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thelancet Vol 364 September 18, 2004

Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s disease Saleh A Naser, George Ghobrial, Claudia Romero, John F Valentine. www.thelancet.com Vol 364 September 18, 2004. A. Oleksik, AMC, 26-10-2004. Achtergrondinformatie.

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thelancet Vol 364 September 18, 2004

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  1. Culture of Mycobacterium avium subspecies paratuberculosisfrom the blood of patients with Crohn’s diseaseSaleh A Naser, George Ghobrial, Claudia Romero, John F Valentine www.thelancet.com Vol 364 September 18, 2004 A. Oleksik, AMC, 26-10-2004

  2. Achtergrondinformatie • De etiologie van de ziekte van Crohn blijft onduidelijk • CARD15 mutaties in 15-22% van Crohn-gevallen • Er bestaat een disscussie over de betekenis van Mycobacterium avium s. paratuberculosis

  3. MAP en Crohn

  4. Methoden • 52 personen (18-77 j; 50% vrouw): • 28 Crohn (60% v) • 9 colitis ulcerosa (20%) • 4 andere darmpathologie • 11 gezonde personen • Klinische gegevens: • Duur van ziekte • Ziekte-activiteit volgens Harvey-Bradshow • Gebruik van immunosuppressiva • Buffy coat van 4 ml bloed • Extractie van DNA (IS900) • Kweek • MGIT (8-12 wk) -> kleuringen + DNA->nested PCR, • BACTEC tot groei-index boven 50 -> idem

  5. Resultaten

  6. Discussie • Bevindingen: • MAP in bloed = systemische ziekte (Johne’s) • MAP en IBD = actieve infectie / colonisatie = gezamelijke triggers? • Geen MAP in controles = verschil in eliminatie? • PCR+ in controles = expositie • Zwakke punten: • Geen associatie met immunosuppressie = type 2 error? • Echter nooit reactivatie van MAP onder immunosuppressie • Sterke punten • Bevestigen MAP door IS900 • Bewezen van heterogeniciteit van de MAP-stammen • Controle voor contaminatie

  7. Conclusie • Geen bewijs voor een causaal verband • Noodzaak voor grotere studies (cohort) • Bloedkweken ter bepaling van de behandelingsindicatie? • “The Australian randomised, placebo-controlled trial of 2 years’ treatment with clarithromycin, rifabutin, and clofazimine in Crohn’s disease has just been completed. The results are being analysed and are eagerly awaited”. Toekomstperspectief (comment by Warwick S Selby)

  8. Wat zegt de Cochrane-review? • A total of seven randomized trials = 355 patients: OR for maintenance of remission = 1.36 (95% CI 0.87-2.13) • The two trials reported as abstracts were excluded from subgroup analyses because they did not include any information on adjunct therapy. • Two trials (only 89 patients) used anti-tuberculous therapy (clofazimine or clofazimine, rafmpin, ethambutol, and dapsone) in combination with corticosteroids to induce remission. Maintenance therapy consisted of the anti-tuberculous agents without corticosteroids. Control patients received corticosteroids to induce remission but no anti-tuberculous therapy. OR for maintenance of remission of 3.37 (95% CI 1.38-8.24). The number needed to treat was three. • The remaining three trials compared the combination of anti-tuberculous therapy and 'standard therapy' with 'standard therapy alone'. The pooled odds ratio was 0.70 (95% CI 0.39-1.25).

  9. Hoe zit het met CARD15 – TLR2? • CARD 15 • Intracellular receptor • Reageert op peptidoglycan “muranyl peptide” = MDP • Stimuleert NFκB = inflammatie • Maar remt TRL 2 • TLR 2 • Transmembrane receptor • Activatie in phagosom • Reageert op peptidoglycanen (G+ bacterieen) • Stimuleert phagocytose en fusie van phagosom met lysosom • Is dus noodzakelijk voor CD4+ activatie en selectie (Th1, Th2) • B7-CD28 • Ag/HLA II - TCR • Stimuleert NFκB = inflammatie • Mycobacterium • Ontwijkt de fusie van phagosom met lysosom

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