Antimycobacterial Therapy in Crohn’s Disease: Game Over?
2007; Elsevier BV; Volume: 132; Issue: 7 Linguagem: Inglês
10.1053/j.gastro.2007.04.027
ISSN1528-0012
AutoresLaurent Peyrin‐Biroulet, Christel Neut, Jean–Frédéric Colombel,
Tópico(s)Inflammatory Bowel Disease
ResumoSee "Two-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease" by Selby W, Pavli P, Crotty B, Florin T, Radford-Smith G, Gibson P, Mitchell B, Connell W, Read R, Merrett M, Ee H, Hetzel D, on page 2313. See "Two-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease" by Selby W, Pavli P, Crotty B, Florin T, Radford-Smith G, Gibson P, Mitchell B, Connell W, Read R, Merrett M, Ee H, Hetzel D, on page 2313. It has been almost a century since Dalziel, who first described what is at the present time known as Crohn's disease (CD), commented on its similarity to Johne's disease, which occurs in dairy herds and is caused by Mycobacterium avium subspecies paratuberculosis (MAP).1Dalziel T.K. Chronic intestinal enteritis.BMJ. 1913; 2: 1068-1070Google Scholar Interest in a possible infectious origin for CD was renewed in 1989 when Chiodini et al2Chiodini R.J. Crohn's disease and the mycobacterioses: a review and comparison of two disease entities.Clin Microbiol Rev. 1989; 2: 90-117PubMed Google Scholar cultured apparently identical MAP from 3 patients with CD. The controversy continues to rage; indeed, it has even increased following alarming reports on the detection of MAP in water supplies and milk,3Millar D. Ford J. Sanderson J. Withey S. Tizard M. Doran T. Hermon-Taylor J. IS900 PCR to detect Mycobacterium paratuberculosis in retail supplies of whole pasteurized cows' milk in England and Wales.Appl Environ Microbiol. 1996; 62: 3446-3452PubMed Google Scholar, 4Mishina D. Katsel P. Brown S.T. Gilberts E.C. Greenstein R.J. On the etiology of Crohn disease.Proc Natl Acad Sci U S A. 1996; 93: 9816-9820Crossref PubMed Scopus (152) Google Scholar although this was not confirmed in a recent case-control study.5Abubakar I. Myhill D.J. Hart A.R. Lake I.R. Harvey I. Rhodes J.M. Robinson R. Lobo A.J. Probert C.S. Hunter P.R. A case-control study of drinking water and dairy products in Crohn's disease—further investigation of the possible role of Mycobacterium avium paratuberculosis.Am J Epidemiol. 2007; 165: 776-783Crossref PubMed Scopus (64) Google Scholar Detection of the specific DNA insertion sequence IS900 of MAP in a significant number of patients with CD, but not in controls,6Autschbach F. Eisold S. Hinz U. Zinser S. Linnebacher M. Giese T. Loffler T. Buchler M.W. Schmidt J. High prevalence of Mycobacterium avium subspecies paratuberculosis IS900 DNA in gut tissues from individuals with Crohn's disease.Gut. 2005; 54: 944-949Crossref PubMed Scopus (146) Google Scholar, 7Sechi L.A. Scanu A.M. Molicotti P. Cannas S. Mura M. Dettori G. Fadda G. Zanetti S. Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn's disease in Sardinia.Am J Gastroenterol. 2005; 100: 1529-1536Crossref PubMed Scopus (162) Google Scholar and the finding of MAP in the bloodstream of these patients8Naser S.A. Ghobrial G. Romero C. Valentine J.F. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease.Lancet. 2004; 364: 1039-1044Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar has also contributed to enhancing the controversy. It is not the purpose of this editorial to review all the arguments for or against MAP as a causative agent for CD, as recently done by Sartor.9Sartor R.B. Does Mycobacterium avium subspecies paratuberculosis cause Crohn's disease?.Gut. 2005; 54: 896-898Crossref PubMed Scopus (137) Google Scholar It is, however, noteworthy that both advocates and detractors of this theory almost invariably conclude their demonstration by saying that the most irrefutable evidence that MAP causes CD lies in long-term remission of clinical manifestations and altered natural history of the disease following clearance of the infection with antibiotics. Antibiotic therapy is indeed effective in 80%–90% of patients with tuberculosis and nontuberculosis lung disease.10Thiam S. LeFevre A.M. Hane F. Ndiaye A. Ba F. Fielding K.L. Ndir M. Lienhardt C. Effectiveness of a strategy to improve adherence to tuberculosis treatment in a resource-poor setting: a cluster randomized controlled trial.JAMA. 2007; 297: 380-386Crossref PubMed Scopus (124) Google Scholar, 11Fujikane T. Fujiuchi S. Yamazaki Y. Sato M. Yamamoto Y. Takeda A. Nishigaki Y. Fujita Y. Shimizu T. Efficacy and outcomes of clarithromycin treatment for pulmonary MAC disease.Int J Tuberc Lung Dis. 2005; 9: 1281-1287PubMed Google Scholar Fourteen studies assessing the efficacy of antimycobacterial therapy in CD, and which enrolled a total of 508 patients, have been published (Table 1).12Afdhal N.H. Long A. Lennon J. Crowe J. O'Donoghue D.P. Controlled trial of antimycobacterial therapy in Crohn's disease Clofazimine versus placebo.Dig Dis Sci. 1991; 36: 449-453Crossref PubMed Scopus (76) Google Scholar, 13Basilisco G. Ranzi T. Campamini M.C. et al.Controlled trial of rifabutin in Crohn's disease.Curr Therapeut Res. 1989; 46: 245-260Google Scholar, 14Borody T.J. Leis S. Warren E.F. Surace R. Treatment of severe Crohn's disease using antimycobacterial triple therapy—approaching a cure?.Dig Liver Dis. 2002; 34: 29-38Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 15Elliott P.R. Burnham W.R. Berghouse L.M. Lennard-Jones J.E. Langman M.J. Sulphadoxine-pyrimethamine therapy in Crohn's disease.Digestion. 1982; 23: 132-134Crossref PubMed Scopus (42) Google Scholar, 16Goodgame R.W. Kimball K. Akram S. Ike E. Ou C.N. Sutton F. Graham D. Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease.Aliment Pharmacol Ther. 2001; 15: 1861-1866Crossref PubMed Scopus (40) Google Scholar, 17Gui G.P. Thomas P.R. Tizard M.L. Lake J. Sanderson J.D. Hermon-Taylor J. Two-year-outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics.J Antimicrob Chemother. 1997; 39: 393-400Crossref PubMed Scopus (145) Google Scholar, 18Hampson S.J. Parker M.C. Saverymuttu S.H. Joseph A.E. McFadden J.J. Hermon-Taylor J. Quadruple antimycobacterial chemotherapy in Crohn's disease: results at 9 months of a pilot study in 20 patients.Aliment Pharmacol Ther. 1989; 3: 343-352Crossref PubMed Scopus (38) Google Scholar, 19Leiper K. Morris A.I. Rhodes J.M. Open label trial of oral clarithromycin in active Crohn's disease.Aliment Pharmacol Ther. 2000; 14: 801-806Crossref PubMed Scopus (77) Google Scholar, 20Prantera C. Bothamley G. Levenstein S. Mangiarotti R. Argentieri R. Crohn's disease and mycobacteria: two cases of Crohn's disease with high anti-mycobacterial antibody levels cured by dapsone therapy.Biomed Pharmacother. 1989; 43: 295-299Crossref PubMed Scopus (28) Google Scholar, 21Prantera C. Kohn A. Mangiarotti R. Andreoli A. Luzi C. Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with a multiple antibiotic regimen.Am J Gastroenterol. 1994; 89: 513-518PubMed Google Scholar, 22Rutgeerts P. Geboes K. Vantrappen G. Van Isveldt J. Peeters M. Penninckx F. Hiele M. Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum.J Clin Gastroenterol. 1992; 15: 24-28Crossref PubMed Scopus (41) Google Scholar, 23Shaffer J.L. Hughes S. Linaker B.D. Baker R.D. Turnberg L.A. Controlled trial of rifampicin and ethambutol in Crohn's disease.Gut. 1984; 25: 203-205Crossref PubMed Scopus (82) Google Scholar, 24Shafran I. Kugler L. El-Zaatari F.A. Naser S.A. Sandoval J. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease.Dig Liver Dis. 2002; 34: 22-28Abstract Full Text PDF PubMed Scopus (92) Google Scholar, 25Swift G.L. Srivastava E.D. Stone R. Pullan R.D. Newcombe R.G. Rhodes J. Wilkinson S. Rhodes P. Roberts G. Lawrie B.W. et al.Controlled trial of anti-tuberculous chemotherapy for two years in Crohn's disease.Gut. 1994; 35: 363-368Crossref PubMed Scopus (75) Google Scholar, 26Thomas G.A. Swift G.L. Green J.T. Newcombe R.G. Braniff-Mathews C. Rhodes J. Wilkinson S. Strohmeyer G. Kreuzpainter G. Controlled trial of antituberculous chemotherapy in Crohn's disease: a five year follow up study.Gut. 1998; 42: 497-500Crossref PubMed Scopus (80) Google Scholar Two small, placebo-controlled trials of antimycobacterial therapy in combination with a tapering course of corticosteroids demonstrated efficacy in the maintenance phase (following corticosteroid withdrawal) for clofazimine monotherapy and for a combination of ethambutol, clofazimine, dapsone, and rifampicin in patients with active CD.12Afdhal N.H. Long A. Lennon J. Crowe J. O'Donoghue D.P. Controlled trial of antimycobacterial therapy in Crohn's disease Clofazimine versus placebo.Dig Dis Sci. 1991; 36: 449-453Crossref PubMed Scopus (76) Google Scholar, 21Prantera C. Kohn A. Mangiarotti R. Andreoli A. Luzi C. Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with a multiple antibiotic regimen.Am J Gastroenterol. 1994; 89: 513-518PubMed Google Scholar By contrast, 5 placebo-controlled trials in which antimycobacterial therapy was administered without corticosteroids failed to demonstrate efficacy.13Basilisco G. Ranzi T. Campamini M.C. et al.Controlled trial of rifabutin in Crohn's disease.Curr Therapeut Res. 1989; 46: 245-260Google Scholar, 15Elliott P.R. Burnham W.R. Berghouse L.M. Lennard-Jones J.E. Langman M.J. Sulphadoxine-pyrimethamine therapy in Crohn's disease.Digestion. 1982; 23: 132-134Crossref PubMed Scopus (42) Google Scholar, 22Rutgeerts P. Geboes K. Vantrappen G. Van Isveldt J. Peeters M. Penninckx F. Hiele M. Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum.J Clin Gastroenterol. 1992; 15: 24-28Crossref PubMed Scopus (41) Google Scholar, 23Shaffer J.L. Hughes S. Linaker B.D. Baker R.D. Turnberg L.A. Controlled trial of rifampicin and ethambutol in Crohn's disease.Gut. 1984; 25: 203-205Crossref PubMed Scopus (82) Google Scholar, 25Swift G.L. Srivastava E.D. Stone R. Pullan R.D. Newcombe R.G. Rhodes J. Wilkinson S. Rhodes P. Roberts G. Lawrie B.W. et al.Controlled trial of anti-tuberculous chemotherapy for two years in Crohn's disease.Gut. 1994; 35: 363-368Crossref PubMed Scopus (75) Google Scholar, 26Thomas G.A. Swift G.L. Green J.T. Newcombe R.G. Braniff-Mathews C. Rhodes J. Wilkinson S. Strohmeyer G. Kreuzpainter G. Controlled trial of antituberculous chemotherapy in Crohn's disease: a five year follow up study.Gut. 1998; 42: 497-500Crossref PubMed Scopus (80) Google Scholar In 2000, a meta-analysis suggested that antimycobacterial treatment may be effective in maintaining remission achieved by corticosteroids.27Borgaonkar M.R. MacIntosh D.G. Fardy J.M. A meta-analysis of antimycobacterial therapy for Crohn's disease.Am J Gastroenterol. 2000; 95: 725-729Crossref PubMed Google Scholar However, because of the heterogeneity of the trials, which used a wide range of antibiotic combinations administered for variable periods to a small number of patients, no definitive conclusion could be drawn. Those studies were also criticized because they used earlier tuberculosis drugs, such as ethambutol and isoniazid, which are not effective against M avium complex infection, and <3 antibiotics (a number considered critical for preventing development of drug resistance). Clarithromycin and azithromycin, macrolide compounds that are considered to be the most effective drugs for treatment of MAP, were then used in 4 subsequent studies with encouraging results.14Borody T.J. Leis S. Warren E.F. Surace R. Treatment of severe Crohn's disease using antimycobacterial triple therapy—approaching a cure?.Dig Liver Dis. 2002; 34: 29-38Abstract Full Text PDF PubMed Scopus (91) Google Scholar, 16Goodgame R.W. Kimball K. Akram S. Ike E. Ou C.N. Sutton F. Graham D. Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease.Aliment Pharmacol Ther. 2001; 15: 1861-1866Crossref PubMed Scopus (40) Google Scholar, 17Gui G.P. Thomas P.R. Tizard M.L. Lake J. Sanderson J.D. Hermon-Taylor J. Two-year-outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics.J Antimicrob Chemother. 1997; 39: 393-400Crossref PubMed Scopus (145) Google Scholar, 19Leiper K. Morris A.I. Rhodes J.M. Open label trial of oral clarithromycin in active Crohn's disease.Aliment Pharmacol Ther. 2000; 14: 801-806Crossref PubMed Scopus (77) Google Scholar, 24Shafran I. Kugler L. El-Zaatari F.A. Naser S.A. Sandoval J. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease.Dig Liver Dis. 2002; 34: 22-28Abstract Full Text PDF PubMed Scopus (92) Google Scholar However, the only placebo-controlled randomized trial was 3 months long, and the antibiotic regimen associated only 2 drugs, namely, clarithromycin and ethambutol.16Goodgame R.W. Kimball K. Akram S. Ike E. Ou C.N. Sutton F. Graham D. Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease.Aliment Pharmacol Ther. 2001; 15: 1861-1866Crossref PubMed Scopus (40) Google Scholar The general conclusion of most experts in the field was that the proof of efficacy of combination antibiotic therapy in CD remained elusive due to the absence of a properly conducted large placebo-controlled randomized trial.Table 1Efficacy of Antimycobacterial Therapy in CD in Open-Label and Randomized Controlled TrialsAuthor (year)Patients included (n)TrialAntibiotic combination therapyConcomitant steroid therapyTreatment period (mos)Primary endpointsEfficacy (main result): Treatment/placebo (%)Elliott (1982)15Elliott P.R. Burnham W.R. Berghouse L.M. Lennard-Jones J.E. Langman M.J. Sulphadoxine-pyrimethamine therapy in Crohn's disease.Digestion. 1982; 23: 132-134Crossref PubMed Scopus (42) Google Scholar51RCTSulfadoxine, pyrimethamineNo12Changes in CDAI scoresClinical remission: 38/50Schaffer (1984)23Shaffer J.L. Hughes S. Linaker B.D. Baker R.D. Turnberg L.A. Controlled trial of rifampicin and ethambutol in Crohn's disease.Gut. 1984; 25: 203-205Crossref PubMed Scopus (82) Google Scholar27RCTEthambutol, rifampinNo12Changes in CDAI scores (or any clinical indicator of disease activity)Clinical remission: 36/64Basilisco (1989)13Basilisco G. Ranzi T. Campamini M.C. et al.Controlled trial of rifabutin in Crohn's disease.Curr Therapeut Res. 1989; 46: 245-260Google Scholar24RCTRifabutinNo6Changes in the Harvey-Bradshaw indexClinical remission: 29/38Hampson (1989)18Hampson S.J. Parker M.C. Saverymuttu S.H. Joseph A.E. McFadden J.J. Hermon-Taylor J. Quadruple antimycobacterial chemotherapy in Crohn's disease: results at 9 months of a pilot study in 20 patients.Aliment Pharmacol Ther. 1989; 3: 343-352Crossref PubMed Scopus (38) Google Scholar20Open labelEthambutol, rifampin, isoniazid, clofazimine (or pyrazinamide)Yes9Clinical remission defined as CDAI < 150Clinical remission: 50Prantera (1989)20Prantera C. Bothamley G. Levenstein S. Mangiarotti R. Argentieri R. Crohn's disease and mycobacteria: two cases of Crohn's disease with high anti-mycobacterial antibody levels cured by dapsone therapy.Biomed Pharmacother. 1989; 43: 295-299Crossref PubMed Scopus (28) Google Scholar5Open labelDapsoneNo1Changes in CDAI scores and mucosal healingClinical remission: 40Afdhal (1991)12Afdhal N.H. Long A. Lennon J. Crowe J. O'Donoghue D.P. Controlled trial of antimycobacterial therapy in Crohn's disease Clofazimine versus placebo.Dig Dis Sci. 1991; 36: 449-453Crossref PubMed Scopus (76) Google Scholar49RCTClofazimineYes12Clinical remission (use of modified CDAI scores)Clinical remission: 64/50Rutgeerts (1992)22Rutgeerts P. Geboes K. Vantrappen G. Van Isveldt J. Peeters M. Penninckx F. Hiele M. Rifabutin and ethambutol do not help recurrent Crohn's disease in the neoterminal ileum.J Clin Gastroenterol. 1992; 15: 24-28Crossref PubMed Scopus (41) Google Scholar16Open labelRifabutin, ethambutolNo6–12Endoscopic healing in the neoterminal ileumMucosal healing: 0Prantera (1994)21Prantera C. Kohn A. Mangiarotti R. Andreoli A. Luzi C. Antimycobacterial therapy in Crohn's disease: results of a controlled, double-blind trial with a multiple antibiotic regimen.Am J Gastroenterol. 1994; 89: 513-518PubMed Google Scholar40RCTClofazimine, rifampinYes9Clinical remission and mucosal healingClinical remission: 84/35Swift (1994)25Swift G.L. Srivastava E.D. Stone R. Pullan R.D. Newcombe R.G. Rhodes J. Wilkinson S. Rhodes P. Roberts G. Lawrie B.W. et al.Controlled trial of anti-tuberculous chemotherapy for two years in Crohn's disease.Gut. 1994; 35: 363-368Crossref PubMed Scopus (75) Google Scholar, Thomas (1998)26Thomas G.A. Swift G.L. Green J.T. Newcombe R.G. Braniff-Mathews C. Rhodes J. Wilkinson S. Strohmeyer G. Kreuzpainter G. Controlled trial of antituberculous chemotherapy in Crohn's disease: a five year follow up study.Gut. 1998; 42: 497-500Crossref PubMed Scopus (80) Google Scholar126RCTEthambutol, rifampin, isoniazidNo24Changes in the Harvey-Bradshaw index and CDAI scores, steroid sparing, need for surgery, radiological changeClinical remission: 35/38Gui (1997)17Gui G.P. Thomas P.R. Tizard M.L. Lake J. Sanderson J.D. Hermon-Taylor J. Two-year-outcomes analysis of Crohn's disease treated with rifabutin and macrolide antibiotics.J Antimicrob Chemother. 1997; 39: 393-400Crossref PubMed Scopus (145) Google Scholar46Open labelRifabutin, clarithromycin (or azithromycin)Yes19Changes in the Harvey-Bradshaw index and serum CRP, steroid sparing, need for surgeryInduction of clinical remission: 93.5Leiper (2000)19Leiper K. Morris A.I. Rhodes J.M. Open label trial of oral clarithromycin in active Crohn's disease.Aliment Pharmacol Ther. 2000; 14: 801-806Crossref PubMed Scopus (77) Google Scholar25Open labelClarithromycinYes1–15Changes in the Harvey-Bradshaw index and serum CRPClinical remission: 32/48Goodgame (2001)16Goodgame R.W. Kimball K. Akram S. Ike E. Ou C.N. Sutton F. Graham D. Randomized controlled trial of clarithromycin and ethambutol in the treatment of Crohn's disease.Aliment Pharmacol Ther. 2001; 15: 1861-1866Crossref PubMed Scopus (40) Google Scholar31RCTClarithromycin, ethambutolYes3Changes in the lactulose-mannitol test and the Harvey-Bradshaw indexChanges in the Harvey-Bradshaw index in the active arm: P = .08 vs placeboShafran (2002)24Shafran I. Kugler L. El-Zaatari F.A. Naser S.A. Sandoval J. Open clinical trial of rifabutin and clarithromycin therapy in Crohn's disease.Dig Liver Dis. 2002; 34: 22-28Abstract Full Text PDF PubMed Scopus (92) Google Scholar36Open labelClarithromycin, rifabutinNoaA probiotic supplement was given to counterbalance antibiotic-induced degradation of the intestinal flora.4–17Response defined as marked improvement in CDAI scoresClinical response: 58.3Borody (2002)14Borody T.J. Leis S. Warren E.F. Surace R. Treatment of severe Crohn's disease using antimycobacterial triple therapy—approaching a cure?.Dig Liver Dis. 2002; 34: 29-38Abstract Full Text PDF PubMed Scopus (91) Google Scholar12Open labelClarithromycin, rifabutin, clofazimineYes24Changes in the Harvey-Bradshaw indexClinical remission: 25CDAI, Crohn's Disease Activity Index; CRP, C-reactive protein.a A probiotic supplement was given to counterbalance antibiotic-induced degradation of the intestinal flora. Open table in a new tab CDAI, Crohn's Disease Activity Index; CRP, C-reactive protein. In this context, results from the Australian trial published in the current issue of Gastroenterology were awaited eagerly.28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar In a large placebo-controlled, double-blind, randomized trial which enrolled a total of 213 patients with active CD (Crohn's Disease Activity Index ≥ 200), Selby et al28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar evaluated the efficacy of 2-year combination therapy with clarithromycin (750 mg/d), rifabutin (450 mg/d), and clofazimine (50 mg/d) in maintaining clinical remission following corticosteroid withdrawal. During a 16-week induction period, patients were randomized to receive a tapering regimen of corticosteroids in association with these 3 antibiotics or placebo. At week 16, 122 patients who achieved remission entered the maintenance phase, during which they continued trial medications for 2 years. After 2 years of treatment, trial medications were ceased, and patients in remission were followed up for 1 more year. The primary endpoints were the proportion of subjects experiencing ≥1 relapse of CD at 1, 2, and 3 years. At the end of the 16-week induction period, there was a significantly higher percentage of subjects in remission in the antibiotic arm (66%) than in the placebo arm (50%; P = .02). The proportion of patients who relapsed at 1, 2, and 3 years was not significantly different in the 2 arms: 39% in the antibiotic group relapsed between weeks 16 and week 52 versus 56% in the placebo group (P = .054); 26% versus 43% relapsed at 2 years (P = .14); and 59% versus 50% at 3 years (P = .54). The number of subjects remaining in the study fell progressively from 16 weeks, and only 32 patients completed the study. The study thus did not meet its primary end points.28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar The authors conclude that these results do not support a role for MAP in CD, and that the use of antibiotics with a broad spectrum of activity against luminal organisms may explain the early efficacy of antibiotic combination added to corticosteroids as induction therapy. Results of this first long-term, large-scale, randomized, placebo-controlled trial seem to be particularly convincing for several reasons. The authors used a combination of 3 antibiotics active intracellularly, with good tissular diffusion and effectiveness against MAP, thus minimizing the risk of drug resistance. Antibiotics were given for up to 2 years. Corticosteroids, which are active against MAP (that resembles M leprae more than M tuberculosis in its response to corticosteroids29Mitchell I.C. Turk J.L. Effect of the immune modulating agents cyclophosphamide, methotrexate, hydrocortisone, and cyclosporin A on an animal model of granulomatous bowel disease.Gut. 1990; 31: 674-678Crossref PubMed Scopus (11) Google Scholar), were given in association during the induction period in order to optimize antibiotic efficacy, as previously shown.27Borgaonkar M.R. MacIntosh D.G. Fardy J.M. A meta-analysis of antimycobacterial therapy for Crohn's disease.Am J Gastroenterol. 2000; 95: 725-729Crossref PubMed Google Scholar The negative message from this study was reinforced by the lack of improvement observed in important secondary parameters such as C-reactive protein and mucosal healing in a subset of patients. The low number (n = 32) of patients remaining at 3 years could raise the possibility of a type II error, but most withdrawals were due to progression of disease, even when repeat courses of prednisolone were used. This finding, together with high observance rates (69%–74% for weeks 53–104) favor true failure of trial medication rather than a statistical bias. The mere take-home message from this study is that the antibiotic regimen that was used has no role in maintenance treatment of CD. Does it definitely refute any therapeutic role of antimycobacterial therapy in CD? The question remains open. Selby et al28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar did not assess IS900 DNA in biopsies by polymerase chain reaction and serologic response to MAP before and after therapy. There is thus no evidence that MAP, if present, was cleared by treatment. MAP may require higher doses of antibiotics or other antibiotics for eradication. Subtherapeutic doses of rifabutin (450 mg), clarithromycin (750 mg), and clofazimine (50 mg) per day28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar were used, whereas the optimal dose of rifabutin, clarithromycin, and clofazimine for treatment of M avium complex infections is 600 mg/d, 1000–2000 mg/d, and 100 mg/d, respectively.30Shafran S.D. Singer J. Zarowny D.P. Phillips P. Salit I. Walmsley S.L. Fong I.W. Gill M.J. Rachlis A.R. Lalonde R.G. Fanning M.M. Tsoukas C.M. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group.N Engl J Med. 1996; 335: 377-383Crossref PubMed Scopus (285) Google Scholar, 31Dunne M. Fessel J. Kumar P. Dickenson G. Keiser P. Boulos M. Mogyros M. White Jr, A.C. Cahn P. O'Connor M. Lewi D. Green S. Tilles J. Hicks C. Bissett J. Schneider M.M. Benner R. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus.Clin Infect Dis. 2000; 31: 1245-1252Crossref PubMed Scopus (61) Google Scholar The minimal inhibitory concentration (MIC90) of clarithromycin (at which 90% of M avium complex isolates are inhibited) is 4 μg/mL.32Naik S. Ruck R. In vitro activities of several new macrolide antibiotics against Mycobacterium avium complex.Antimicrob Agents Chemother. 1989; 33: 1614-1616Crossref PubMed Scopus (76) Google Scholar When the drug is given orally at a dose of 400 mg, blood levels attain 2 μg/mL, and they rise to 4.4 μg/mL at a dose of 1200 mg.32Naik S. Ruck R. In vitro activities of several new macrolide antibiotics against Mycobacterium avium complex.Antimicrob Agents Chemother. 1989; 33: 1614-1616Crossref PubMed Scopus (76) Google Scholar Despite being used in combination, low-dose antibiotics may fail in the long run owing to the development of drug resistance. Another retrospective study from Australia demonstrated mucosal healing in 22 of 39 (56.4%) patients treated with higher doses of rifabutin (up to 600 mg/d), clofazimine (up to 100 mg/d), and clarithromycin (up to 1 g/d) for 6 months to 9 years.33Borody T.J. Bilkey S. Wettstein A.R. Leis S. Pang G. Tye S. Anti-mycobacterial therapy in Crohn's disease heals mucosa with longitudinal scars.Dig Liver Dis. 2007; Google Scholar Important reservoirs of bacteria may not have been reached by antibiotics. One possible example is mesenteric fat, which is in close contact with the intestine. Mesenteric fat is hypertrophied in CD and is heavily colonized by bacteria.34Peyrin-Biroulet L. Chamaillard M. Gonzalez F. Beclin E. Decourcelle C. Antunes L. Gay J. Neut C. Colombel J.F. Desreumaux P. Mesenteric fat in Crohn's disease: a pathogenetic hallmark or an innocent bystander?.Gut. 2007; 56: 577-583Crossref PubMed Scopus (195) Google Scholar It has been recently shown that M tuberculosis can enter into adipocytes, where it accumulates intracytoplasmic lipid inclusions and survives in a nonreplicating state that is insensitive to the major antimycobacterial drug, isoniazid.35Neyrolles O. Hernandez-Pando R. Pietri-Rouxel F. Fornes P. Tailleux L. Payan J.A. Pivert E. Bordat Y. Aguilar D. Prevost M.C. Petit C. Gicquel B. Is adipose tissue a place for Mycobacterium tuberculosis persistence?.PLoS ONE. 2006; 1: e43Crossref PubMed Scopus (243) Google Scholar Whether the same phenomenon occurs for MAP in the mesenteric fat of patients with CD remains unknown. A better understanding of the virulence mechanisms of MAP is required to develop more targeted therapies against this intracellular pathogen. In this setting, the recent identification of novel virulence factors, by generating a mutant library of MAP, may help us to design more effective vaccines and chemotherapies directed against animal and human infections with MAP.36Shin S.J. Wu C.W. Steinberg H. Talaat A.M. Identification of novel virulence determinants in Mycobacterium paratuberculosis by screening a library of insertional mutants.Infect Immun. 2006; 74: 3825-3833Crossref PubMed Scopus (77) Google Scholar Selby et al28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar did not consider genes or the environment in the etiology of CD. MAP may be responsible for, and anti-MAP therapy effective in, a subset of patients who are genetically predisposed. The common truncation mutation of the nucleotide-binding oligomerization domain 2 (NOD2) is associated with defective clearance of invasive Salmonella infection in epithelial cells.37Hisamatsu T. Suzuki M. Reinecker H.C. Nadeau W.J. McCormick B.A. Podolsky D.K. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.Gastroenterology. 2003; 124: 993-1000Abstract Full Text Full Text PDF PubMed Scopus (556) Google ScholarNOD2 mutations in CD are associated with diminished mucosal antimicrobial peptide expression.38Wehkamp J. Salzman N.H. Porter E. Nuding S. Weichenthal M. Petras R.E. Shen B. Schaeffeler E. Schwab M. Linzmeier R. Feathers R.W. Chu H. Lima Jr, H. Fellermann K. Ganz T. Stange E.F. Bevins C.L. Reduced Paneth cell alpha-defensins in ileal Crohn's disease.Proc Natl Acad Sci U S A. 2005; 102: 18129-18134Crossref PubMed Scopus (809) Google Scholar Thus, an attractive explanation linking NOD2 to CD is that of ineffective clearance of intracellular MAP infection. NOD2 status was not assessed in Australian patients, but available phenotypic information argues against an association, because the disease site, including the ileum where NOD2 is predominantly expressed, did not affect response rates.28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar Likewise, no relation was found between NOD2 mutations and a positive MAP serology in a Canadian study.39Bernstein C.N. Wang M.H. Sargent M. Brant S.R. Collins M.T. Testing the interaction between nod-2 status and serological response to Mycobacterium paratuberculosis in cases of inflammatory bowel disease.J Clin Microbiol. 2007; 45: 968-971Crossref PubMed Scopus (26) Google Scholar Other susceptibility genes may influence intracellular MAP clearance and infection in CD. A genome-wide association study identified the interleukin-23 receptor (IL-23R) as a novel susceptibility gene for CD.40Duerr R.H. Taylor K.D. Brant S.R. Rioux J.D. Silverberg M.S. Daly M.J. Steinhart A.H. Abraham C. Regueiro M. Griffiths A. Dassopoulos T. Bitton A. Yang H. Targan S. Datta L.W. Kistner E.O. Schumm L.P. Lee A.T. Gregersen P.K. Barmada M.M. Rotter J.I. Nicolae D.L. Cho J.H. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.Science. 2006; 314: 1461-1463Crossref PubMed Scopus (2481) Google Scholar Mounting evidence suggests that IL-23, similar to IL-12, is critical for generation of an adaptive immune response that is protective against intracellular pathogens, including M tuberculosis infection.41Happel K.I. Lockhart E.A. Mason C.M. Porretta E. Keoshkerian E. Odden A.R. Nelson S. Ramsay A.J. Pulmonary interleukin-23 gene delivery increases local T-cell immunity and controls growth of Mycobacterium tuberculosis in the lungs.Infect Immun. 2005; 73: 5782-5788Crossref PubMed Scopus (79) Google Scholar, 42Verreck F.A. de Boer T. Langenberg D.M. Hoeve M.A. Kramer M. Vaisberg E. Kastelein R. Kolk A. de Waal-Malefyt R. Ottenhoff T.H. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria.Proc Natl Acad Sci U S A. 2004; 101: 4560-4565Crossref PubMed Scopus (736) Google Scholar Finally, as stated by the authors, the aim of this trial was not to definitively prove or disprove the hypothesis that MAP plays a role in the etiology of CD.28Selby W. Pavli P. Crotty B. Florin T. Radford-Smith G. Gibson P. Mitchell B. Connell W. Read R. Merrett M. Ee H. Hetzel D. Antibiotics in Crohn's Disease Study GroupTwo-year combination antibiotic therapy with clarithromycin, rifabutin and clofazimine for Crohn's disease.Gastroenterology. 2007; 132: 2313-2319Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar Interestingly, in Selby et al's trial, concomitant use of immunomodulatory therapy was the only parameter that was associated with a significantly greater response in the antibiotic group. It has recently been shown that 6-mercaptopurine and methotrexate inhibit MAP growth in vitro.43Greenstein R.J. Su L. Haroutunian V. Shahidi A. Brown S.T. On the action of methotrexate and 6-mercaptopurine on M. avium subspecies paratuberculosis.PLoS ONE. 2007; 2: e161Crossref PubMed Scopus (66) Google Scholar These data are compatible with the hypothesis that clinical improvement in patients with inflammatory bowel disease treated with immunomodulators could be due to treatment of a MAP infection.43Greenstein R.J. Su L. Haroutunian V. Shahidi A. Brown S.T. On the action of methotrexate and 6-mercaptopurine on M. avium subspecies paratuberculosis.PLoS ONE. 2007; 2: e161Crossref PubMed Scopus (66) Google Scholar In conclusion, this is a landmark study, because it is the largest randomized placebo-controlled antibiotic trial ever performed in CD. Despite some caveats, as mentioned, it should help to refute arguments favoring MAP as an etiologic agent, although it does not definitively eradicate that hypothesis. Nor does it dismiss the connection between the bacteria and the disease. Despite its broad-spectrum activity, the antimycobacterial antibiotic regimen used in the Australian study is not particularly effective against Gram-negative bacteria. New therapeutic trials should target members of the intestinal flora, such as Bacteroides and adhesive Escherichia coli, which have now been associated with CD by different groups throughout the world.44Martin H.M. Campbell B.J. Hart C.A. Mpofu C. Nayar M. Singh R. Englyst H. Williams H.F. Rhodes J.M. Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer.Gastroenterology. 2004; 127: 80-93Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar, 45Darfeuille-Michaud A. Boudeau J. Bulois P. Neut C. Glasser A.L. Barnich N. 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High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease.Gut. 2006; 56: 669-675Crossref PubMed Scopus (326) Google Scholar Two-Year Combination Antibiotic Therapy With Clarithromycin, Rifabutin, and Clofazimine for Crohn's DiseaseGastroenterologyVol. 132Issue 7PreviewBackground & Aims: Mycobacterium avium subspecies paratuberculosis has been proposed as a cause of Crohn's disease. We report a prospective, parallel, placebo-controlled, double-blind, randomized trial of 2 years of clarithromycin, rifabutin, and clofazimine in active Crohn's disease, with a further year of follow-up. Methods: Two hundred thirteen patients were randomized to clarithromycin 750 mg/day, rifabutin 450 mg/day, clofazimine 50 mg/day or placebo, in addition to a 16-week tapering course of prednisolone. Full-Text PDF
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