with the immunomodulators azathioprine and 6-mercaptopurine. In practice this is not a common problem, and the two classes of drugs are usually co-prescribed successfully. The risk of bowel cancer is increased in patients with longstanding colitis. Epidemiological evidence and a meta-analyses indicate that chronic 5-ASA treatment reduces this risk. Long-term 5-ASA maintenance therapy can also be advocated as a preventive strategy. 8 Corticosteroids Corticosteroids such as prednisolone are highly effective for inducing remission in acute flares of IBD. In UC they are prescribed when 5-ASAs have not been effective. In of the ileum and right colon, budesonide can be used. Budesonide is poorly absorbed from the gastrointestinal tract and has extensive firstpass metabolism, therefore reducing systemic sideeffects. It is slightly less effective than prednisolone, particularly in those with extensive colonic or severe disease. Typical oral starting doses are prednisolone 40mg or budesonide 9mg ( only) daily, tapered over 8 12 weeks. If administered in hospital in those patients with severe exacerbations, then intravenous hydrocortisone is commonly prescribed. In UC, a controlled-release beclometasone dipropionate (Clipper) preparation in a ph-dependent resin can be used for mild/moderate disease; however, its efficacy is similar to that of mesalazine. 9 Side-effects Corticosteroids block both the early and late stages of the inflammatory pathway, but their wellknown side-effects limit their use in IBD treatment such that they are not used for maintenance therapy. Common side-effects include hypertension, glucose intolerance, osteoporosis, acne, depression, psychosis and increased susceptibility to infections. It has been suggested that patients taking as little as 10mg for more than three weeks may have a suppressed hypothalamic-pituitary-adrenal axis for more than a year after stopping, and may need to receive supplemental steroids in further illnesses or surgery. 10 Patients on long-term steroid therapy should receive supplemental calcium and vitamin D and should be considered for bone densitometry to assess if further treatment of bone loss is indicated. The potential systemic side-effects of cortico - steroids may be reduced by using topical preparations, of which there are now a large number in liquid or foam vehicles as well as suppositories. Examples include Predsol, Colifoam and Predfoam, and prednisolone suppositories. Of note, topical steroids are slightly less effective than topical 5-ASAs. Other immunosuppressive drugs Immunomodulators, which are unlicensed for IBD but advocated in the BNF and by the National Institute for Health and Clinical Excellence (NICE), include azathioprine in daily doses of 2 2.5mg per kg, its metabolite 6-mercaptopurine in daily doses of 1 1.5mg per kg, as well as methotrexate. They are used in the treatment Prescriber 5 February

5 Drug Sulfasalazine tablets Mesalazine Olsalazine tablets or capsules for UC Balsalazide capsules for UC Prednisolone Budesonide for Azathioprine Anti-TNF agents Potential adverse effects diarrhoea, nausea, headache, exacerbation of colitis, hypersensitivity reactions rarely blood dyscrasias, hepatitis, pancreatitis, renal damage diarrhoea, nausea, headache, exacerbation of colitis rarely blood dyscrasias, hepatitis, pancreatitis, renal damage diarrhoea, nausea, headache, exacerbation of colitis rarely blood dyscrasias, hepatitis, pancreatitis, renal damage diarrhoea, nausea, headache, exacerbation of colitis, abdominal pain and vomiting, cholelithiasis rarely blood dyscrasias, hepatitis, pancreatitis hypertension, glucose intolerance, osteoporosis, acne, depression, psychosis, increased susceptibility to infections as for other corticosteroids but with less systemic effects nausea, diarrhoea, myalgia, bone marrow suppression, pancreatitis, hepatotoxicity, infection infusion (infliximab) or injection site (adalimumab) reactions, infections especially (adalimumab, infliximab) tuberculosis, worsening of heart failure, autoimmune phenomena including demyelinating syndromes, autoimmune hepatitis, lupoid-like syndrome, palmar/plantar psoriatic eruptions Table 3. Drugs commonly used to treat IBD in the community and their potential adverse effects (for a comprehensive list refer to the BNF or the drug s SPC) of patients with IBD who are refractory to steroid therapy, are steroid dependent and in perianal, and as concomitant immunosuppression alongside biological therapy. They are effective in both induction and maintenance of remission, although their slow onset of action often necessitates another agent to act as a bridge to therapy. In patients unable to take azathioprine because of nausea, diarrhoea or myalgia, 6-mercaptopurine may be better tolerated. These drugs are known as steroid-sparing agents and are used as maintenance therapy for mucosal disease or as treatment of fistulating. Both azathioprine and 6-mercaptopurine (the thiopurines) are cytotoxic drugs that inhibit DNA synthesis and lymphocyte proliferation and have several potential serious toxicities, including bone-marrow suppression, pancreatitis, hepatotoxicity and infection. There is an increased relative risk of non-hodgkin lymphoma in patients with IBD who receive these agents, although the absolute risk remains relatively low (approximately 4 in , compared to 1 in in the general population). The enzyme thiopurine methyltransferase (TPMT) metabolises azathioprine and 6-mercaptopurine and the risk of bone marrow suppression is increased in people with low TPMT activity, especially in those who are homozygous for low TPMT activity (approximately 1 in 300). This test is widely available, allowing identification of those patients at increased risk of sideeffects. Careful monitoring of liver function tests and blood cell counts is needed in patients being treated with these agents, and although treatment and monitoring are initially started in secondary care, primarycare doctors may play a role in monitoring the FBC. These patients need weekly FBC monitoring for at least the first four weeks of therapy, followed by an FBC at eight weeks to be repeated thereafter at least three monthly. The toxicity of azathioprine and 6-mercaptopurine is increased with allopurinol, which inhibits xanthine oxidase, one of the enzymes responsible for their metabolism. Accidental co-prescription of these drugs can lead to severe and potentially fatal bone marrow suppression. Measurement of the thiopurine metabolites 6-thioguanine and methylmercaptopurine may be useful in patients who fail to respond or who lose response, to check adherence or to investigate the potential for an increase in dose. This is available in a few laboratories. In patients who have failed to respond to steroids or who are intolerant of azathioprine or 6-mercaptopurine, methotrexate has been shown to induce remission of in 40 per cent of patients. 11 In this trial, 25mg methotrexate by weekly intramuscular injection was used, but another study suggests a similar response when it is given orally. 12 Lower doses (15mg a week) maintain remission. The only randomised controlled trial of methotrexate in UC did not show it to be effective; however, it was used at a lower dose than that shown to be effective in. 13 Although methotrexate is as efficacious in inducing remission as azathioprine, it does not appear to work any faster. 14 Ciclosporin and mycophenolate In patients who present with acute colitis and who fail to respond to intravenous steroids, the addition of 32 Prescriber 5 February

6 ciclosporin, a calcineurin inhibitor and potent immunosuppressant, has been shown to induce remission in up to 50 to 80 per cent. The drug is usually given by continuous intravenous infusion (2 4mg per kg per day), although the oral formulation may be as effective. 15 Ciclosporin as a rescue therapy is usually prescribed after three to five days of steroid therapy. Most patients respond within three to four days, and in those in whom surgery becomes necessary a decision about colectomy can be made after a week or so of treatment, or sooner if there is evidence of deterioration. Those who do respond to drug therapy can be converted to oral treatment as out - patients, in addition to initiating azathioprine or 6-mercaptopurine; the aim is to reduce the New suspected patients new patients where diagnosis of IBD suspected refer urgently to hospital consultant if abdominal pain and tenderness, severe bloody diarrhoea or fever, refer for possible admission Known patients with IBD known IBD patients with symptoms of a flare mild-to-moderate disease acute treatment moderate-to-severe disease acute treatment pancolitis (UC) proctitis or distal colitis (UC) UC oral and/or topical 5-ASAs oral corticosteroids oral and/or topical 5-ASAs oral or topical steroids oral corticosteroids antibiotics for perianal disease/ fistulae iv corticosteroids consider infliximab iv corticosteroids consider ciclosporin/infliximab/ colectomy Maintenance therapy UC oral/topical 5-ASAs immunomodulators immunomodulators antibiotics infliximab if fistulating Figure 3. Recommended management of new and known patients with IBD 34 Prescriber 5 February

7 prednisolone dose and stop the ciclosporin once azathioprine or 6-mercaptopurine have had a chance to work. The limitations of ciclosporin are its toxic sideeffects, which include hypertension, infection and renal impairment, and it should only be initiated under specialist supervision in hospital. There is an increased risk of seizures in patients with low magnesium and cholesterol, and these should be measured before it is given. The use of the immunosuppressant mycophenolate mofetil in refractory IBD remains controversial. This is due to lack of evidence regarding its efficacy and, although it is not routinely prescribed, it may have a role in those patients with IBD who are intolerant of thiopurines. Antibacterials Antibacterials, such as metronidazole and ciprofloxacin, may be prescribed to treat infectious complications of IBD, in perianal (and possibly colonic), and in prevention of postoperative recurrence of. There is limited evidence for their use in UC, other than in pouchitis. Apart from their antimicrobial effect it is thought that they have a role in modulating the immune response, although the exact mechanisms are not clear. They may also reduce diarrhoea in bacterial overgrowth in small-bowel. Significant sideeffects of metronidazole include peripheral neuropathy if used long term (over three months), a bad taste in the mouth and a disulfiram-like interaction with alcohol. Biological therapy Biological agents target specific immunological and inflammatory pathways implicated in disease pathogenesis such as T-cell activation, proinflammator y cytokines, ie TNF-alpha, and anti-inflammator y cytokines, ie interleukin-ii. Infliximab is a monoclonal antibody to TNF-alpha. It is licensed for intravenous use in the treatment of severe, active, mucosal and fistulating in patients who have failed therapy with corticosteroids or immunosuppressants. 16,17 The main drawback is its cost; it has also been associated with the development of tuberculosis, often in extrapulmonary sites, and worsening heart failure. Patients should, therefore, be risk assessed for tuberculosis and screened where appropriate. It is prescribed and administered in hospital. It is also effective for the induction and maintenance of remission in UC 18 both for acute severe and chronic active disease. However, NICE has recently restricted its use to three induction doses for acute severe UC only in patients for whom ciclosporin is considered inappropriate. Adalimumab is a humanised monoclonal antibody to TNF-alpha, also effective in induction and maintenance of remission of. 19 This is available as a subcutaneous injection and can therefore be self-administered at home. In recent years there has been a move towards topdown therapy of IBD patients with biological agents rather than a bottom-up approach in other words, the use of disease-modifying drugs early in the course of the disease to limit long-term damage. Time will tell whether this approach leads to lower long-term morbidity than the traditional approach. Lifestyle, probiotics and fish oil supplements Patients with who smoke should be advised to stop, as it is positively associated with their condition and negatively with prognosis, response to treatment and postoperative remission. This is in contrast to UC where smoking has a negative association; however, patients with UC should also be advised to stop smoking due to the significant risk of morbidity otherwise. There is ongoing interest in the use of probiotics in the treatment of IBD. These are live nonpathogenic organisms such as various Lactobacillus species, which aim to confer health benefits by improving the gut micro-organism environment. Probiotics modulate the local production of proinflammatory cytokines, and in animal models of colitis they have been shown to prevent and treat established intestinal inflammation. Some controlled studies have also shown a benefit with probiotics in pouchitis 20 and in the prevention of UC, 21 but a lack of consistent study data currently precludes the widespread use of probiotics in the management of. Similarly, the anti-inflammator y omega-3-poly - unsaturated fatty acids (PUFAs) from fish oils have also generated interest in the management of chronic inflammator y diseases. In IBD, the importance of dietary intake of PUFA has been gleaned from anecdotal observations that the Inuit have a low incidence of and UC. However, a Cochrane database analysis of the placebo-controlled trials of PUFA from fish oils in chronic inflammatory diseases has failed to demonstrate significant benefit. Trichuris suis, the pig whipworm, has now appeared as an interesting alternative treatment that has shown early promise, but further study is needed. Whether Prescriber 5 February

8 the association of IBD with Western culture includes a lack of intestinal parasites is one speculation that has been attached to this observation. Conclusion The exact cause of IBD is unknown, but it commonly affects young as well as older people, and its chronicity and potential for complications impact greatly on the lives of those affected. As no single therapy is uniformly effective, it is important to discuss treatments and possible future therapies with patients at the time of diagnosis. Generally, disease-modifying drugs such as the immunomodulators and biological therapy are being used earlier than hitherto in an attempt to modify the long-term course of the disease. Hospitals may be fortunate enough to have designated IBD clinical nurse specialists for ongoing advice and support. Resources to aid patient education should be provided and include patient information leaflets and information about IBD support groups (see Resources). References 1. Ford AC, et al. Am J Gastroenterol 2011;106: Hanauer SB, et al. Clin Gastroenterol Hepatol 2004;2: Dignass A, et al. J Crohns Colitis 2010;4: Mowat C, et al. Gut 2011;60: Ford AC, et al. Am J Gastroneterol 2011;106: Marteau P, et al. Gut 2005;54: Ransford RA, et al. Gut 2002;51: Eaden J. Aliment Pharmacol Ther 2003;18(Suppl 2): Manguso F, et al. Aliment Pharmacol Ther 2007;26: Yamada T, et al. Inflammatory bowel disease. In: Yamada T, ed. Handbook of gastroenterology. Philadelphia: Lippincott- Raven, Feagan BG, et al. N Engl J Med 1995;332: Arora S, et al. Hepatogastroenterology 1999;46(27): Oren R, et al. Gastroenterology 1996;110: Ardizzone S, et al. Dig Liver Dis 2003;35: Loftus CG, et al. Gut 2003;52: Ricart E, et al. Am J Gastroenterol 2001;96: Targan SR, et al. N Engl J Med 1997;337: Rutgeerts P, et al. N Engl J Med 2005;353: Colombel J-F, et al. Gastroenterology 2007;132: Mimura T, et al. Gut 2004;53: Kruis W, et al. Gut 2004;53: Declaration of interests None declared. Dr Taylor is specialist registrar and Dr Wilkinson is consultant gastroenterologist at Guy s and St Thomas NHS Foundation Trust, London Resources Guidelines Guidelines for the management of inflammatory bowel disease in adults. British Society of Gastroenterology Infliximab for subacute manifestations of ulcerative colitis. TA140. NICE, April Infliximab for acute exacerbations of ulcerative colitis. TA163. NICE, December Infliximab (review) and adalimumab for the treatment of Crohn s disease. TA187. NICE, May Groups and organisations The Colostomy Association (CA). Helpline ; cass@colostomyassociation.org.uk; website: A charity that supports people with a colostomy. CORE. Tel: ; website: org.uk. Core is a charity that produces a series of leaflets providing clear, helpful information for the public about common digestive disorders. Crohn s and Colitis UK (previously known as NACC). Information line: ; info@crohns andcolitis.org.uk; website: org.uk. Crohn s and Colitis provides general information and support for patients with IBD and their families. Patient information Inflammatory bowel disease: a guide for patients and their families. Stein SH, et al. 2nd ed. Philadelphia: Lippincott-Raven Publishers, Inflammatory bowel disease (the facts). Langmead L, et al. Oxford: Oxford University Press, The first year, Crohn s disease and ulcerative colitis: a patientexpert guide for the newly diagnosed. Sklar J. London: Robinson, Prescriber 5 February