Indications for use of Infliximab

Transcription

1 Indications for use of Infliximab Moscow, June 10 th 2006 Prof. Dr. Dr. Gerhard Rogler Klinik und Poliklinik für Innere Medizin I Universität Regensburg

2 Case report 1989: Diagnosis of Crohn s disease of the colon and the ileum at the age of 14 steroid-dependent and later steroid-refractory disease course; treatment attempts with azathioprine and antibiotics failed. Abdominal surgery performed six times multiple persistent enteroenteric and periumbilical enterocutaneous fistulas. Attempts to surgically remove the fistulas failed. August 2001: Patient admitted with dysphagia, pneumonia and abscess formation of the right upper lung: Esophagobronchial fistula from the upper third of the esophagus. Surgery not possible.

3 Case report (continued) September 2001: Abscess drained. Treatment with methotrexate, antibiotics and parenteral nutrition. Clinical improvement. Patient asymptomatic. March 2004: Severe pneumonia secondary to the esophagobronchial fistula. Additionally: esophageal stenosis below the fistula tract. A covered esophageal stent had to be removed immediately after placement. April 2004: The esophageal stenosis was dilated and the fistula closed by endoscopically guided injection of Onyx sealant.

4 Case report (continued) Department of Internal Medicine I

5 Case report (continued) Subsequently infliximab therapy with regular retreatment intervals as well as azathioprine was started. January 2005: the Onyx polymer was coughed out, fistula is still closed June 2006: the patient is in remission

6 Infliximab Chimeric IgG1-monoclonal antibody Tumor necrosis factor alpha (TNF-α) binding Indications in IBD: Crohn s disease and ulcerative colitis Administration: Two hour infusion Short stability (three hours)

7 Infliximab: Mechanism of action Macrophage or activated T-cell Activation of complement Outside-in signaling soluble TNF Membrane bound TNF Infliximab TNF-receptor Target cell

8 Healing of colonic ulceration with infliximab in Crohn s s disease Pretreatment 4 weeks post-treatment treatment Van Dullemen HM et al. Gastroenterology 1995;109:

9 Infliximab for active Crohn s s disease remission (CDAI < 150 Punkte) % remission (%) after 4 weeks 25 25% 25% 0 4% Placebo Targan S, et al. NEJM. 1997; 337: /27 5mg/kg p< /28 10mg/kg p= mg/kg p=0.067

10 Long-term effects of infliximab - ACCENT I Responder to first infusion (week 2; 335/573 patients) 54 weeks Remission Remission Response Time to steroid free LOR (%) (%) (%) (weeks) Placebo mg * 10 mg > 54 * 32 % infections, 3.8 % serious, 4 deaths (2 sepsis, 1 lymphoma), 49 % new ANA (> 1 : 160), 26 % Anti ds DNA AB (> 1:10) 54 % steroids, 24 % immunomodulators, 50 % 5-ASA Hanauer, Rutgeerts; 2001

11 Infliximab for Crohn s s disease ACCENT I % patients (%) % non responder 59 % response 30 % response 23 % remission Start 10 weeks 30 weeks According to E.F. Stange, Stuttgart 2001

12 Infliximab in patients with fistulizing Perianal Fistula Case Study Crohn s s disease Pretreatment 2 weeks 10 weeks 18 weeks Present D, et al. NEJM. 1999; 340:

13 Infliximab in patients with fistulizing 100 Crohn s s disease P=0.04 % responding P= % 38% 25 13% * Present D, et al. NEJM. 1999; 340: /31 17/31 12/32 placebo 5 mg/kg 10 mg/kg IFX IFX *Placebo = conventional Therapy

14 ACCENT II: Fistula response at week 54 Patients in Response (%) Among patients responding at Weeks 10 and 14 P= % 49% Fistula Response P= % 40% 24/89 41/83 24/89 41/83 Complete Response Placebo maintenance 5 mg/kg infliximab maintenance Sands BE, et al NEJM 2004, Lichtenstein GR, et al, Gastroenterology, 2005

15 Incidence of human anti-chimeric antibody (HACA) in maintenance studies Human anti-chimeric antibody (HACA) status % of Pts with HACA % of Pts inconclusive % of Pts without HACA n = 514 Week 72 ACCENT I CD n = 258 Week 54 ACCENT II CD n = 295 Week 102 ATTRACT RA n = 629 Week 54 ASPIRE RA pts with long-lasting lasting serum concentrations of infliximab and never HACA (+) ASPIRE: Integrated Safety Summary, Sep. 18, 2003

16 Immunogenicity of infliximab Antibodies against infliximab (μg/ml) Patients without fistulae No immunosuppression immunosuppression Antibodies against infliximab (μg /ml) Patients with fistulae 0 no immunosuppression immunosuppression Baert et al. N Engl J Med 2003;348:7

17 ECCO Statement: European Consensus: For those who have relapsed (to steroid treatment in severe disease or sulfasalazine and steroids in moderate disease), azathioprine/6-mercaptopurine should be added (or, if intolerant methotrexate should be considered). Infliximab should be considered in addition for corticosteroid refractory disease or intolerance although surgical options should also be considered and discussed. There is no need to have failed both AZA/6-MP AND MTX before Infliximab. Travies, Stange et al; European evidence based consensus..., Gut 2006; 55, Suppl 1, i16-i35

18 CD: moderate to severe Department of Internal Medicine I Moderate CD Severe CD Observe Success Taper Adequate response PO Steroids Adequate response IV Steroids Failure Inadequate response Inadequate response Adequate response 6-MP/AZA Inadequate response/ intolerant Consider infliximab + 6-MP/AZA or MTX Consider surgery Maintain 6-MP/AZA or MTX Adequate response Consider change to MTX Maintain infliximab + 6-MP/AZA or MTX Adequate response Inadequate response/ intolerant Add infliximab Inadequate response/intolerant Surgery or investigational therapy

19 Fistula Fistula Diagnostic evaluation Fistula type Not superficial Superficial Tacrolimus Failure Seton Antibiotics Failure Antibiotics Consider fistulotomy Failure Definitive surgery Failure 6-MP/AZA ± infliximab Maintain 6-MP/AZA and/or infliximab Observe

20 Infliximab for the induction and maintenance of remission in active ulcerative colitis p = p < p < p < ACT 1 ACT 2 Rutgeerts et al. NEJM 2005;353: remission after 8 weeks (%) Placebo Inflix. 5 mg/kg Inflix. 10 mg/kg Infliximab 5 mg/kg or 10 mg/kg in ACT 1 and 2 significantly better than placebo

21 Infliximab for the induction and maintenance of remission in active ulcerative colitis Patients without steroids 30 % ,7% ,1% 5 0 Week 30 Rutgeerts et al. NEJM 2005;353:

22 Infliximab as rescue-therapy in severe ulcerative colitis 45 patients with severe ulcerative colitis Recruitment on day 4 after start of steroid therapy if fulminant colitis on day 3, or on day 6-8 after start of steroid treatment if severe colitis on day 5-7: Infliximab (5 mg/kg) or placebo i.v. primary end point: colectomy or death after 3 months. secondary end points: clinical and endoscopic remission. Infliximab n=24 placebo n=21 p colectomy in 3 mo 29% 67% 0,017 death (n) 0 0 adverse events (n) 9 8 post-op. adverse events (n) 4 5 Järnerot et al. Gastroenterology 2005;128:

23 When should infliximab be used in patients with ulcerative colitis? left sided 5-ASA rectally Infliximab remission 5-ASA rectally for maintencance of remission remission refractory Colectomy standardtherapy Refractory (or) initially severe flare Other reasons? systemic glucocorticoids refractory Ciclosporin i.v. pancolitis 5-ASA orally remission? 5-ASA orally or maintenance of remission remission remission Azathioprin/6-MP

24 Risik of infliximab therapy Retrospective analysis of 500 patients Average of 3 infusions during an observation period of 17 months 3,8 % acute infusion reactions 2,8 % Serum disease, 3 patients with med.-induced Lupus, 1 patient with demyelinating disease 48 patients with infectious complications, 20 severe infections 2 patients with fatal sepsis, 2 patients with fatal pneumonia 10 patients died in 5 cases (1%) infliximab likely to be causative 9 patients with diagnosis of malignoma Colombel 2004

25 Risk and advantage of treatment with infliximab Model-calculation: Two cohorts of patients: Infliximab versus standard therapy All available data for 48 weeks of therapy with infliximab Benefits calculated based on ACCENT1 data Infliximab versus standard therapy patients in remission operations Death caused by Crohn s disease lymphoma death by complications caused by infliximab (infections a.o.).) quality adjusted life years more 4255 less 33 less 201 more 249 more 0.77 versus 0.75 Siegel, Hur, Korzenik, Sands, DDW 2006

26 Safety of infliximab therapy: TREAT registry 6273 patients, 3272 had infliximab, 3001 had other therapies Average observation time: 2,7 years Infliximab Standard therapy relative risk (RR) Mortality 0,47 per 100 py 0,47 per 100 py 1,0 Malignancies 0,58 per 100 py 0,53 per 100 py 1,1 Lymphoma 0,06 per 100 py 0,05 per 100 py 1,3 Lichtenstein et al, DDW 2006

27 Summary Infliximab (probably similar to Adalimumab and Certolizumab) is effective in patients with steroid-refractory and azathioprininresponsive severe Crohn s disease It may be used as an alternative to surgery Long term remission rates for all patients initially treated are 25% Thank you for your attention Infliximab is also effective in ulcerative colitis; its place in treatment algorithm for UC has still to be defined Risk (HACA, allergic reactions, tuberculosis, severe infections, lymphoma) and benefits (better quality of life) have to be carefully considered for each patient