practical management of inflammatory bowel

disease patients taking immunomodulators

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Comprised of two major disorders:

Ulcerative Colitis (UC)

Crohn’s Disease (CD)

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• Ulcerative colitis is a disease that causes ulcers in the lining of the rectum and colon. It is one of a group of diseases called inflammatory bowel disease. Ulcers form where inflammation has killed the cells that usually line the colon.

• Ulcerative colitis can happen at any age, but it usually starts between the ages of 15 and 30. It tends to run in families.

Ulcerative Colitis Symptoms :• Bloody diarrhea • Symptoms of rectal urgency and tenesmus • Weight loss• rectal pain Some patients with Ulcerative Colitis also develop symptoms

outside of the gastrointestinal tract; these symptoms include:

• Osteoporosis• Oral ulcerations• Arthritis

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• Crohn's disease causes inflammation of the digestive system. It is one of a group of diseases called inflammatory bowel disease. The disease can affect any area from the mouth to the anus. It often affects the lower part of the small intestine called the ileum.

• Crohn's disease seems to run in some families. It can occur in people of all age groups but is most often diagnosed in young adults.

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Common symptoms of Crohn's disease:• abdominal pain• diarrhoea• weight lossLess common symptoms include:• poor appetite• fever, night sweats• rectal pain/rectal bleeding Some patients with Crohn's disease also develop symptoms

outside of the gastrointestinal tract; these symptoms include:

• arthritis• skin rash• inflammation of the iris of the eye.

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1-Azathioprine and Mercptopurine2-Ciclosporin3-Methotrexate4-Tacrolimus

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Introduction :•The purine analogues azathioprine and mercaptopurine are effective in inducing and maintaining remission in patients with ulcerative colitis and Crohn’s disease.•Azathioprine is a prodrug which is converted to mercaptopurine and then metabolised to the active metabolite 6-thioguanine. thioguanine has been used for treatment of IBD, but caution is appropriate because of potential hepatotoxicity. •Thiopurine Methyl Transferase (TPMT) converts mercaptopurine to 6-methyl-mercaptopurine. When TPMT levels are low, higher levels of 6-thioguanine are produced and this is associated with a greater risk of myelosuppression. •The onset of action of these drugs is very variable and in many patients, the beneficial effects may not be seen for 3 – 4 months, and in some cases even longer.

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azthioprine given in doses between 2–2.5 mg/kg/day and 6-MPof 1–1.5 mg/kg/day in both UC and CD.

Monitoring therapyMeasurement of full blood count and liver function tests areadvisable before and within 4 weeks of starting therapy, thenmonthly.

Direct Toxicity :Pancreatitis; bone marrow suppression; allergic reactions including nausea, swinging fevers); drug induced hepatitis

Indirect toxicity : Infections – bacterial and viral (including herpes zoster and simplex, Epstein Barr virus (EBV); Cytomegalovirus (CMV).

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• Nausea / vomiting and loss of appetite• Abdominal pain – should this develop, the drug should be stopped immediately• Hair loss• Adverse effects on the blood• Fever, weakness and fatigue (rare)• Unusual bleeding / bruising (rare)• Jaundice (rare)• Rashes (rare)

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Introduction :• The main role for ciclosporin is in the treatment of patients with

severe steroid refractory Ulcerative Colitis. • Response rates are improved by the addition of azathioprine or

Mercaptopurine2,3, and ciclosporin can be used as a bridge for maintenance therapy having a slow onset of action.

• Ciclosporin is of little benefit in Crohn’s disease and should be avoided

Mechanism of Action: Ciclosporin (CsA) is an inhibitor of calcineurin, preventing clonal expansion of T-cell subsets. it has effective in the management of severe UC.

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Ciclosporin may be given either intravenously (2mg/kg/day) or orally in a microemusion formula (Neoral) in doses between 4.6 – 7.5 mg kg/day.

Cautions :1.Uncontrolled hypertension2.Use of potassium sparing diuretics3.Pregnancy and lactation4.Grape fruit juice – to be avoided within one hour of ingestion 5.Drug interactions

Agents likely to increase Ciclopsorin levels such as:1-Calcium channel blockers(Diltiazem, Verapamil, -Nifedipine, Amlodipine)

2-Grapefruit juice3-Tacrolimus4-Oral contraceptives(Danazol) 11

1.Uncontrolled hypertension2.Renal and liver failure3.Severe electrolyte disturbance i.e. hyperkalaemia

Side effectNephrotoxicity, hemolytic–uremic syndrome, hypertension, neurotoxicity, gum hyperplasia, skin changes, hirsutism, post-transplantation diabetes mellitus, hyperlipidemia; trough monitoring or checking levels two hours after administration required

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Introduction : Methotrexate is an immunomodulator used to induce and maintain remission of Crohn’s disease and Ulcerative colitis in patients who have steroid dependent or refractory disease, or who have been intolerant of either azathioprine or 6-Mercaptopurine. Methotrexate inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines. Although unlicensed to treat inflammatory bowel disease, methotrexate is widely used in Crohn’s disease (BNF section 1.5) and less commonly in ulcerative colitis.

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• Much of the evidence for the beneficial effects for methotrexate has been with the intramuscular route of administration. The evidence for the efficacy and bioavailability of oral methotrexate is limited in Crohn’s disease.

• Intramuscular route : 25mg once per week for up to 16 weeks, then reduced to 15mg once a week.

• Oral route : Intially 15mg once per week as a single dose, increasing to 20mg once per week after 2 weeks and up to a maximum of 25mg once a week after a further 2 weeks as tolerated and according to response.

Cautions :•Patients with clinically significant renal impairament from any

cause•Localised or systemic infection including hepatitis B & C and

past history of TB•Unexplained anaemia or cytopenia associated with bone

marrow failure

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• Phenytoin, Co-trimoxazole, Trimethoprim – the antifolate effect of methotrexate is increased

• Probenacid, Penicillin, Azapropazone, NSAID’s – Methotrexate excretion is reduced (but a clinically significant interaction between methotrexate and NSAID’s is rare

• Tolbutamide – serum concentrations of methotrexate may be increased

Side effects:1. Early toxicity from methotrexate is primarily

gastrointestinal (nausea, vomiting, diarrhoea, and stomatitis)

2. Other rare side effects include : headache; acne; skin irritation; dry cough and / or shortness of breath.

Folic acid treatment : Folic acid reduces the toxicity of methotrexate treatment and

improves continuation of therapy and compliance. Folic acid should be taken ONCE weekly, but SHOULD NOT be taken on the same day as the methotrexate.

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Introduction : Tacrolimus has been used to suppress the inflammation associated with ulcerative colitis, Tacrolimus has shown to be significantly effective in the suppression of outbreaks of UC.Tacrolimus has similar actions to those of cyclosporine,but Tacrolimus is more potent than cyclosporine.

Mechanism of Action:*Tacrolimus binds to FK-binding protein,inhibiting cacineurin, a cytoplasmic phosphatase.*Calineurin regulates the ability of the nuclear factor of activated T cells to translocate the nucleus and increase the production of cytokines.*by this way,tacrolimus in hibit the synthesis of cytokines that Normaly occur in response to T cell activation

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*administrated orally or intravenously.Dosing should be 0.1-0.2mg/kg/day if given orally or 0.01-0.02 mg/kg/day if given IV.*oral absorption is in complete*absorption is decrease if drug is taken with high fat or high carbohydrate meals.*highly bound to serum protein.*metabolized in the liver by CYTP3A4.*most of the drug and its metabolites are found in the fecesrenal excretion is very low.

Drug-Drug Ineraction:*anti-bacterial drugs.e.g.erythromycin*anti-viral drugs*calcium channels blockers.e.g.nifedipine*danazole*all these drugs increase the level of tacrolimus

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Nephrotoxicity Neurotoxicity-Tremor, headache, motor

disturbances, seizures Hypertension Hyperglycemia Risk of tumors, infections itching, insomnia, confusion, loss of appetite,

weakness, depression and cramps

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6-mercaptopurine and azathioprine are cornerstones in the long-term management of Crohn’s disease and ulcerative colitis. Methotrexate is an effective 2nd lineagent in Crohn’s disease. Trends in early aggressivemanagement and “top-down” therapy are bringing these medications to patients at an earlier point in their disease. Safe and effective use of immunomodulators is imperative to optimize the risk/benefit profile.

one third of patients treated with long term tacrolimus required surgery. Although a proportion responded to tacrolimus therapy, the majority of patients ultimately required alternative therapies.

Cyclosporin is a narrow therapeutic index drug whose high pharmacokinetic variability markedly influences clinical outcomes The first 4 hours post-dose are the period of highest inter-subject pharmacokinetic variability and greatest pharmacodynamic effects

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1- Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347: 417-29. 2-Siegel CA, Sands BE. Review article : practical management of inflammatory bowel disease patients taking immunomodulators. Aliment. Pharmacol. Ther. 2005; 22 : 1-163-Pearson DC, May GR. Fick OH. Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's disease. A meta-analysis. Ann Intern Med 1995; 123: 132-42.4-de Jong DJ, Goullet M, Naber TH. Side effects of azathioprine in patients with Crohn's disease. Eur J Gastroenterot Hepatol 2004: 16: 207-12.5-Dubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol 2004;2:731.6-Hawthorne AB. Ciclosporin and refractory colitis. Eur J Gastroenterol Hepatol 2003;15:239–44.7-Nathan DM, Iser JH, Gibson PR. A single center experience of methotrexate in the treatment of Crohn’s disease and ulcerative colitis: A case for subcutaneous administration. J Gastroenterol Hepatol 2007 Jun 7 [epub ahead of print].8-Sternthal M, George J, Kornbluth A, et al. Toxicity associated with the use of cyclosporin in patients with inflammatory bowel disease (IBD). Gastroenterology 1996;110:A1019.9-Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology 2003;125:380.

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