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Jacques-Eric Gottenberg Universitary Hospital of Strasbourg, France

How real life rituximab data supports the use of rituximab following an inadequate response to one TNF inhibitor. Jacques-Eric Gottenberg Universitary Hospital of Strasbourg, France National center for systemic autoimmune diseases. Main objections to rituximab.

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Jacques-Eric Gottenberg Universitary Hospital of Strasbourg, France

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  1. How real life rituximab data supports the use of rituximabfollowing an inadequateresponseto one TNF inhibitor Jacques-Eric Gottenberg UniversitaryHospital of Strasbourg, France National center for systemicautoimmunediseases

  2. Main objections to rituximab • Clinicians afraid of long term B cell depletion • Clinicians may not trust safety data from clinical trials as it excludes patients with comorbidities • What to do next in case of failure? • Registries provide safety & efficacy data for rituximab from real life practice

  3. Controlled trials / registries Controlled trials Registries Comorbidities : impact on previous use of anti-TNF…safety…efficacy Safety of biologics after RTX Selection of patients Limited follow-up Insufficiently powered for the detection of unfrequent severe adverse side events (SAE) Large population Unselected patients Long follow-up

  4. AIR Autoimmunity and Rituximab (AIR) registry 5-year multicenter prospective follow-up Objective : safety & efficacy of rituximab in real life Promotion : French Society of Rheumatology Funded by Roche (e-crf and data collection) Coordinator : Xavier Mariette Independent scientific committee : 2 / year T Bardin, P Cacoub, A Cantagrel, B Combe, M Dougados, RM Flipo, B Godeau, JE Gottenberg, L Guillevin, E Hachulla, X Le Loët, X Mariette, P Ravaud, T Schaeverbeke, J Sibilia

  5. State of the inclusions : 2073 patients (March 18th 2009) • 68 centers, 40% non universitary • RA : 1703 patients • Other refractory autoimmune diseases : 370 patients • SLE : 102 • pSS : 60 • Vasculitis : 47 • Myositis : 35 • Other : 126

  6. A high number of RA patients treated with RTX have comorbidities Record of severe infections : 31 % (36 tuberculoses) Record of cancer : 13%

  7. Record of cancerin 13% of RA patients • breast : 32 • skin : 22 (9 melanoma) • lymphoma : 19 • uterus : 7 • ovary : 1 • thyroide : 4 • bladder : 2 • kidney : 3 • lung : 2 • prostate : 9 • colon-rectum : 5

  8. No previous use of anti-TNF in 21% of RA patients % 32.6% 23.3% 21.5% 22.6% 2 anti- TNF 3 anti-TNF 0 anti-TNF 1 anti-TNF In patients without any previous anti-TNF : counter-indication in 82% of patients

  9. RA: diseaseactivitybefore RTX Age: 57.7 ± 12.6 years (women: 80%) Mean disease duration: 13.8 ± 9.4 years RF+ : 73.8 % Mean number of previous DMARDs: 3.2 ± 1.4 Mean DAS28 (data available in 81.1% of patients): 5.7 ± 1.2 Corticosteroidintake : 80.3% of patients Mean prednisone : 12.4 ± 9.7 mg/day

  10. Monotherapy with RTX in 33% of patients Monotherapy with RTX : 33.5 % Concomitant IS: 66.5 % including Methotrexate : 76.5 % Leflunomide : 11.5 % Hydroxychloroquine : 1.9 % AZA: 2.3% CPH : 0.9% Other /association of DMARDs : 6.9%

  11. RA : follow-up • 1072 (80.4%) patients had at least 1 follow-up visit • Mean follow-up : 57 weeks • Total : 1175 patients/year

  12. RA : tolerance 213 infusion reactions (24 severe) on 1333 patients 5 deaths (2 infections, 3 cancers) 10 DVT, 3 pulmonary embolisms 16 cancers : 1.3 / 100 patients / year

  13. Severe infections in AIR registry 77 severe infections (69 patients) : 6.5 / 100 patients/year DANCER : 5.9 / 100 patients / year REFLEX : 5.2 / 100 patients / year SERENE : 1.9-2.6 / 100 patients / year MIRROR : 2.4-4.7 / 100 patients / year

  14. Baseline predictive factors of severe infections (preliminary results) Similar incidence of severe infections in patients whether or not they received no, 1, 2 or 3 anti-TNF prior to rituximab Only baseline parameter associated with severe infections : older age 62.9 ± 10.5 years vs 57.3 ± 12.7 years, p= 0.0001

  15. Efficacy (EULAR response at 6 months) AIR (441 patients) REFLEX (308 patients) EULAR response (%) Moderate No Moderate 45,4% No 40,8% 35% Good Good 15%

  16. Predictive factors of efficacy (preliminary results) No difference in efficacy regarding past use of TNF inhibitors

  17. Predictive factors of efficacy 58,5% RF + are responders vs 47,6% RF - p= 0.016 57.8% anti-CCP + are responders vs 50.2%, p= 0.08 Baseline DAS28 (ESR) responders vs non responders: 5.92 ± 1.1 vs 5.56 ± 1.2, p= 0.0005

  18. Use of TNF inhibitors after rituximab : safety and restoration of efficacy ? 24 patients received a TNF inhibitor after RTX 11 etanercept; 7 infliximab; 6 adalimumab, mean DAS28 of 6.1 (4.3–7.8) Mean time between rituximab and TNF inhibitor : 5.2 (3–9) months After 3 months, 83% of patients had achieved a EULAR good or moderate response After 6 months, 16 of 21 (73%) evaluated patients had a EULAR good or moderate response Combe B, et al. French Society of Rheumatology 2008

  19. Conclusion In real life, comparable safety and efficacy of rituximab after 1 TNF inhibitor or after 2 or more Safety and possible restoration of efficacy by reintroduction of TNF inhibitors (immunological reset ?)

  20. Hoping that no concerns remain ! • Clinicians afraid of long term B cell depletion • Clinicians may not trust safety data from clinical trials as it excludes patients with comorbidities • What to do next in case of failure?

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