Editorial Notes Corticosteroids for Crohn's Disease D R U G T H E R A P Y FOR C R O H N ' S DISEASE has been largely
empirical. Sulfasalazine (Azulfidine®) is widely used and recommended (1) in mild disease, the rationale being by analogy from its proven effect in ulcerative colitis. Azathioprine, found useful in some small controlled trials and not in others (2), was not significantly better than placebo in the National Cooperative Crohn's Disease Study (NCCDS) (3). A recent well-controlled trial in London found that withdrawal of azathioprine after the disease had been in remission 6 or more months precipitated flare-up (4). It is currently under study in a large cooperative European trial. The metabolic product of azathioprine, 6-mercaptopurine, has been reported to be effective when given for more than 6 months (5). Corticosteroids, first reported in the 1950s to be useful in Crohn's disease, have become one of the mainstays of its medical therapy. Several recent controlled trials have confirmed previous anecdotal reports, so that a surprisingly consistent picture emerges concerning indications and expectations for their use. Steroids have been most widely adopted for treatment of active symptomatic Crohn's disease. Two large uncontrolled studies reported that a good initial symptomatic response to prednisone, at a dose of 30 m g / d or its equivalent, occurred in 7 5 % to 9 0 % of patients (6, 7). Fever, pain, and diarrhea subsided, appetite and well-being improved, and in more than one half of patients, hematocrit rose and erythrocyte sedimentation rate or serum seromucoid levels fell (7). These favorable clinical responses were not necessarily associated with discernable improvement of the barium roentgenogram results. The only double-blind controlled trial of steroids in active Crohn's disease, a part of the N C C D S , confirmed these results (3) and offers some prognostic help to the beleaguered clinician and his patient with Crohn's disease. Active disease involving the small bowel was especially responsive to steroids (8). Previous sulfasalazine therapy seemed to blunt subsequent response to steroids; the study found that symptomatic patients switched from sulfasalazine to prednisone responded no better than similar patients switched from sulfasalazine to placebo. Disappointingly, the extraintestinal complications and perianal disease of patients in the N C C D S were as unresponsive to prednisone as to placebo. The toxicity of steroids at doses high enough to suppress active Crohn's disease is appreciable. Sparberg and Kirsner (6) noted 35 major complications among 22 of the 54 patients they treated with steroids for 6 months or longer. Cooke and Fielding (7) attributed to steroids 12 of the 24 deaths that occurred in their group of 124 patients treated for more than 2 years with steroids. The N C C D S observed steroid toxicity sufficient to cause withdrawal from the study of 1 8 % of patients treated for 4 months with a dose of prednisone sufficient to suppress clinical activity of the disease. Similar events occurred in only 6 % of patients receiving placebo. Thus toxicity must be weighed against beneficial effect in active disease. The role of prophylactic steroids in both quiescent disease and after complete surgical extirpation of Crohn's disease has been examined in three recent controlled trials (3, 9, 10). A range of dosages was represented in the
three studies: 7.5 mg of prednisone per day for 3 years in the Welsh trial (10); a decreasing dose from 15 to 5 mg of prednisone per day combined with sulfasalazine for 33 weeks, with subsequent follow up for 3 years in the Swedish study (9); and '/ 4 mg per kilogram body weight for 2 years in the N C C D S (3). In all three studies, patients taking steroids fared no better than those taking placebo or nothing. In fact they fared noticeably but not significantly worse in all three. N o significant toxicity was attributed to steroid treatment in the two trials that used a daily prednisone dose of 7.5 mg or less; however, 2 0 % of N C C D S patients given l / 4 mg per kilogram body weight per day required dose reduction or withdrawal because of side-effects (3). One can safely conclude that prophylactic steroids are not indicated in Crohn's disease. How safe is withdrawing steroid therapy? Once symptomatic remission was obtained in the patients studied in Birmingham (7) and Chicago (6), reduction of dosage below approximately 7.5 mg of prednisone per day led to recrudescence of symptoms within a year in at least one third of patients. Because these studies did not include a control group, whether these flare-ups were due to steroid withdrawal is unclear. In the NCCDS, where a placebo control group was available for comparison, withdrawal of steroids in quiescent disease was not associated with more relapses than was their continuance. However, in active symptomatic disease, withdrawal of steroids caused the condition of significantly more patients to deteriorate than occurred with continued steroids. These results suggest that an attempt should be made to withdraw steroids from patients with quiescent Crohn's disease and that this will usually be successful. A definitive therapy for Crohn's disease before its cause is discovered is probably too much for which to hope. Meanwhile, however, patients and their physicians can be grateful for the relief provided by prudently used corticosteroid therapy. ( J O H N W. S I N G L E T O N , M.D.; De-
partment of Medicine, University Center; Denver, Colorado)
of Colorado
References 1. KIRSNER JB, W A L L AJ: The medical treatment of ulcerative colitis and Crohn's disease of the colon, in Inflammatory Bowel Disease, edited by KIRSNER JB, SHORTER RJ. Philadelphia, Lea & Febiger, 1975, pp. 279293 2. SACHAR DB, PRESENT DH: Immunotherapy in inflammatory bowel disease. Med Clin North Am 62:173-183, 1978 3. SINGLETON JW: National Cooperative Crohn's Disease Study (NCCDS): results of drug treatment (abstract). Gastroenterology 72:1133, 1977 4. O ' D O N O G H U E DP, D A W S O N AM, P O W E L L - T U C K J, B R O W N RL, L E N -
NARD-JONES JE: Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet 2:955-957, 1978 5. P R E S E N T DH, WISCH N, G L A S S JL, K O R E L I T Z AB: The efficacy of
immunosupressive therapy in Crohn's disease. A randomized long term double blind study (abstract). Gastroenterology 72:1114, 1977 6. SPARBERG M, KIRSNER JB: Long-term corticosteroid therapy for regional enteritis: an analysis of 58 courses in 54 patients. Am J Dig Dis 11:865-880, 1966 7. COOKE WT, FIELDING JF: Corticosteroid or corticotropin therapy in Crohn's disease. Gut 11:921-927 8. SUMMERS RW, SESSIONS JT, S W I T Z DM, SINGLETON JW: National
Cooperative Crohn's Disease Study (NCCDS): response of subgroups to drug treatment (abstract). Gastroenterology 74:1100, 1978 9. BERGMAN L, KRAUSE U: Postoperative treatment with corticosteroids and salazosulphapyridene (Salazopyrin®) after radical resection for Crohn's disease. Scand J Gastroenterol 11:651-656, 1976 Editorial Notes
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Medical
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10. S M I T H RC, R H O D E S J, H E A T L E Y RV, H U G H E S LE, CROSBY DL, R E E S BI, J O N E S H, E V A N S KT, L A W R I E BW: Low-dose steroids and clinical
relapse in Crohn's disease: a controlled trial. Gut 19:606-610, 1978 © 1 9 7 9 American College of Physicians
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empirical. Sulfasalazine (Azulfidine®) is widely used and recommended (1) in mild disease, the rationale being by analogy from its proven effect in ulcerative colitis. Azathioprine, found useful in some small controlled trials and not in others (2), was not significantly better than placebo in the National Cooperative Crohn's Disease Study (NCCDS) (3). A recent well-controlled trial in London found that withdrawal of azathioprine after the disease had been in remission 6 or more months precipitated flare-up (4). It is currently under study in a large cooperative European trial. The metabolic product of azathioprine, 6-mercaptopurine, has been reported to be effective when given for more than 6 months (5). Corticosteroids, first reported in the 1950s to be useful in Crohn's disease, have become one of the mainstays of its medical therapy. Several recent controlled trials have confirmed previous anecdotal reports, so that a surprisingly consistent picture emerges concerning indications and expectations for their use. Steroids have been most widely adopted for treatment of active symptomatic Crohn's disease. Two large uncontrolled studies reported that a good initial symptomatic response to prednisone, at a dose of 30 m g / d or its equivalent, occurred in 7 5 % to 9 0 % of patients (6, 7). Fever, pain, and diarrhea subsided, appetite and well-being improved, and in more than one half of patients, hematocrit rose and erythrocyte sedimentation rate or serum seromucoid levels fell (7). These favorable clinical responses were not necessarily associated with discernable improvement of the barium roentgenogram results. The only double-blind controlled trial of steroids in active Crohn's disease, a part of the N C C D S , confirmed these results (3) and offers some prognostic help to the beleaguered clinician and his patient with Crohn's disease. Active disease involving the small bowel was especially responsive to steroids (8). Previous sulfasalazine therapy seemed to blunt subsequent response to steroids; the study found that symptomatic patients switched from sulfasalazine to prednisone responded no better than similar patients switched from sulfasalazine to placebo. Disappointingly, the extraintestinal complications and perianal disease of patients in the N C C D S were as unresponsive to prednisone as to placebo. The toxicity of steroids at doses high enough to suppress active Crohn's disease is appreciable. Sparberg and Kirsner (6) noted 35 major complications among 22 of the 54 patients they treated with steroids for 6 months or longer. Cooke and Fielding (7) attributed to steroids 12 of the 24 deaths that occurred in their group of 124 patients treated for more than 2 years with steroids. The N C C D S observed steroid toxicity sufficient to cause withdrawal from the study of 1 8 % of patients treated for 4 months with a dose of prednisone sufficient to suppress clinical activity of the disease. Similar events occurred in only 6 % of patients receiving placebo. Thus toxicity must be weighed against beneficial effect in active disease. The role of prophylactic steroids in both quiescent disease and after complete surgical extirpation of Crohn's disease has been examined in three recent controlled trials (3, 9, 10). A range of dosages was represented in the
three studies: 7.5 mg of prednisone per day for 3 years in the Welsh trial (10); a decreasing dose from 15 to 5 mg of prednisone per day combined with sulfasalazine for 33 weeks, with subsequent follow up for 3 years in the Swedish study (9); and '/ 4 mg per kilogram body weight for 2 years in the N C C D S (3). In all three studies, patients taking steroids fared no better than those taking placebo or nothing. In fact they fared noticeably but not significantly worse in all three. N o significant toxicity was attributed to steroid treatment in the two trials that used a daily prednisone dose of 7.5 mg or less; however, 2 0 % of N C C D S patients given l / 4 mg per kilogram body weight per day required dose reduction or withdrawal because of side-effects (3). One can safely conclude that prophylactic steroids are not indicated in Crohn's disease. How safe is withdrawing steroid therapy? Once symptomatic remission was obtained in the patients studied in Birmingham (7) and Chicago (6), reduction of dosage below approximately 7.5 mg of prednisone per day led to recrudescence of symptoms within a year in at least one third of patients. Because these studies did not include a control group, whether these flare-ups were due to steroid withdrawal is unclear. In the NCCDS, where a placebo control group was available for comparison, withdrawal of steroids in quiescent disease was not associated with more relapses than was their continuance. However, in active symptomatic disease, withdrawal of steroids caused the condition of significantly more patients to deteriorate than occurred with continued steroids. These results suggest that an attempt should be made to withdraw steroids from patients with quiescent Crohn's disease and that this will usually be successful. A definitive therapy for Crohn's disease before its cause is discovered is probably too much for which to hope. Meanwhile, however, patients and their physicians can be grateful for the relief provided by prudently used corticosteroid therapy. ( J O H N W. S I N G L E T O N , M.D.; De-
partment of Medicine, University Center; Denver, Colorado)
of Colorado
References 1. KIRSNER JB, W A L L AJ: The medical treatment of ulcerative colitis and Crohn's disease of the colon, in Inflammatory Bowel Disease, edited by KIRSNER JB, SHORTER RJ. Philadelphia, Lea & Febiger, 1975, pp. 279293 2. SACHAR DB, PRESENT DH: Immunotherapy in inflammatory bowel disease. Med Clin North Am 62:173-183, 1978 3. SINGLETON JW: National Cooperative Crohn's Disease Study (NCCDS): results of drug treatment (abstract). Gastroenterology 72:1133, 1977 4. O ' D O N O G H U E DP, D A W S O N AM, P O W E L L - T U C K J, B R O W N RL, L E N -
NARD-JONES JE: Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet 2:955-957, 1978 5. P R E S E N T DH, WISCH N, G L A S S JL, K O R E L I T Z AB: The efficacy of
immunosupressive therapy in Crohn's disease. A randomized long term double blind study (abstract). Gastroenterology 72:1114, 1977 6. SPARBERG M, KIRSNER JB: Long-term corticosteroid therapy for regional enteritis: an analysis of 58 courses in 54 patients. Am J Dig Dis 11:865-880, 1966 7. COOKE WT, FIELDING JF: Corticosteroid or corticotropin therapy in Crohn's disease. Gut 11:921-927 8. SUMMERS RW, SESSIONS JT, S W I T Z DM, SINGLETON JW: National
Cooperative Crohn's Disease Study (NCCDS): response of subgroups to drug treatment (abstract). Gastroenterology 74:1100, 1978 9. BERGMAN L, KRAUSE U: Postoperative treatment with corticosteroids and salazosulphapyridene (Salazopyrin®) after radical resection for Crohn's disease. Scand J Gastroenterol 11:651-656, 1976 Editorial Notes
Downloaded from https://annals.org by Tulane University user on 01/18/2019
Medical
983
10. S M I T H RC, R H O D E S J, H E A T L E Y RV, H U G H E S LE, CROSBY DL, R E E S BI, J O N E S H, E V A N S KT, L A W R I E BW: Low-dose steroids and clinical
relapse in Crohn's disease: a controlled trial. Gut 19:606-610, 1978 © 1 9 7 9 American College of Physicians
984
June'1979 • Annals of Internal Medicine • Volume 90 • Number 6
Downloaded from https://annals.org by Tulane University user on 01/18/2019
