The therapeutic goal is to induce remission, maintain remission, and prevent disease complications. Though there is a treatment overlap of ulcerative colitis and Crohn’s Disease, it is best to review the treatment separately, before which one should be differentiated from the other. Ulcerative colitis (UC) is inflammation typically involving the mucosa and occasionally the submucosa of the colon. Crohn’s disease (CD) is characterized by inflammation of the deeper layers of the gastrointestinal tract extending from the mouth to the anus. The transmural involvement of the disease gives rise to certain unique conditions like fistulae and stricture formation. UC and CD can be distinguished from each other using clinical, endoscopic, pathological, and serological criteria in 90% of patients. Endoscopically in UC there is diffuse inflammation and ulcerations without any normal intervening mucosa. Crypt abscess may be present. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), is positive in 75% of patients. In CD there are aphthous or linear ulcerations with discontinuous or “skip” areas of inflammation. Non-caseating granulomas are present in 30% of patients and 60% are positive for anti-saccharomyces cerevisiae antibodies (ASCA).

Now that we have identified the two disease entities, we can proceed to discuss the treatment. The three main drugs are 5-acetyl salicylic acid (5-ASA) compounds, corticosteroids, immunomodulators. Sulphasalazine (SASP) composed of 5-ASA and sulphapyridine joined by a diazo bond was the main stay for years. The active anti-inflammatory moiety 5-ASA is cleaved from its carrier the sulphapyridine by the colonic bacteria. With better drug delivery systems, it was possible to deliver 5-ASA to various parts of the gastrointestinal tract without the sulpha molecule, thereby, greatly reducing the side effects of sulpha, namely nausea, anaemia secondary to folic acid malabsorption. 5-ASA drugs can be used in induction, as well as maintenance of remission.

Glucocorticoids have powerful anti-inflammatory action by suppressing levels of phospho lipase A2, thromboxane A2, and cytokine levels. They can be administered intravenously, orally, or in enema form for induction of remission. They are not used to maintain remission because of their well known long-term complications like osteoporosis and aseptic necrosis of long bones.

Immunomodulators are potent and effective medications used to control active inflammation, and allow for the withdrawal of steroids and ultimately maintain remission. Azathioprine (AZA), 6 mercaptopurine (6MP), methotrexate, and cyclosporin are among the immunomodulators used in UC and CD. They potentially have serious toxicities, like infections, leucopenia, pancreatitis, paraesthesias and liver toxicity. AZA is a pro drug that is converted to 6MP and then metabolized to an active metabolite thioguanine (TG). An enzyme thiopurine methyl transferase (TPMT) converts 6MP to 6-methyl-mercaptopurine diverting metabolism away from TG. Individuals with low levels of TPMT are at risk of developing severe bone marrow suppression because of high levels of TG. When TPMT blood tests are available, it must be done to avoid toxicity from AZA/6MP.

The therapeutic approach to UC depends on both the extent of colonic involvement and the severity of the disease.

Proctitis - 30% of patients with UC present with proctitis. The treatment consists of topical administration of 5-ASA suppository, 500 mg, twice a day, until the patient goes into remission. Maintenance therapy is not recommended for the first episode of proctitis. If relapse occurs, restart 5-ASA suppository. Oral 5-ASA/SASP needs to be started if no improvement occurs with the suppository. Systemic steroids are rarely needed, except in severe and refractory disease.

Left-sided colitis - Treatment is initiated with 5-ASA enemas once or twice a day for 4-6 weeks and the dose is tapered to every third night for maintenance of remission. If the response is poor, a combination of 5-ASA enemas and oral preparations in maximum tolerable doses is helpful to obtain remission. Sometimes an addition of oral budesonide, 9 mg/day, a locally acting glucocorticoid with very few systemic side effects, is effective.
Extensive colitis and pancolitis - Treatment is initiated with oral and enema forms of 5-ASA. Consider oral prednisone, 40-60 mg/day for patients who fail oral and topical 5-ASA therapy. Treat anaemia with iron supplements and diarrhoea with loperamide.

Severe or fulminant colitis - This category of patients are hospitalized after 10 or more bouts of bloody diarrhoea, weight loss, dehydration. Fulminant refers to a subgroup of patients with fever, abdominal pain, and are at risk of progressing to toxic megacolon and bowel perforation. Treatment consists of IV steroid, bowel rest, and nutrition, in addition to IV ciprofloxacin and metronidazole. Methylprednisolone 16-20 mg every 8 hrs. Patients who have not received glucocorticoids in the last 30 days can be given an infusion of ACTH, 120 units/24 hrs. If abdominal X-rays reveal a toxic megacolon (> 6 cm), insert nasogastric and rectal tube to decompress the colon. If there is no response to treatment in 72 hours, consider colectomy, prior to which patients could be offered 7-10 day course of IV cyclosporine, 2 mg/kg. Maintain levels of cyclosporine between 150-250, ng/ml. Seizures can be precipitated by low cholesterol levels. If patients respond to IV cyclosporine, oral cyclosporine, along with AZA/6MP should be started and subsequently oral cyclosporine can be discontinued. Serum creatinine, potassium, liver function tests, should be checked every two days unless abnormal, in which case, they should be checked daily. Cyclosporine dose should be decreased if drug levels are > 500 ng/ml or if serum creatinine rises > 30% over baseline, liver enzymes double, and if blood pressure is > 150 mm/90 mmHg with antihypertensive drugs. Trimethoprim sulpha 160/800 mg tablets, 3 x week at prophylaxis against pneumocystis carinii pneumonia (PCP).

Proctocolectomy with ileo-anal anastomosis with a continent ileal pouch is reserved for refractory UC, toxic megacolon, and for patients with long standing UC (> 8 years) found to have dysplastic lesions on surveillance colonoscopy.

General recommendations in ulcerative colitis include multivitamins, folic acid, calcium supplements, and lactose free diet in patients confirmed to have lactose intolerance by breath tests. Restrict fresh fruit and vegetables and sorbitol containing products, like gum, in patients with abdominal cramps and diarrhoea.

Crohn’s disease comprises of a wide spectrum of clinical presentations which have to be considered separately in deciding the proper therapeutic approach.

Oral Lesions - The most common lesions are aphthous ulcers while cheilitis, granulomatous masses, and fial adenitis are not uncommon. Local treatment with hydrocordisone or sucralafate, may be helpful besides treatment directed at intestinal disease.

Gastroduodenal Crohn’s lesions of antrum duodenum coexist in 5% of cases with intestinal involvement. Local treatment with proton pump inhibitors. H2 blockers, and sucralfate along with systemic treatment with 5-ASA preparations are used. Prednisone is needed for moderate to severe disease. AZA/6MP can be used to maintain remission.

Active Ileitis - The ileum is the most common part of the small intestine involved in patients presenting with diarrhoea, abdominal pain, fever, and weight loss. Initial treatment is with 5-ASA which is gradually increased to the maximum tolerable dose to which antibiotics like ciprofloxacin, 500 mg bid, and clarithromycin, 500 mg bid are added. If there is still no response, locally acting budesonide, 9 mg per day, or oral prednisone, 40-60 mg per day is added. If the disease responds well, prednisone is tapered by 5 mg every week. Budesonide is continued for 8-16 weeks and then tapered by 3 mg per week. Maintenance therapy consists of 5-ASA and budesonide.

Incomplete responders - Symptomatic treatment with loperamide and sometimes cholestyramine, 4 mg TID, a bile salt binding resin is used, especially in patients who have previous ileal resection. Vitamin B₁₂ injection is recommended in patients with severe ileal disease.
Localized peritonitis - Patients present with abdominal pain, fever, chills, and leucocytosis with a negative pelvic and abdominal CT scan. Treatment consists of IV third generation cephalosporin and metronidazole.

Abscess - Treated with IV antibiotics, and possible steroids, percutaneous drainage, and surgery with resection.

Small Bowel Obstruction (SBO) - SBO could be due to stricture formation, stenotic area with superimposed spasm and inflammation, and adhesions from previous surgery. Conservative treatment with nasogastric suction, total peritoneal nutrition (TPN), may be tried for 24-48 hrs before IV steroids. Surgery is recommended if medical treatment fails.

Ileocolitis and colitis - The treatment is similar to that of active colitis. The only difference is the presence of metronidazole 10 mg per kg or ciprofloxacin and clarithromycin, prednisone 40-60 mg per day is added to the above regimen which is tapered and discontinued once remission is achieved.

Refractory disease - It is defined as symptomatic disease, despite 5-ASA antibiotics and corticosteroids (steroid resistant). Therapy should also consist of bowel rest and TPN. AZA/6MP treatment at 50 mg per day is initiated and the dose can be increased to 2 mg per kg per day for 6MP, and 2.5 mg per kg day for AZA. These drugs may take 3-6 months to take effect, during which time corticosteroids are continued. Once remission is achieved, steroids can be tapered and discontinued.

Methotrexate (MTX) is used as an alternative when AZA/6MP have produced intolerability and side effects. Initial treatment is begun with intramuscular or subcutaneous MTX, 25 mg per week and then reduced to 15 mg per week once remission is achieved. Oral MTX is not as effective. Co-administration of folic acid 1 mg per day prevents anaemia and may reduce nausea and mouth sores. A complete blood count and liver function tests need to be done initially and then every two months during the duration of therapy. Liver biopsy is recommended when liver enzymes are elevated.

Infliximab - A monoclonal antibody against tumour necrosis alpha can be used to induce remission.

Perineal disease - Perineal abscess can be treated with metronidazole 10 mg/kg per day for at least a year. Ciprofloxacin, 500 mg twice a day can be used alternatively. When both these drugs fail, surgical treatment or treatment with AZA/6MP should be considered.

Fistulae - Infliximab, 5 mg per kg is administered at weeks 0, 2 and 6, along with AZA/6MP. In entero-enteric fistulae, 6MP is preferred.

Post-operative recurrence varies depending on the surgery. The highest rate of endoscopic recurrence is in patients with colon resection. The lowest is in patients with total colectomy and ileostomy. Recurrences can be prevented by using metronidazole and 5-ASA oral agents. Recurrences can be treated with 5-ASA and AZA/6MP indefinitely.

References

1. Vecchi, et al. Oral vs Combination Nesalazine Therapy in Active UC. A Double-Dummy Randomized Multicenter Study. Aliment Pharm Ther 2001; 15 : 251.
2. Brattsand. Overview of Newer Corticosteroid Preparations for IBD. Can J Gastro 1990; 4407.
3. Barrett, et al. Pharmacological Aspects of Therapy in IBD : Anti-Diarrheal Agents. J Clin Gastro 1988; 10 : 57.
4. Meyers, et al. Corticotropin vs. Hydrocortisone in the Intravenous Treatment of UC : Prospective, Randomized Double-Blind Clinical Trial. Gastro 1983; 85 : 351.
5. Lichtiger, et al. Cyclosporin in Severe UC Refractory to Steroid Therapy. NEJM 1994; 330 : 1841.
6. Traprantera, et al. An Antibiotic Regimen for the TX of Active CD, Randomized Control Clinical Trial of Metronidazole Ciprofloxacin. AJG 1996; 91 : 328.
7. Gervais, et al. A Percutaneous Abscess Drainage in CD, Technical Success and Short and Long-term outcomes during 14 years. Radiology 2002; 232 : 645.
8. Present, et al. Infliximab for the Treatment of Fistulae in Patients with CD. NEJM 1999; 340 : 1398.
9. Farrell and Peppercorn - Medical Management of Ulcerative Colitis and Crohn’s Disease - Up to Date.

Diplomat of the American Board of Internal Medicine and Gastroenterology and Chief of Gastroenterology, Kimball Medical Centre, Lakewood, New Jersey.