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Dr. X. Baraliakos Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Germany

Anti-TNF therapy in ankylosing spondylitis - Clinical and structural outcomes -. Dr. X. Baraliakos Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Germany. Ankylosing spondylitis: a chronic inflammatory rheumatic disease leading to high clinical impairment. 24 years.

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Dr. X. Baraliakos Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Germany

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  1. Anti-TNF therapy in ankylosing spondylitis - Clinical and structural outcomes - Dr. X. Baraliakos Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Germany

  2. Ankylosing spondylitis: a chronic inflammatory rheumatic disease leading to high clinical impairment 24 years • Involvement of axial skeleton, entheses, perhipheral joints and other organs (e.g. eyes) • Main clinical symptom: inflammatory back pain • 1/3 of patients with severe clinical course • High prevalence (0.5%) • Strong association with HLA-B27 • Late delay of diagnosis (5-7 years) • Decreased QoL • High risk of sick leave • Increased direct / indirect costs AS 49 years Braun J, Sieper J. Lancet 2007

  3. InflammationdrivenbyTNFa in AS Detection of TNF α mRNA in thebonemarrow of inflammedsacroiliacjoints • mRNABraun J et al.Arthritis Rheum 1995; 38: 499 • proteinBraun J et al.Ann Rheum Dis 2000; 59S: 85 • bone marrowFrancois R et al.Ann Rheum Dis 2005

  4. NSAIDs areefficaciousin AS within 24 hours ! Amor B, et al. Rev Rheum Engl Ed 1995;62:10–5 Van der Heijde, et al. Arthritis Rheum 2005;52:1205–15

  5. Many AS patients are refractory to NSAIDs % Patients 42% 29% Clinical trials*n = 462 OASIS†n = 209 *Patients after 6 weeks of treatment with an active NSAID †Epidemiological study = systematic recruitment of consecutive patients in daily practice

  6. Sulfasalazine in early SpA Disease activity in SpA patients with inflammatory back pain, with vs. without peripheral arthritis BASDAI BASDAI IBP+, Peripheral arthritis - IBP+, Peripheral arthritis + IBP+, Peripheral arthritis - p = 0.027 p = 0.3 IBP+, Peripheral arthritis + at 6 months at baseline at 6 months at baseline Placebo (n = 118) Sulfasalazine (n = 112) Braun J, Baraliakos X et al. Ann Rheum Dis 2006 Sep;65(9):1147-53

  7. ASAS/EULAR recommendations for the management of AS Education, exercise, physical therapy, rehabilitation, patient associations, self help groups NSAIDs Ana l ges i cs Peripheral disease Axial disease Su r ge r y Sulfasalazine Local corticosteroids TNF blockers Zochling J et al. Ann Rheum Dis 2006 Apr;65(4):442-52

  8. TNF Antagonists – a mile stone in the history of treatment of the (spondylo)arthritides Physikalische und pharmakologische Eigenschaften

  9. Anti-TNF therapy in AS- clinicaldata Short-term data: Baseline - 6 months

  10. The pilot study: infliximab in AS– open continuation phase Infusions given according to disease activity (BASDAI) Brandt J et al. Arthritis Rheum 2000; 43(6):1346

  11. Anti-TNF therapy in AS: Most patients achieve at least a 50% reduction of disease activity 2 6 12 weeks Braun J et al. Lancet 2002; 359:1187-93

  12. Significant improvement of function and spinal mobility Braun J et al. Lancet 2002; 359:1187-93

  13. Early experiences with etanercept in AS Improvement of disease activity (BASDAI) n=30 ETN treatment in ETN group ETN treatment in Placebo group p = 0.003 Brandt J et al. Arthritis Rheum 2003; 48: 1667

  14. Approval of etanercept for AS ASAS 20 Response Weeks 12 and 24 *P < 0.0001 Patients Responding (%) Davis JC, Arthritis Rheum 2003; 8: 3230-3236

  15. Etanercept treatment in ASReduction of acute phase reactants Etanercept 2 x 25 mg/Wk (n=138) Placebo (n=139) BSG (mm/h) Mittlere Änderung gegenüber dem Ausgangswert in % Mittlere Änderung gegenüber dem Ausgangswert in % CRP (mg/dl) † p < 0,0001 † p < 0,0001 † † † † † † Week 2 Month 6 Month 3 Week 2 Month 6 Month 3 Davis JC, Arthritis Rheum 2003; 8: 3230-3236

  16. Efficacy of Adalimumab in patients with AS – The ATLAS Trial – *** *** *** *** *** *** Week 24 Week 12 van der Heijde D, Arthritis Rheum, 2006. 54(7): 2136-2146 ***Statistically significant at p<0.001 level (ANCOVA)

  17. Adalimumab1 Etanercept2 * Pbon=107 Ada 40 mg eown=208 Pbo n=139 Etan 25 mg BIWn=138 Infliximab Golimumab * * * Pbon=78 Ifx 5 mg/kgn=201 Pbon=75 Glm 50 mgn=130 Glm 100 mgn=138 ASAS 40 Response at Week 24 in Trials of Biologics for AS 1van der Heijde D, et al. Arthritis Rheum. 2006;54:2136-2146; 2Davis JC, et al. Arthritis Rheum. 2003;48:3230-3236; 3van der Heijde D, et al. Arthritis Rheum. 2005;52:582-591. * P <.001 vs placebo

  18. Anti-TNF therapy in AS- clinical data Long-term follow-up: 6 months – 8 years

  19. Patients with BASDAI 50% Response after 3 years of infliximab treatment Placebo-controlled phase Open phase Braun J, Rheumatology 2005. 44(5):670-6

  20. Continuous improvement of spinal mobility and function over 3 years Placebo-controlled phase Placebo controlled phase Open phase Open Phase Mean BASMI Mean BASFI Braun J, Rheumatology 2005. 44(5):670-6

  21. Anti-TNFα therapy in patients with ASResults after 8 years Infliximab Baraliakos X, EULAR 2009, Copenhagen

  22. Anti-TNFα therapy in patients with ASResults after 6 years Etanercept Baraliakos X, EULAR 2009, Copenhagen

  23. Anti-TNFα therapy in patients with ASResults after 6 years Etanercept 35.1% 33.3% Baraliakos X, EULAR 2009, Copenhagen

  24. Efficacy of Adalimumab in patientswith AS – long-termdatafromthe ATLAS Trial 2 years 3 years vd Heijde D et al, Ann Rheum Dis2008 vd. Heijde D, Arthritis Res Ther 2009, 11:R124

  25. Golimumab - ASAS Partial Remission after 104 weeks Placebo/ Golimumab 50mg (n = 78) Golimumab 50 mg(n = 138) Golimumab 100 mg(n = 140) GO-RAISE Anteil Patienten (%) Braun J. et al. ACR 2009, Abstract 1259 Braun J et al, ACR 2009, Abstract 1259

  26. Placebo/ Golimumab 50mg (n = 78) Golimumab 50 mg(n = 138) Golimumab 100 mg(n = 140) GO-RAISE Golimumab – ASAS 40 Response after 104 weeks Anteil Patienten (%) Braun J. et al. ACR 2009, Abstract 1259 Braun J et al, ACR 2009, Abstract 1259

  27. Discontinuationof anti-TNF- treatment Anti-TNF therapy in AS- clinical data

  28. Design of studies • Withdrawal of biologic in all patients • Regular visits to assess clinical relapse (BASDAI > 4 and PhysGA > 4) • Retreatment with same dosis • Assessment of clinical parameters ETN: Brandt J et al. Arthritis Rheum 2003; 48: 1667 Baraliakos X et al, Arthritis Rheum 2005 (53): 856-863 INF: Baraliakos X et al, Arthritis Res Ther 2005. 7(3): R439-44

  29. Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions Infliximab withdrawal Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44

  30. Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions Infliximab withdrawal Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44

  31. Clinically successful readministration of infliximab after withdrawal in all patients without infusion reactions Infliximab withdrawal Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44

  32. BASDAI 50%, ASAS 40% response and partial remission after infliximab readministration Infliximab withdrawal after infliximab readministration Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44

  33. Duration of response after withdrawal mean time to relapse: 17.5 ± 7.9 weeks (range 7 – 45 wk, median 15 wk)

  34. Correlation between disease activity (BASDAI) and response to withdrawal 100% 100% (p=0.039) (p=0.039) 80% 80% 60% 60% 40% 40% 20% 20% 0% 0% 0 0 6 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48 time to relapse (weeks) time to relapse (weeks) pts. with BASDAI < 3 pts. with BASDAI < 3 pts. with BASDAI >= 3 pts. with BASDAI >= 3 100% (p=0.039) 80% 60% 40% 20% 0% 0 6 12 18 24 30 36 42 48 Kaplan-Meier Analysis Log rank test pts. with BASDAI < 3 pts. with BASDAI >= 3 Baraliakos X, Arthritis Res Ther 2005. 7(3): R439-44

  35. Response to retreatment • Clear improvement of signs and symptoms • Disease status similar to before withdrawal • No adverse event, no other safety concern after resumption of etanercept and infliximab therapy ETN: Brandt J et al. Rheumatology (Oxford). 2005 Mar;44(3):342-8. Baraliakos X et al, Arthritis Rheum 2005 (53): 856-863 INF: Baraliakos X et al, Arthritis Res Ther 2005. 7(3): R439-44

  36. Anti-TNF therapy in AS- clinicaldata Additional data

  37. Anti-TNFα in AS Patientswithtotal spinal ankylosis– Data fromthe ATLAS Trial – • Total spinal ankylosis (TSA) represents end-stage fusion of the spine in patients (pts) with ankylosing spondylitis (AS) • It is not uncommon for pts who already have TSA to still have symptoms of active disease. vd Heijde et al, Ann Rheum Dis 2008;67:1218-1221

  38. Anti-TNFα in AS Patientswithtotal spinal ankylosis– Data fromthe ATLAS Trial – • Total spinal ankylosis (TSA) represents end-stage fusion of the spine in patients (pts) with ankylosing spondylitis (AS) • It is not uncommon for pts who already have TSA to still have symptoms of active disease. vd Heijde et al, Ann Rheum Dis 2008;67:1218-1221

  39. Etanercept25mg/week- effectivein somepatientswithactive AS Berthelot J, Joint Bone Spine 74 (2007); 144-147 n = 21 n = 20

  40. Improvement of key disease parameters by 3 mg/kg Infliximab Maksymowych WP et al., J Rheumatol 2002; 29:959-65

  41. Infliximab every 6 w. vs on demand therapy- response after 54 weeks:continuous treatment is superior % 75% 46% 27% 7% Breban M et al, Arthritis Rheum 2008 (58):88-97

  42. Addition of MTX to infliximab in patients with ankylosing spondylitis – response after 54 weeks:almost no difference % 10% 40% 5% 51% Breban M et al, Arthritis Rheum 2008 (58):88-97

  43. Evidence for different types of response to anti-TNF treatment in AS Three groups of patients according to level and degree of response after 5 years of infliximab treatment: Group A: remission at most time points (> 20/25 visits) Group B: low disease activity (BASDAI < 3) (> 20/25 visits) Group C: limited improvement, not fulfilling ASAS 20 at all time points, BASDAI > 4 at some time points Differences between groups: mean age (< / > 40 yrs, mean disease duration (< / > 10 yrs, mean BASFI at BL < / > 5) Braun J, Baraliakos X et al, in press

  44. Switching anti-TNF therapy in SpA infliximab toetanercept • patients with SpA n = 15 • 11 female, 4 male, mean age 43 • AS (n = 7) • uSpA (n = 6) • PsA (n = 2) • predominat axial involvement (n=13) • mean time of treatment with infliximab 11 months • inadequate response or loss of response (n=11) • side effects (n=5) • after 9 months 9/13 patients responded Delaunay C et al. J Rheumatol 2005

  45. Which AS patientsshouldbetreatedwith TNF-blockers?

  46. ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis Diagnosis of AS 2 NSAIDs within3 m. Non-respondersto NSAIDs Increaseddiseaseactivity BASDAI > 4 + Positive expert‘sopinion Braun J, Ann Rheum Dis 2003, 62: 817-24 Braun J, Ann Rheum Dis 2006, 65: 201-8

  47. Positive expert‘sopinion:based on objectivesigns of inflammation • Clinical examination/Patient‘sclinicalhistory • Pos. CRP/ESR • Pos. MRI • Radiographicprogression

  48. ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis Start of therapywith TNF-blockers Improvement after 3 months BASDAI-Improvement> 50% or BASDAI-Improvement> 2 (0-10) + Pos. expert´sopition Braun J, Ann Rheum Dis 2003, 62: 817-24 Braun J, Ann Rheum Dis 2006, 65: 201-8

  49. Safetydata– Infliximab – Braun J, Baraliakos X et al, Ann Rheum Dis. 2008 March 1, 2008;67(3):340-5

  50. Anti-TNF therapy in AS Imaging

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