Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991), pp. 449--453
Controlled Trial of Antimycobacterial Therapy in Crohn's Disease Clofazimine versus Placebo N.H. A F D H A L , MRCPI, A. LONG, MRCPI, J. L E N N O N , FRCPI, J. CROWE, MD, FRCPI, and D.P. O'DONOGHUE, MD, FRCPI
In order to study the effect of clofazimine, a powerful antimycobacterial and antiinflammatory agent, 49 patients with active Crohn's disease were randomized to either corticosteroids plus clofazimine 100 mg daily (N = 25) or to steroids and matching placebo (N = 24). A total of 28 patients (58%) went into disease remission (clofazimine 16, placebo 12; P = NS) with a fall in disease activity score from 10.5 +- 4.4 to 3.3 +- 3.5. Patients were treated for a further eight months with clofazimine or placebo and 18 of 28 maintained their remission and completed the study (clofazimine 12, placebo 6; P = NS). Side effects were minor and consisted of skin rash and increased pigmentation. Clofazimine as a solitary antimycobacterial agent appears ineffective in inducing remission in Crohn's disease but may have a role in either disease maintenance or combination chemotherapy. KEY WORDS: Crohn's disease; antimycobacterial; clofazimine.
The etiology of Crohn's disease remains obscure. Allergic, autoimmune, dietary, and infective theories have all been proposed (1-4). Atypical mycobacteria have been isolated from Crohn's disease tissue and may cause a clinical and pathological intestinal lesion in animals very similar to that seen in Crohn's disease and have therefore been proposed as a putative infective agent (5-7). Clofazimine, a substituted imino-phenazine initially used for the treatment of M. leprae, is a broad-spectrum antimycobacterial agent effective against cell-wall-deficient mycobacteria with secondary neutrophil stimulating and antiinflammatory Manuscript received March 1, 1989; revised manuscript received August 11, 1990; accepted September 27, 1990. From the Departments of Gastroenterology, St. Vincents and Mater Misericordiae Hospitals and University College, Dublin, Ireland. Presented to the British Society of Gastroenterology, Jubilee meeting, London, September 1987. Address for reprint requests: Dr. N.H. Afdhal, Boston City Hospital, Thorndike 507,818 Harrison Avenue, Boston, Massachusetts 02118.
properties (8). Clofazimine is effective particularly a s therapy for the lepromatous and erythema nodosum forms of leprosy, in which an allergic granulomatous-type skin lesion is frequently seen (8). Inital pilot studies of clofazimine used openly in patients with both ulcerative colitis and Crohn's disease suggested that this agent might be effective (9). The present study reports the results of a controlled study of clofazimine in Crohn's disease. MATERIALS AND METHODS
Forty-nine patients (34 women, 15 men) with Crohn's disease as defined by standard clinical, radiological, and histological criteria were included in the study. The clinical features, disease site, and duration are shown in Table 1. The study design was double blind and placebo controlled. Patients were randomized to either the clofazimine group (N = 25) or placebo (N = 24), with a further substratification for disease site (small or large bowel). Exclusion criteria were an indication for surgery including strictures causing bowel obstruction, fistulae, and
Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
0163-2116/91/0400-044956.50/0~r 1991PlenumPublishingCorporation
449
AFDHAL ET AL Phase 1
Phase 2
Phase 3
Remission induction (0-3 months)
Observation (3-4 months)
Maintenance (4-12 months)
Clofazimine 100 mg and corticosteroids (N = 25)
Clofazimine 100 mg (N = 16)
Clofazimine 100 mg (N = 15)
Placebo and corticosteroids (N = 24)
Placebo (N = 12)
Placebo (N = 12)
Fig 1. Study design for clofazimine versus placebo in Crohn's disease. (N = number patients entering each phase of the study.)
abcess formation; and pregnancy. All other patients with active disease were eligible for inclusion into the study. Disease activity was monitored using a modifed simple disease activity score (DAS) as previously described (10). The DAS combines both the subjective symptoms used in the Crohn's disease activity index with the more objective features of fever, hypoalbuminemia, weight loss, anemia, and an elevation in the ESR. Using the DAS system, a score of >10 indicates active disease and 10). The total study duration was therefore one year in those treated successfully. During the study period patients were seen by the same clinician (N.A. or A.L.) at entry to the study, on discharge from the hospital, initially as out patients on a monthly basis and then as frequently as clinically indicated. At each visit DAS, routine biochemistry and hematology, any side effects, and a tablet count for compliance were recorded. Corneal slit lamp examinations were performed at entry to and during the study to exclude corneal crystal deposits. The study was approved by the Ethics Commitees of St. Vincents and the Mater Misericordiae hospitals and written informed consent was obtained for each patient. Statistical Analysis. Comparison of the efficacy of the two treatment groups was performed using Fisher's exact test, changes in DAS were analyzed using a two-tailed Mann-Whitney U test, and the significance level was 5%. RESULTS Clinical features, site and duration of disease, initial DAS, and dose of steroids were similar for
450
both groups (Table 1). Twenty-eight (58%) of the 49 patients successfully completed phase 1 (clofazimine 16, placebo 12; P = 0.39). During phase 1, 17 patients were unable to either achieve remission or withdraw from steroid therapy, and six of these patients subsequently required surgery. F o u r patients, two from each group, were lost to follow-up or asked to be withdrawn. The mean initial steroid dose was 45 mg of prednisone daily, and there was no difference between groups for either total dose or rate of withdrawal of steroids. In patients who responded to therapy in phase 1, DAS fell from I0 - 4.4 to 3.1 3.4 in the clofazimine group and from 10 -+ 4 to 3.6 -+ 3.7 in the placebo patients (P = NS). The individual objective components of the DAS, including serum hemoglobin, albumin, and ESR were similar for both groups at entry, and at three and 12 months (Table 2). Analyzing the DAS for all patients including treatment failures and withdrawals, there was no significant difference between the groups. At the completion of phase 1 or on withdrawal, DAS was 7.44 +-- 3.5 in the group on clofazimine and 6.52 - 2.9 in the group on placebo (P = NS). Of the 28 patients who were placed on maintenance therapy, 18 patients (38%) were still in remission after one year and successfully completed phase 3 of the study (clofazimine 12, placebo 6; P =
TABLE 1. CLINICAL CHARACTERISTICS OF PATIENTS RANDOMIZED TO CLOFAZIMINE OR PLACEBO
Sex (M/F) Mean age (years) Site of disease Small bowel Large bowel Duration of disease (years) Previous surgery 1st episode Steroid dose at entry (mean mg)
Clofazimine (N = 25)
Placebo (N = 24)
6:19 25 • 11.3
9:15 32 - 14
12 13 7 -+ 3 4 9 45
12 12 6.4 ~ 4 4 12 45
Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
CLOFAZIMINE IN CROHNS DISEASE TABLE 2. DISEASE ACTIVITY IN PATIENTS ON CLOFAZIMINE AND PLACEBO AT ENTRY, 3 AND 12 MONTHS*
End of phase 1 (3 months)
At entry Clofazimine Patients (N) DAS Albumin (g/liter) Hemoglobin (g/all) ESR(mm/hr)
25 10.4--- 4.4 36 m 5 11.6 -+ 1,8 35 • 25
Placebo 24 10 +36 --11.8 • 24 --.
4 6 2 19
Clofazimine 3.1 35 12 22
16 • 3.4 • 3 • 1.3 - 20
End of trial (12 months)
Placebo
Clofazimine
12 3.6• 3.7 36 +-- 5 12.7 ~- 2.2 21 +-- 16
12 1.4----- 1.6 38 • 12.4 -----2 13 -----8
Placebo 4 39 12.9 17
6 • 5.3 • 6 + 2 • 10
*Results e x p r e s s e d as the m e a n --- SD.
0.37). The total DAS at the end of the trial was markedly less for clofazimine patients (1.4 +-- 1.6) when compared to placebo patients (4 --- 5.3, Table 2). Although these results suggest a trend in favor of clofazimine, they failed to reach statistical significance. Site of disease, whether predominantly large or small bowel, was not significant in determining outcome in either phase of the study. Side effects were mild and self-limiting. Seventeen patients had increased skin pigmentation predominantly on the face and trunk (clofazimine 12, placebo 5), three patients on clofazimine developed skin rashes, and no patient had abnormal eye examinations. DISCUSSION Successful treatment of Crohn's disease with antimycobacterial agents has been reported in multiple case reports and in small uncontrolled studies (11-13). Results from a randomized trial of combination therapy with rifampicin and ethambutol were disappointing (14), and this current study represents the largest prospective randomized trial undertaken to date. Clofazimine 100 mg daily in combination with steroids appears to be no better than placebo and steroids in inducing remission in active Crohn's disease in two well-matched groups. Because of the variable natural history of Crohn's disease, the trend in favor of clofazimine in maintenance of remission is difficult to interpret. Unfortunately due to the large number of treatment failures and withdrawals in phase 1, a type-2 error cannot be excluded from this study. Assuming a 50% response in the placebo group and a 75% response in the clofazimine group, the study only had a 1:2 chance of detecting a significant difference between the two treatment groups. An overall trend in favor of clofazimine therapy was apparent. At the end of one year, 50% of patients on clofazimine had completed the study compared to only 25% of patients Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
on placebo. This trend continued to be apparent in continued follow-up of these patients by the investigators for the year following cessation of the study. A study of a greater number of patients will be required to define the role of clofazimine in the treatment of Crohn's disease. The role of a cell-wall-deficient Mycobacterium spp. in Crohn's disease or a variant of M. paratuberculosis has received renewed interest, and several papers have reported the isolation of mycobacteria from Crohn's disease tissue and even the reproduction of experimental disease in animals inoculated by these isolates (7, 15, 16). The biochemical and genetic similarity between M. paratuberculosis and other mycobacteria of the M. avium complex (17, 18) is also interesting considering the clinical similarity between stricturing intestinal M. avium intracellulare infection in the immunosuppressed and Crohn's disease (19). The rationale for the use of clofazimine was based on several interesting properties of this agent. Clinically in vivo clofazimine is effective against a wide range of mycobacteria including M. leprae, M. ulcerans, M. avium intracellulare, and isolates of Mycobacterium spp. from patients with Crohn's disease. Postmortem studies of its tissue distribution in man demonstrate predominant deposition in fatty tissue, the reticuloendothelial system, and the small intestine, especially the terminal ileum (8). Although crystal deposition is seen in the terminal ileum of patients on 300 mg a day of clofazimine, an inflammatory lesion is rare and the drug appears safe in patients with coexisting intestinal disease. Clofazimine has been used as monotherapy for lepromatous leprosy and erythema nodosum leprosum and in combination with rifampicin for dapsoneresistant leprosy (20). The antimycobacterial effect of clofazimine is enhanced in vitro and in AIDS patients with M. avium intracellulare when it is used as combination chemotherapy with other 451
AFDHAL ET AL agents such as rifabutin (21, 22). In addition to this antimycobacterial effect, clofazimine is also an antiinflammatory agent with a prooxidative effect on polymorphonuclear leukocytes, preventing their transformation and migration in response to leukoattractants (23-25). The poor response of ileocecal tuberculosis to chemotherapy (26) and the inability to treat or prevent paratuberculosis in animals with antimycobacterial drugs including clofazimine (2732) outlines the difficulty in successfully eradicating intestinal mycobacteria. Therefore the interpretation that the lack of response seen to clofazimine in this study argues against a mycobacterial etiology for Crohn's should be viewed with caution. The fastidious nature of these organisms and the difficulty with isolation has plagued investigators and obviously renders the in vitro testing of chemotherapeutic agents extremely difficult. Clofazimine has been shown to be bacteriacidal against human and animal isolates of M. paratuberculosis and also against a Mycobacterium spp. isolated from a patient with Crohn's disease (33, 34). However, the use of standard microbiological endpoints such as the eradication of organisms from culture has not been applied to clinical studies of this possible mycobacterial disease and thus a response has to be determined on clinical criteria. Therefore, choice of agent, dosage, and duration of administration remain somewhat arbitrary. The issues of dosage and combination therapy were not addressed by this study. The close of clofazimine in leprosy is between 100 and 300 mg daily and, although the onset of bacterial killing does not occurr until 50 days, its efficacy does not appear to be dose related (8). A 100-mg dose of clofazimine was chosen since side effects are uncommon at this dosage, which was previously shown to be efficacious in Crohn's disease (9). In dealing with this putative mycobacteria, combinations of antimycobacterials may be valuable. In one report of an uncontrolled study a favorable remission rate in 10 of 20 Crohn's disease patients was seen with a combination of isoniazid, rifampicin, ethambutol, pyrazinamide, and clofazimine added for resistant patients (35). The current recomendation for antimycobacterial therapy of pulmonary infection in nonimmunosupressed patients includes combination therapy regimes of three to four agents for periods of one to three years with a 67% response rate (36). A prolonged trial of combination chemotherapy therefore may also be required in patients with intestinal atypical mycobacterial in-
452
fection. The use of corticosteroids in association with antimycobacterial therapy initially may appear a little irrational. However, corticosteroids have proven useful in treating the chronic inflammation produced by other mycobacterial diseases such as chronic meningeal M. tuberculosis and the reversal reaction of M. leprae infection and are also useful disease-modifying agents in Crohn's disease. In conclusion it would appear that clofazimine alone has little therapeutic role as primary treatment for active Crohns disease. Clofazimine's potential chronic use for maintenance of remission and its possible role in combination chemotherapy will have to wait for further trials and, more importantly, for further advances in understanding the etiology of this perplexing disease. ACKNOWLEDGMENTS We would like to thank Ciba-Geigy for their assistance with this study and for supplying the medications. REFERENCES 1. James SP, Strober W, Quinn TC, Danovitch SH: Crohn's disease; new concepts of pathogenesis and current approaches to treatment. Dig Dis Sci 32:1297-1310, 1987 2. Burnham WR, Lennard-Jones JE, Stanford TL, Bird RG: Mycobacteria as a possible cause of inflammatory bowel disease. Lancet 2:693-696, 1978 3. Donnelly BJ, Delaney PV, Healy TM: Evidence for a transmissible agent in Crohn's disease. Gut 18:360-363, 1977 4. Levi AJ: Diet in the management of Crohn's disease. Gut 26:985-988, 1985 5. Cave DR, Mitchell DN, Kane SP, Brooke BN: Further animal evidence of a transmissible agent in Crohn's disease. Lancet 2:1120-1122, 1973 6. Graham DY, Markesich DC, Yoshimura HH: Mycobacteria and inflammatory bowel disease. Gastroenterology 92:436442, 1987 7. Kruiningen H J, Chiodini RJ, Thayer WR, Coutu JA, Merkal RS, Runnels PL: Experimental disease in infant goats induced by a mycobacterium isolated from a patient with Crohn's disease. Dig Dis Sci 31:1351-1360, 1986 8. Yawalkar SJ, Vischer W: Lamprene (clofazimine) in leprosy. Lepr Rev 50:135-144, 1979 9. Kelleher D, O'Brien S, Weir DG: Preliminary trial of clofazimine in chronic inflammatory bowel disease. Gut 23 :A449, 1982 10. O'Donoghue DP, Dawson AM, Powelt-Tuck J, Bowen RL, Lennard-Jones JE: Double blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet 2:955-957, 1978 11. Schultz MG, Rieder HL, Hersh T, Riepe S: Remission of Crohn's disease disease with antimycobacterial chemotherapy. Lancet 2:1391-1392, 1987 12. Jarnerot G, Rolny P, Wickbom G, Elemayehu G: Antimycobacterial chemotherapy ineffective in Crohn's disease after one year. Lancet 1:164-165, 1989 Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
C L O F A Z I M I N E IN CROHNS DISEASE 13, Piccioto A, Gesu GP, Schito GC, Testa R, Varagona G, Celle G: Antimycobacterial chemotherapy in two cases of inflammatory bowel disease. Lancet 1:536-537, 1988 14. Shaffer JL, Hughes S, Linaker BD, Baker RD, Turnberg LA: Controlled trial of rifampicin and ethambutol in Crohn's disease. Gut 25:203--205, 1984 15. Chiodini RJ, van Kruiningen HJ, Thayer WR, Merkal RS, Couteau JA: Possible role of mycobacteria in inflammatory bowel disease. An unclassified mycobacterial species isolated from patients with Crohn's disease. Dig Dis Sci 29:1073-1079, 1984 16. Chiodini RJ, van Kruiningen HJ, Thayer WR, Merkal RS, Couteau JA: Characteristics of an unclassified mycobacterial species isolated from patients with Crohn's disease. J Clin Microbiol 20:966-971, 1984 17. McFadden JJ, Butcher PD, Chiodini R, Hermon-Taylor J: Crohns disease isolated mycobacteria are identical to Mycobacterium paratuberculosis, as determined by DNA probes that distinguish between mycobacterial species. J Clin Microbiol 25:796-801, 1987 18. Meissner GK, Schroder KH, Amadio GE, Anz W, Chaparas S, Engel HW, Jenkins PA, Kappler W, Kleeberg HH, Kubala E, Kubin M, Lauterbach D, Lind A, Magnusson M, Mikova Z, Pattyn SR, Schaefer WB, Stanford JL, Tsukamura M, Wayne LG, Willers I, Wolinsky E: A cooperative numerical analysis of nonscoto- and nonphochromogenic slowly growing mycobacteria. J Gen Microbiol 83:207-235, 1974 19. Schneebaum CW, Novick DM, Chabon AB, Strutynsky N, Yancovitz SR, Freund S: Terminal ileitis associated with Mycobacterium avium-intracellulare infection in a homosexual man with AIDS. Gastroenterology 92:1127-1132, 1987 20. Gatti JC, Cardama JI, Belima LM: Treatment of leprosy with B 663. Lepr Rev 41:89-92, 1970 21. Ganghadaram PR, Perumal VK, Jairam BT, Rao PN, Nguyen AK, Farhi DC, Iseman MD: Activity of rifabutine alone or in combination with clofazimine or ethambutol or both against acute and chronic experimental Mycobacterium intracellulare infections. Am Rev Respir Dis 136:329-333, 1987 22. Masur H, Tuazon C, Gill V, Grimes G, Baird B, Fauci AS, Lane HC: Effect of combined clofazimine and ansamycin therapy on Mycobacterium aviam intracellulare bacteremia in patients with AIDS. J Infect Dis 155:127-129, 1987 23. Anderson R, Lukey P, Van Rensburg C, Dippenaar U: Clofazimine meediated regulation of human polymorphonuclear leukocyte migration by pro-oxidative inactivation of
Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
24.
25.
26. 27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
both leukoattractants and cellular migratory responsiveness. Int J Immunopharmacol 8:605-620, 1986 Zeiss BM, Anderson R: Clofazimine mediated stimulation of prostaglandin synthesis and free radical production as novel mechanisms of drug induced immunosuppression. Int J Immunopharmacol 8:731-739, 1986 Niwa Y, Sakani T, Miyachi Y, Ozaki M: Oxygen metabolism in phagocytes of leprotic patients: Enhanced endogenous superoxide dismutase activity and hydroxyl radical generation by clofazimine. J Clin Microbiol 20:837-842, 1984 Bentley G, Webster JHH: Gastrointestinal tuberculosis--a 10 year review. Br J Surg 54:90-96, 1967 Chiodini RJ, van Kruiningen HJ, Merkal RS: Ruminant paratuberculosis (Johnes disease); the current status and future prospects. Cornell Vet 74:2t8-262, 1984 Gilmour NJL: The effect of the riminophenazine B663 on preclinical M. johnei infections in sheep. Br Vet J 124:492497, 1968 Gilmour NJL, Angus KW: Effect of the riminophenazine B663 on M. johnei infection and reinfection in sheep. 1. Bacteriology and hypersensitivity. J Comp Pathol 81:221226, 1971 Merkal RS, Larsen AB: Clofazimine treatment of cows naturally infected with mycobacterium paratuberculosis. Am J Vet Res 34:27-28, 1973 Rankin JD: Isoniazid; its effect on M. johnei in vitro and its failure to cure clinical Johnes disease in cattle. Vet Rec 65:649-651, 1953 Rankin JD: An attempt to prevent the establishment of M. paratuberculosis in calves by means of isoniazid alone and in combination with streptomycin. Vet Rec 67:1105-1107, 1955 Chiodini RJ: Bactericidal activities of various antimicrobial agents against human and animal isolates of Mycobacterium paratuberculosis. Antimicrob Agents Chemother 34:366367, 1990 Chiodini RJ, Van Kruiningen HJ, Thayer WR. Coutu JA, Merkal RS: In vitro antimicrobial susceptibility of a Mycobacterium sp. isolated from patients with Crohn's disease. Antimicrob Agents Chemother 26:930-932. 1984 Hampson SJ, Parker MC, Saverymuttu SH. Joseph AE, McFadden JP, Hermon-Taylor J: Quadruple antimycobacteriai chemotherapy in Crohn's disease: Results at 9 months in a study of 20 patients. Aliment Pharmacol Ther 3:343-352, 1989 Hornick DB, Dayton CS, Bedell GN. Fick RB: Nontuberculous mycobacterial lung disease: Substantiation of a less agressive approach. Chest 93:550-555, 1988
453
Controlled Trial of Antimycobacterial Therapy in Crohn's Disease Clofazimine versus Placebo N.H. A F D H A L , MRCPI, A. LONG, MRCPI, J. L E N N O N , FRCPI, J. CROWE, MD, FRCPI, and D.P. O'DONOGHUE, MD, FRCPI
In order to study the effect of clofazimine, a powerful antimycobacterial and antiinflammatory agent, 49 patients with active Crohn's disease were randomized to either corticosteroids plus clofazimine 100 mg daily (N = 25) or to steroids and matching placebo (N = 24). A total of 28 patients (58%) went into disease remission (clofazimine 16, placebo 12; P = NS) with a fall in disease activity score from 10.5 +- 4.4 to 3.3 +- 3.5. Patients were treated for a further eight months with clofazimine or placebo and 18 of 28 maintained their remission and completed the study (clofazimine 12, placebo 6; P = NS). Side effects were minor and consisted of skin rash and increased pigmentation. Clofazimine as a solitary antimycobacterial agent appears ineffective in inducing remission in Crohn's disease but may have a role in either disease maintenance or combination chemotherapy. KEY WORDS: Crohn's disease; antimycobacterial; clofazimine.
The etiology of Crohn's disease remains obscure. Allergic, autoimmune, dietary, and infective theories have all been proposed (1-4). Atypical mycobacteria have been isolated from Crohn's disease tissue and may cause a clinical and pathological intestinal lesion in animals very similar to that seen in Crohn's disease and have therefore been proposed as a putative infective agent (5-7). Clofazimine, a substituted imino-phenazine initially used for the treatment of M. leprae, is a broad-spectrum antimycobacterial agent effective against cell-wall-deficient mycobacteria with secondary neutrophil stimulating and antiinflammatory Manuscript received March 1, 1989; revised manuscript received August 11, 1990; accepted September 27, 1990. From the Departments of Gastroenterology, St. Vincents and Mater Misericordiae Hospitals and University College, Dublin, Ireland. Presented to the British Society of Gastroenterology, Jubilee meeting, London, September 1987. Address for reprint requests: Dr. N.H. Afdhal, Boston City Hospital, Thorndike 507,818 Harrison Avenue, Boston, Massachusetts 02118.
properties (8). Clofazimine is effective particularly a s therapy for the lepromatous and erythema nodosum forms of leprosy, in which an allergic granulomatous-type skin lesion is frequently seen (8). Inital pilot studies of clofazimine used openly in patients with both ulcerative colitis and Crohn's disease suggested that this agent might be effective (9). The present study reports the results of a controlled study of clofazimine in Crohn's disease. MATERIALS AND METHODS
Forty-nine patients (34 women, 15 men) with Crohn's disease as defined by standard clinical, radiological, and histological criteria were included in the study. The clinical features, disease site, and duration are shown in Table 1. The study design was double blind and placebo controlled. Patients were randomized to either the clofazimine group (N = 25) or placebo (N = 24), with a further substratification for disease site (small or large bowel). Exclusion criteria were an indication for surgery including strictures causing bowel obstruction, fistulae, and
Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
0163-2116/91/0400-044956.50/0~r 1991PlenumPublishingCorporation
449
AFDHAL ET AL Phase 1
Phase 2
Phase 3
Remission induction (0-3 months)
Observation (3-4 months)
Maintenance (4-12 months)
Clofazimine 100 mg and corticosteroids (N = 25)
Clofazimine 100 mg (N = 16)
Clofazimine 100 mg (N = 15)
Placebo and corticosteroids (N = 24)
Placebo (N = 12)
Placebo (N = 12)
Fig 1. Study design for clofazimine versus placebo in Crohn's disease. (N = number patients entering each phase of the study.)
abcess formation; and pregnancy. All other patients with active disease were eligible for inclusion into the study. Disease activity was monitored using a modifed simple disease activity score (DAS) as previously described (10). The DAS combines both the subjective symptoms used in the Crohn's disease activity index with the more objective features of fever, hypoalbuminemia, weight loss, anemia, and an elevation in the ESR. Using the DAS system, a score of >10 indicates active disease and 10). The total study duration was therefore one year in those treated successfully. During the study period patients were seen by the same clinician (N.A. or A.L.) at entry to the study, on discharge from the hospital, initially as out patients on a monthly basis and then as frequently as clinically indicated. At each visit DAS, routine biochemistry and hematology, any side effects, and a tablet count for compliance were recorded. Corneal slit lamp examinations were performed at entry to and during the study to exclude corneal crystal deposits. The study was approved by the Ethics Commitees of St. Vincents and the Mater Misericordiae hospitals and written informed consent was obtained for each patient. Statistical Analysis. Comparison of the efficacy of the two treatment groups was performed using Fisher's exact test, changes in DAS were analyzed using a two-tailed Mann-Whitney U test, and the significance level was 5%. RESULTS Clinical features, site and duration of disease, initial DAS, and dose of steroids were similar for
450
both groups (Table 1). Twenty-eight (58%) of the 49 patients successfully completed phase 1 (clofazimine 16, placebo 12; P = 0.39). During phase 1, 17 patients were unable to either achieve remission or withdraw from steroid therapy, and six of these patients subsequently required surgery. F o u r patients, two from each group, were lost to follow-up or asked to be withdrawn. The mean initial steroid dose was 45 mg of prednisone daily, and there was no difference between groups for either total dose or rate of withdrawal of steroids. In patients who responded to therapy in phase 1, DAS fell from I0 - 4.4 to 3.1 3.4 in the clofazimine group and from 10 -+ 4 to 3.6 -+ 3.7 in the placebo patients (P = NS). The individual objective components of the DAS, including serum hemoglobin, albumin, and ESR were similar for both groups at entry, and at three and 12 months (Table 2). Analyzing the DAS for all patients including treatment failures and withdrawals, there was no significant difference between the groups. At the completion of phase 1 or on withdrawal, DAS was 7.44 +-- 3.5 in the group on clofazimine and 6.52 - 2.9 in the group on placebo (P = NS). Of the 28 patients who were placed on maintenance therapy, 18 patients (38%) were still in remission after one year and successfully completed phase 3 of the study (clofazimine 12, placebo 6; P =
TABLE 1. CLINICAL CHARACTERISTICS OF PATIENTS RANDOMIZED TO CLOFAZIMINE OR PLACEBO
Sex (M/F) Mean age (years) Site of disease Small bowel Large bowel Duration of disease (years) Previous surgery 1st episode Steroid dose at entry (mean mg)
Clofazimine (N = 25)
Placebo (N = 24)
6:19 25 • 11.3
9:15 32 - 14
12 13 7 -+ 3 4 9 45
12 12 6.4 ~ 4 4 12 45
Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
CLOFAZIMINE IN CROHNS DISEASE TABLE 2. DISEASE ACTIVITY IN PATIENTS ON CLOFAZIMINE AND PLACEBO AT ENTRY, 3 AND 12 MONTHS*
End of phase 1 (3 months)
At entry Clofazimine Patients (N) DAS Albumin (g/liter) Hemoglobin (g/all) ESR(mm/hr)
25 10.4--- 4.4 36 m 5 11.6 -+ 1,8 35 • 25
Placebo 24 10 +36 --11.8 • 24 --.
4 6 2 19
Clofazimine 3.1 35 12 22
16 • 3.4 • 3 • 1.3 - 20
End of trial (12 months)
Placebo
Clofazimine
12 3.6• 3.7 36 +-- 5 12.7 ~- 2.2 21 +-- 16
12 1.4----- 1.6 38 • 12.4 -----2 13 -----8
Placebo 4 39 12.9 17
6 • 5.3 • 6 + 2 • 10
*Results e x p r e s s e d as the m e a n --- SD.
0.37). The total DAS at the end of the trial was markedly less for clofazimine patients (1.4 +-- 1.6) when compared to placebo patients (4 --- 5.3, Table 2). Although these results suggest a trend in favor of clofazimine, they failed to reach statistical significance. Site of disease, whether predominantly large or small bowel, was not significant in determining outcome in either phase of the study. Side effects were mild and self-limiting. Seventeen patients had increased skin pigmentation predominantly on the face and trunk (clofazimine 12, placebo 5), three patients on clofazimine developed skin rashes, and no patient had abnormal eye examinations. DISCUSSION Successful treatment of Crohn's disease with antimycobacterial agents has been reported in multiple case reports and in small uncontrolled studies (11-13). Results from a randomized trial of combination therapy with rifampicin and ethambutol were disappointing (14), and this current study represents the largest prospective randomized trial undertaken to date. Clofazimine 100 mg daily in combination with steroids appears to be no better than placebo and steroids in inducing remission in active Crohn's disease in two well-matched groups. Because of the variable natural history of Crohn's disease, the trend in favor of clofazimine in maintenance of remission is difficult to interpret. Unfortunately due to the large number of treatment failures and withdrawals in phase 1, a type-2 error cannot be excluded from this study. Assuming a 50% response in the placebo group and a 75% response in the clofazimine group, the study only had a 1:2 chance of detecting a significant difference between the two treatment groups. An overall trend in favor of clofazimine therapy was apparent. At the end of one year, 50% of patients on clofazimine had completed the study compared to only 25% of patients Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
on placebo. This trend continued to be apparent in continued follow-up of these patients by the investigators for the year following cessation of the study. A study of a greater number of patients will be required to define the role of clofazimine in the treatment of Crohn's disease. The role of a cell-wall-deficient Mycobacterium spp. in Crohn's disease or a variant of M. paratuberculosis has received renewed interest, and several papers have reported the isolation of mycobacteria from Crohn's disease tissue and even the reproduction of experimental disease in animals inoculated by these isolates (7, 15, 16). The biochemical and genetic similarity between M. paratuberculosis and other mycobacteria of the M. avium complex (17, 18) is also interesting considering the clinical similarity between stricturing intestinal M. avium intracellulare infection in the immunosuppressed and Crohn's disease (19). The rationale for the use of clofazimine was based on several interesting properties of this agent. Clinically in vivo clofazimine is effective against a wide range of mycobacteria including M. leprae, M. ulcerans, M. avium intracellulare, and isolates of Mycobacterium spp. from patients with Crohn's disease. Postmortem studies of its tissue distribution in man demonstrate predominant deposition in fatty tissue, the reticuloendothelial system, and the small intestine, especially the terminal ileum (8). Although crystal deposition is seen in the terminal ileum of patients on 300 mg a day of clofazimine, an inflammatory lesion is rare and the drug appears safe in patients with coexisting intestinal disease. Clofazimine has been used as monotherapy for lepromatous leprosy and erythema nodosum leprosum and in combination with rifampicin for dapsoneresistant leprosy (20). The antimycobacterial effect of clofazimine is enhanced in vitro and in AIDS patients with M. avium intracellulare when it is used as combination chemotherapy with other 451
AFDHAL ET AL agents such as rifabutin (21, 22). In addition to this antimycobacterial effect, clofazimine is also an antiinflammatory agent with a prooxidative effect on polymorphonuclear leukocytes, preventing their transformation and migration in response to leukoattractants (23-25). The poor response of ileocecal tuberculosis to chemotherapy (26) and the inability to treat or prevent paratuberculosis in animals with antimycobacterial drugs including clofazimine (2732) outlines the difficulty in successfully eradicating intestinal mycobacteria. Therefore the interpretation that the lack of response seen to clofazimine in this study argues against a mycobacterial etiology for Crohn's should be viewed with caution. The fastidious nature of these organisms and the difficulty with isolation has plagued investigators and obviously renders the in vitro testing of chemotherapeutic agents extremely difficult. Clofazimine has been shown to be bacteriacidal against human and animal isolates of M. paratuberculosis and also against a Mycobacterium spp. isolated from a patient with Crohn's disease (33, 34). However, the use of standard microbiological endpoints such as the eradication of organisms from culture has not been applied to clinical studies of this possible mycobacterial disease and thus a response has to be determined on clinical criteria. Therefore, choice of agent, dosage, and duration of administration remain somewhat arbitrary. The issues of dosage and combination therapy were not addressed by this study. The close of clofazimine in leprosy is between 100 and 300 mg daily and, although the onset of bacterial killing does not occurr until 50 days, its efficacy does not appear to be dose related (8). A 100-mg dose of clofazimine was chosen since side effects are uncommon at this dosage, which was previously shown to be efficacious in Crohn's disease (9). In dealing with this putative mycobacteria, combinations of antimycobacterials may be valuable. In one report of an uncontrolled study a favorable remission rate in 10 of 20 Crohn's disease patients was seen with a combination of isoniazid, rifampicin, ethambutol, pyrazinamide, and clofazimine added for resistant patients (35). The current recomendation for antimycobacterial therapy of pulmonary infection in nonimmunosupressed patients includes combination therapy regimes of three to four agents for periods of one to three years with a 67% response rate (36). A prolonged trial of combination chemotherapy therefore may also be required in patients with intestinal atypical mycobacterial in-
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fection. The use of corticosteroids in association with antimycobacterial therapy initially may appear a little irrational. However, corticosteroids have proven useful in treating the chronic inflammation produced by other mycobacterial diseases such as chronic meningeal M. tuberculosis and the reversal reaction of M. leprae infection and are also useful disease-modifying agents in Crohn's disease. In conclusion it would appear that clofazimine alone has little therapeutic role as primary treatment for active Crohns disease. Clofazimine's potential chronic use for maintenance of remission and its possible role in combination chemotherapy will have to wait for further trials and, more importantly, for further advances in understanding the etiology of this perplexing disease. ACKNOWLEDGMENTS We would like to thank Ciba-Geigy for their assistance with this study and for supplying the medications. REFERENCES 1. James SP, Strober W, Quinn TC, Danovitch SH: Crohn's disease; new concepts of pathogenesis and current approaches to treatment. Dig Dis Sci 32:1297-1310, 1987 2. Burnham WR, Lennard-Jones JE, Stanford TL, Bird RG: Mycobacteria as a possible cause of inflammatory bowel disease. Lancet 2:693-696, 1978 3. Donnelly BJ, Delaney PV, Healy TM: Evidence for a transmissible agent in Crohn's disease. Gut 18:360-363, 1977 4. Levi AJ: Diet in the management of Crohn's disease. Gut 26:985-988, 1985 5. Cave DR, Mitchell DN, Kane SP, Brooke BN: Further animal evidence of a transmissible agent in Crohn's disease. Lancet 2:1120-1122, 1973 6. Graham DY, Markesich DC, Yoshimura HH: Mycobacteria and inflammatory bowel disease. Gastroenterology 92:436442, 1987 7. Kruiningen H J, Chiodini RJ, Thayer WR, Coutu JA, Merkal RS, Runnels PL: Experimental disease in infant goats induced by a mycobacterium isolated from a patient with Crohn's disease. Dig Dis Sci 31:1351-1360, 1986 8. Yawalkar SJ, Vischer W: Lamprene (clofazimine) in leprosy. Lepr Rev 50:135-144, 1979 9. Kelleher D, O'Brien S, Weir DG: Preliminary trial of clofazimine in chronic inflammatory bowel disease. Gut 23 :A449, 1982 10. O'Donoghue DP, Dawson AM, Powelt-Tuck J, Bowen RL, Lennard-Jones JE: Double blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet 2:955-957, 1978 11. Schultz MG, Rieder HL, Hersh T, Riepe S: Remission of Crohn's disease disease with antimycobacterial chemotherapy. Lancet 2:1391-1392, 1987 12. Jarnerot G, Rolny P, Wickbom G, Elemayehu G: Antimycobacterial chemotherapy ineffective in Crohn's disease after one year. Lancet 1:164-165, 1989 Digestive Diseases and Sciences, Vol. 36, No. 4 (April 1991)
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