Combination immunomodulatory therapy with cyclosporine and azathioprine in corticosteroid-resistant severe ulcerative colitis: the Edinburgh experience of outcome.
BACKGROUND
Cyclosporine is a fungal metabolite and a powerful immunosuppressant. While response to intravenous steroids in severe ulcerative colitis is in excess of 60%, the remainder of patients are left with the options of curative panproctocolectomy or administration of intravenous rescue therapy with cyclosporine. There have been conflicting reports on the efficacy of intravenous cyclosporine in acute ulcerative colitis, and there are serious concerns about potential toxicity and opportunistic infections such as Pneumocystis carnii pneumonia. There are also concerns about early relapse and colectomy following cyclosporine rescue. To date there has been a paucity of data available to help guide the gastroenterologist in the use of cyclosporine and the maintenance of remission once achieved.


METHODS
Between 1994 and 2001, a total of sixteen patients who had received intravenous cyclosporine for acute exacerbation of their known UC (seven females, nine males, mean age 33 years) whose records were available for analysis. All patients were refractory to intravenous methylprednisolone (60 mg/24 h). Patients who responded to cyclosporine were discharged on a regimen of oral cyclosporine, oral steroids oral azathioprine and 5-aminosalicylate.


RESULTS
Median disease duration was 5.4 years (range 0.9-25 years). All sixteen patients were initially treated with cyclosporine at a dose of 4 mg/kg/day. Nine patients were started on oral azathioprine (median dose 1.8 mg/kg). Seven patients underwent surgery (panproctocolectomy), although none had surgery after 6 months. Comparisons were made between patients with <7 days and >7 days intravenous steroid. Other parameters analysed were stool frequency at 3 days and CRP at 3 days. There were no significant differences between these groups. Median bowel frequency at day 3 was higher in patients who finally underwent surgery. At 3 years follow-up, 56% of the sixteen patients had avoided surgery by using azathioprine immunosuppression.


CONCLUSIONS
The initial response rate to intravenous cyclosporine was high (69%). Side effects were documented in the majority of patients, but none of the patients had to discontinue treatment on account of these. Azathioprine has a useful role in maintaining the remission achieved by i.v. cyclosporine for acute ulcerative colitis patients. More than half the patients will avoid colectomy long-term when using triple immunosuppressive therapy including azathioprine adding support for its relative safety and another role for its use.
The Gastrointestinal Unit, University of Edinburgh, Department of Medical Sciences, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
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Campbell
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Ghosh
D000284:Administration, Oral; D000328:Adult; D000890:Anti-Infective Agents / Q000627:therapeutic use; D001379:Azathioprine / Q000627:therapeutic use*; D003093:Colitis, Ulcerative / Q000628:therapy*; D016572:Cyclosporine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D016720:Pneumocystis Infections / Q000517:prevention & control; D011239:Prednisolone / Q000627:therapeutic use; D016879:Salvage Therapy; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use
D000890:Anti-Infective Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D016572:Cyclosporine; D011239:Prednisolone; D001379:Azathioprine; D008775:Methylprednisolone