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

Ankylosing spondylitis: a chronic inflammatory rheumatic disease leading to high clinical impairment 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 24 years AS 49 years Braun J, Sieper J. Lancet 2007

Inflammation driven by TNFa in AS Detection of TNF α mRNA in the bone marrow of inflammed sacroiliac joints mRNA Braun J et al. Arthritis Rheum 1995; 38: 499 protein Braun J et al. Ann Rheum Dis 2000; 59S: 85 bone marrow Francois R et al. Ann Rheum Dis 2005

NSAIDs are efficacious in 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 4

Many AS patients are refractory to NSAIDs 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 5

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 baseline at 6 months at baseline at 6 months Sulfasalazine (n = 112) Placebo (n = 118) Braun J, Baraliakos X et al. Ann Rheum Dis 2006 Sep;65(9):1147-53

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

human/murine chimerik mAb TNF Antagonists – a mile stone in the history of treatment of the (spondylo)arthritides Physikalische und pharmakologische Eigenschaften Infliximab Etanercept Adalimumab Golimumab Design human/murine chimerik mAb human TNF-Receptor/ Fc-Fusionsprotein recombinant human mAb Structure Applic.-frequency 1 x / 6 weeks 1 -2 x / week 1 x / 2 weeks 1 x / month Half-elimin. time 8–10 d ca. 3 d ca. 2 wks ca. 12 d

Anti-TNF therapy in AS - clinical data Short-term data: Baseline - 6 months

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

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

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

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 Phase III Brandt J et al. Arthritis Rheum 2003; 48: 1667

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

Etanercept treatment in AS Reduction of acute phase reactants BSG (mm/h) Etanercept 2 x 25 mg/Wk (n=138) Placebo (n=139) Mittlere Änderung gegenüber dem Ausgangswert in % CRP (mg/dl) Mittlere Änderung gegenüber dem Ausgangswert in % † p < 0,0001 † p < 0,0001 Hauptaussage: Die Konzentrationen der Akute-Phase-Parameter hatten bei den Patienten der Enbrel® (Etanercept)-Gruppe nach zweiwöchiger Therapie signifikant abgenommen, verglichen mit einem deutlichen Anstieg unter Placebo. In der Grafik bedeuten Werte unter Null eine Besserung.1 Der mediane CRP-Wert der mit Etanercept behandelten Patienten hatte sich nach 6 Monaten von 1,1 mg/dl auf 0,3 mg/dl gebessert.1 Die mediane BSG der Patienten unter Etanercept war nach 6 Monaten von 23,0 mm/h auf 7,0 mm/h gefallen.1 In der Etanercept-Gruppe wiesen zu Beginn der Studie 46 % der Patienten und nach 6 Monaten 83 % der Patienten BSG-Werte innerhalb des Referenzbereichs auf.1 1 Davis JC, et al. Arthritis Rheum 2003; 48:3230-3236 † † † † † † Week 2 Month 3 Month 6 Week 2 Month 3 Month 6 Davis JC, Arthritis Rheum 2003; 8: 3230-3236

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

ASAS 40 Response at Week 24 in Trials of Biologics for AS Pbo n=107 Ada 40 mg eow n=208 Pbo n=139 Etan 25 mg BIW n=138 Adalimumab1 Etanercept2 Pbo n=78 Ifx 5 mg/kg n=201 Pbo n=75 Glm 50 mg n=130 Glm 100 mg n=138 Infliximab Golimumab * * P <.001 vs placebo 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.

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

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

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

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

Anti-TNFα therapy in patients with AS Results after 6 years Etanercept Baraliakos X, EULAR 2009, Copenhagen

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

Efficacy of Adalimumab in patients with AS – long-term data from the ATLAS Trial 2 years 3 years vd Heijde D et al, Ann Rheum Dis 2008 vd. Heijde D, Arthritis Res Ther 2009, 11:R124

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

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

Discontinuation of anti-TNF- treatment Anti-TNF therapy in AS - clinical data Discontinuation of anti-TNF- treatment

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

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

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

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

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

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

Correlation between disease activity (BASDAI) and response to withdrawal TtR (weeks) 95 % CI (weeks) Patients with low BASDAI (< 3) 18.9 15.4 – 18.9 Patients with high BASDAI (≥3) 14.8 10.0 – 19.6 (p=0.039) 6 12 18 24 30 36 42 48 time to relapse (weeks) 0% 20% 40% 60% 80% 100% pts. with BASDAI < 3 pts. with BASDAI >= 3 (p=0.039) 6 12 18 24 30 36 42 48 time to relapse (weeks) 0% 20% 40% 60% 80% 100% pts. with BASDAI < 3 pts. with BASDAI >= 3 100% (p=0.039) 80% 60% 40% 20% 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

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

Anti-TNF therapy in AS - clinical data Additional data

Anti-TNFα in AS Patients with total spinal ankylosis – Data from the 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

Anti-TNFα in AS Patients with total spinal ankylosis – Data from the 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. 1 year follow-up (n=11 with TSA) 2 years (n=8 with TSA) Total ATLAS (2 years follow-up) (n=304) ASAS20 73% 75% 79% ASAS40 36% 63% 67% ASAS 5/6 55% 38% 49% BASDAI50 45% 71% vd Heijde et al, Ann Rheum Dis 2008;67:1218-1221

Etanercept 25mg/week - effective in some patients with active AS Berthelot J, Joint Bone Spine 74 (2007); 144-147

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

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

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

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

Switching anti-TNF therapy in SpA infliximab to etanercept 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

Which AS patients should be treated with TNF-blockers?

ASAS-Consensus Statement TNF-Blockers in ankylosing spondylitis Diagnosis of AS 2 NSAIDs within 3 m. Non-responders to NSAIDs Increased disease activity BASDAI > 4 + Positive expert‘s opinion Braun J, Ann Rheum Dis 2003, 62: 817-24 Braun J, Ann Rheum Dis 2006, 65: 201-8

Positive expert‘s opinion: based on objective signs of inflammation Clinical examination/Patient‘s clinical history Pos. CRP/ESR Pos. MRI Radiographic progression

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

Safety data – Infliximab – Adverse event n=41 pat. Upper respiratory tract infection 10 Infection at any site 6 Gum infection 4 Herpes simplex 3 Dry skin with pruritus 2 Infusion reactions 1 Elevation of liver enzymes Nausea Aphthen Tachycardia Swelling of the fingers Paraesthesia in the forearm region Total 26 Serious adverse events (2 hospitalized injuries, 1 repeated local infection) Braun J, Baraliakos X et al, Ann Rheum Dis. 2008 March 1, 2008;67(3):340-5

Anti-TNF therapy in AS Imaging

T- Cell infiltrates in Sacroiliitis Good Correlation of MRI with histology of SIJ biopsies in AS patients T- Cell infiltrates in Sacroiliitis Bollow M, Ann Rheum Dis 2000; 59(2):135-40 51

Infliximab in AS – 2-year-MRI results Sieper J, Baraliakos X et al. Rheumatology 2005

Spinal MRI during etanercept therapy improvement T2-FS MRI sequence worsening Baraliakos X, Arthritis Rheum. 2005 Apr;52(4):1216-23

STIR MRI of the SIJ after 6 weeks and 24 weeks of etanercept treatment at baseline after 6 weeks after 24 weeks Rudwaleit M, Baraliakos X et al, Ann Rheum Dis. 2005 Sep;64(9):1305-10

The challenge in ankylosing spondylitis: less radiographic progression in continuous vs. on demand users of NSAIDs n = 214 p < 0.02 Wanders A, Arthritis Rheum. 2005 Jun;52(6):1756-65

Radiographic spinal progression after 2 years of treatment with anti-TNF Baseline characteristics TNF antagonists and OASIS (matched) are comparable Etanercept1 OASIS (all) OASIS (matched) n.s. Infliximab2 OASIS (all) OASIS (matched) n.s. Adalimumab3 OASIS (all) OASIS (matched) n.s. Title: 670 - Adalimumab (HUMIRA®) Therapy for Ankylosing Spondylitis Over 2 Years Does Not Demonstrate Inhibition of Radiographic Progression Compared With a Historical Control Group Location: Room 300 Category: 28. Spondylarthropathies and psoriatic arthritis: clinical aspects and treatment Author(s): Désirée van der Heijde1, Robert Landewe1, Walter Maksymowych2, Barbara Weissman 3, David Salonen4, Shaila Ballal5, Fred Holdbrook5, Robert Wong5, Hartmut Kupper6, John Medich5. 1Leiden University Medical Center, Leiden, Netherlands; 2University of Alberta, Edmonton, AB, Canada; 3Brigham and Women’s Hospital, Boston, MA; 4Mount Sinai Hospital, Toronto, ON, Canada; 5Abbott Laboratories, Parsippany, NJ; 6Abbott GmbH & Co. KG, Abbott GmbH & Co. KG, Germany Abstract: Purpose: To evaluate the long-term effects of adalimumab on radiographic progression in patients with active AS. Methods: Radiographs of the lateral cervical and lumbar spine were obtained at baseline and Year 2 from patients in 2 Phase III clinical studies of adalimumab (M03-606 [N=82] and M03-607 [ATLAS, N=315]). Results were compared with baseline and 2-year radiographs of lateral cervical and lumbar spine from a natural history cohort (OASIS) of AS patients naïve to TNF-antagonist therapy. Patients with total spinal ankylosis at baseline were excluded. Radiographs from the OASIS cohort and the 2 adalimumab studies were combined and read in 1 batch by 2 independent assessors (both blinded to origin of cohort, treatment allocation and sequence) using the modified Stoke AS Spinal Score (mSASSS). Results: Findings for 307 adalimumab patients who had radiographs at baseline and Year 2 were compared with 169 controls from the OASIS cohort. Patients in this combined analysis were primarily male (76% for the adalimumab studies and 69% for OASIS), with a mean age of approximately 42 years for both groups. Baseline disease activity as measured by the Patient Global Assessment of Disease Activity and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was greater for adalimumab patients than for OASIS participants, but baseline mSASSS scores were comparable between groups. NSAID use was slightly greater (88%) for adalimumab patients than OASIS patients (77%). After 2 years of therapy, there was no statistically significant difference in the mean change in mSASSS for adalimumab patients vs. OASIS cohort control patients (0.8, standard error [SE]=0.16 vs. 0.9, SE=0.22, respectively; p=0.771). When only OASIS controls with baseline disease characteristics comparable to those enrolled in the adalimumab trials (n=77) were compared with the adalimumab -treated patients, the mean changes in mSASSS after 2 years for adalimumab-treated patients and OASIS cohort participants were 0.8, (SE=0.17) and 0.9 (SE=0.33), respectively (p = 0.744). Conclusions: Despite providing substantial and significant improvements in clinical efficacy, adalimumab therapy did not lead to inhibition of radiographic progression in AS patients treated for 2 years. These findings are comparable to what has been observed for both etanercept and infliximab in AS.1,2 1van der Heijde D, et al. Ann Rheum Dis. 2006;65(Suppl II):81. 2van der Heijde D, et al. Ann Rheum Dis . 2007 1van der Heijde et al. Arthritis Rheum 2008; 58: 1324-1331 2 van der Heijde et al. Arthritis Rheum 2008; 58: 3063-3070 3van der Heijde et al. ACR 2008 Abstract 670

Radiographic progression in AS after 4 years treatment with the anti-TNF-a antibody infliximab Baraliakos X et al, Rheumatology, 2007;46(9):1450-3 57

The long-term radiographic progression in AS Linear mean radiographic progression Retrospective evaluation FU = 13 years n = 146 Baraliakos X et al, J Rheumatol 2009 May;36(5):997-1002 58

No Syndesmophytes at baseline (n=59) Syndesmophytes at baseline (n=59) Higher risk of radiographic progression with syndesmophytes at baseline after 2 years Change in scoring units (mSASSS) p <0.05 No Syndesmophytes at baseline (n=59) All patients (n=116) Syndesmophytes at baseline (n=59) Baraliakos X, Ann Rheum Dis 2007 Jul;66(7):910-5

Anti-TNF therapy in AS Future perspectives

Efficacy of Infliximab in Patients with HLA-B27+ Very Early AS Diagnosis: Inflammatory back pain RCT: 16 weeks (n=40) Primary endpoints: change in MRI scores from baseline to week 16 Patients with spinal lesions resolved 50 100 % of patients 60% 25% NS 3/5 1/4 n=9 pts with BL spinal lesions IFX (n=20) 62.7% 29.4% P=0.001 50 100 % of lesions resolving 47/75 20/68 Sacroiliac MRI lesions resolving PBO (n=20) New sacroiliac MRI lesions 100 P=0.004 % new lesions 50 12% 1.2% Title: A Randomised Controlled Trial of Infliximab shows clinical and MRI efficacy in patients with HLA B27 positive very early ankylosing spondylitis Category: 28. Spondylarthropathies and psoriatic arthritis: clinical aspects and treatment Presentation Number: L11 Author(s): Nick Barkham, Helen Keen, Laura Coates, Phil O'Connor, Elizabeth Hensor, Alexander Fraser, Lorna Cawkwell, Dennis McGonagle, Paul Emery. University of Leeds, Leeds, United Kingdom PURPOSE: Untreated, patients with inflammatory back pain, HLA B27 and positive MRI would progress to ankylosing spondylitis in more than 90% of cases. Current diagnosis of AS relies on plain film sacroiliitis, which can take 10 years to develop. TNF alpha blocking agents have revolutionized the treatment of established ankylosing spondylitis. The benefits of treatment of AS in the preradiographic phase have not been established. The objective of this study was to assess the infliximab-induced changes of the spine and sacroiliac joints. METHOD: Patients with inflammatory back pain by Calin criteria who were HLA B27 positive underwent MRI scanning of the spine and sacroiliac joints. 40 patients within 3 years of onset of symptoms were recruited if oedema could be detected at the sacroiliac joints. In double-blinded, placebo-controlled fashion, patients were randomized equally to infusions of placebo or infliximab 5 mg/kg at 0, 2, 6 and 12 weeks. Concomitant NSAIDS at a stable dose was permitted for the duration of the study. MRI scans of the spine and sacroiliac joints (subdivided into 8 regions) were performed at baseline and at 16 weeks. Two assessors who were blinded to treatment and orderek read T1 and fat-suppressed T2 MRIs. Paired scoring was performed for each lesion using a semi-quantitative scale. The primary endpoint was change in MRI score from baseline to week 16. Clinical assessments were included as secondary endpoints. RESULTS: Forty of 49 patients with early inflammatory back pain and HLA B27 had bone oedema on MRI and were randomised. Twenty patients received infliximab, 20 placebo. The mean age was 28.8 years (SD 7.5), mean symptom duration was 15.3 months (SD 8.8), NSAID use was 90%, and 75% of patients were male. There were no statistically significant differences between the baseline characteristics of the 2 groups. Primary and secondary endpoints are described in the table. Compared to the placebo group, significant improvements in MRI and clinical endpoints were observed in the infliximab group. Overall, infliximab was well tolerated, and no patients discontinued due to adverse events. Table of Contents Parameters All patients Infliximab Placebo P-value (baseline) (change from baseline) (change from baseline) Primary endpoints Total MRI score of sacroiliac joints, mean (95% CI) 5.1 -2.0 (-6.25 -0) 0(-2 - 1.5) 0.033† Patients with spinal lesions, N (%) 9 (22.5%) 3/5 resolved (60%) 1/4 resolved (25%) Sacro-iliac MRI lesions resolving, N (%) - 47 (62.7) 20(29.4) 0.001† New SI lesions on MRI, N (%) - 1(1.2) 11 (12) 0.004† Secondary endpoints HAQ, median (IQR) 0.88 (0.5-1.25) -0.44 (-0.93 to -0.13) -0.13 (-0.38 to 0.00) 0.065 ASQoL, median (IQR) 10.5 (8.0-13.0) -6.18 (-10.0 to -2.25) -1.00 (-4.50 to 0.75) 0.009† BASFI, mean (SD) 4.26 (1.71) -2.70 (2.36) -0.47 (2.25) 0.004† *BASDAI, mean (SD) 5.81 (1.46) -3.41 (2.53) -0.75 (2.42) 0.002† *BASDAI50, N (%) - 12 (60.0) 3 (15) 0.006† **ASAS partial remission, N (%) - 10 (55.6) 2 (10) 0.009† **ASAS20, N (%) - 14 (77.8) 5 (31.3) 0.006† **ASAS50, N (%) - 11 (61.1) 3 (18.8) 0.012† **ASAS70, N (%) 10 (55.6) 2 (12.5) 0.009† * N=38 (P=18, I=20), **N = 34 (P=16, I=18) SUMMARY: Infliximab appears to be an effective therapy for very early inflammatory back pain by providing a rapid reduction in disease activity on MRI and measures of clinical efficacy. This is the first therapy to show suppression of the inflammatory lesions on MRI in very early ankylosing spondylitis. Further research should establish whether the effect of infliximab on bone oedema would also halt ankylosis. Disclosures:  N. Barkham, Centocor; H. Keen, Centocor; L. Coates, Centocor; P. O'Connor, None; E. Hensor, None; A. Fraser, None; L. Cawkwell, None; D. McGonagle, None; P. Emery, Centocor. Secondary endpoints 25 50 75 100 ASAS50 partial remission PBO (n=16) IFX (n=18) % of patients 12.5 55.6 P=0.009 61.1 18.8 P=0.012 Baseline values Age (yrs)*: 28.8 Symptom duration (months)*: 15.3 % male pts: 75 % HLA-B27+ pts: 100 Barkham N, Arthritis Rheum 2009 Apr;60(4):946-54 61 61

Adalimumab reduces SIJ inflammation in active pre-radiographic active axial SpA Baseline: 84% of patients with active sacroiliitis in MRI but no sacroiliitis on x-rays RCT: 12 weeks (n=19) OLE: 52 weeks (n=28) p>0.05 p>0.05 p=0.003 p=0.004 Mean SI Joint Score (MRI) SAT0266 ADALIMUMAB REDUCES INFLAMMATION IN THE SACROILIAC JOINTS OF PATIENTS WITH ACTIVE SPONDYLOARTHRITIS WITHOUT RADIOGRAPHIC SACROILIITIS — RESULTS OF A PLACEBO-CONTROLLED, DOUBLE-BLIND CLINICAL TRIAL THROUGH 52 WEEKS H. Haibel1, X. Baraliakos2, M. Rudwaleit1, J. Listing3, R. Wong4, H. Kupper5, J. Braun2, J. Sieper*1 1Charité, University Medicine Berlin, Berlin, 2, Centre of Rheumatology, Herne, 3, German Rheumatism Research Centre, Berlin, Germany, 4, Abbott Laboratories, Parsippany, NJ, United States, 5, Abbott GmbH & Co KG, Ludwigshafen, Germany Background: Adalimumab is very effective in improving the signs and symptoms of active axial spondyloarthritis.1 No data are currently available on the course of the active inflammatory lesions in the sacroiliac (SI) joints as detected by magnetic resonance imaging (MRI) in patients with active spondyloarthritis without radiographic sacroiliitis. Objectives: We investigated SI joint inflammation at baseline, Week 12, and Week 52 in patients with active spondyloarthritis without radiographic sacroiliitis who were included in a placebo-controlled, double-blind trial of adalimumab. Methods: MRI investigations were conducted for patients at 2 centers in Germany enrolled in a 12-week, placebo-controlled trial with a 40-week, open-label extension. Adult patients with active SpA (BASDAI ≥4) and insufficient responses to ≥1 prior NSAIDs were included in this study. MRIs of the SI joints were performed at baseline, Week 12 and Week 52. Active inflammation in the SI joints was scored according to Hermann et al.,2 with each SI joint divided into quadrants and with modifications for additional points of intensity for each SI joint (range: 0–34). MRIs were scored independently by 2 readers blinded to time points of the MRIs. Mean scores of the 2 readings were included in the analysis. Results: Of the 37 patients with complete MRI data for the SI joints at baseline, 84% had a SI joint score ≥1; 78% had ≥2, and 24% had a score ≥10 (reflecting extended SI joint inflammation). Of the 19 patients with complete MRI data for baseline and week 12, mean SI joint score changed from 11.8 at baseline to 10.5 (median: 6.5 to 8.5) at Week 12 for the placebo group (n=9) and from 3.9 to 2.5 (median: 3.3 to 1.3) for the adalimumab group (n=10), p>0.05 (not significant) for both groups. Of 28 patients with complete MRI data for baseline and Week 52, the mean SI joint score changed from 10.1 to 4.3 (median: 6 to 2) for the initial placebo group (n=16), p=0.012, and from 4.8 to 3.0 (median: 3.25 to 3) for the adalimumab group (n=12), p>0.05 (not significant). For the pooled group, there was also a significant improvement from 7.9 at baseline to 3.8 (median: 5.3 to 3) at Week 52 (p=0.003). Of the pooled group of patients, 18% had a score of 0 at Week 52, reflecting no inflammation of the SI joints, and 54% had an MRI improvement of >50%. A score of ≥2 at Week 52 was found in 61% of patients. Inter-reader correlations were substantial: 0.88 at baseline, 0.91 at Week 12, and 0.88 at Week 52. Conclusion: Of patients with active axial spondyloarthritis without radiologic sacroiliits in this study, the majority had inflammatory lesions as detected by MRI in the SI joints, and a substantial number of patients also had extensive SI joint inflammation. Adalimumab therapy significantly improved inflammation as observed by MRI for patients treated for 1 year. References: 1Haibel H, et al. Arthritis Rheum. 2008;58:1981-91. 2Hermann KG, et al. Radiologe. 2004;44:217-28. Disclosure of Interest: H. Haibel, Abbott, Scherring Plough, Speakers fees X. Baraliakos, Abbott, Consultant M. Rudwaleit, Abbott, MSD, Schering-Plough, Pfizer, and Wyeth, Consultancies, speaking fees, honoraria J. Listing, Abbott, Consultant R. Wong, Abbott, Employee, stocks H. Kupper, Abbott, Employee, stocks J. Braun, Abbott, Schering-Plough, Wyeth, Centocor, Amgen, Reiumbursements, fees, grant J. Sieper, Abbott, Schering-Plough, Wyeth, Research grants, Abbott, BMS, Roche, Schering-Plough, Wyeth, Consulting fees or other remuneration, Abbott, Roche, Pfizer, Scheering-Plough, Wyeth, Speakers bureau ADA therapy significantly improved inflammation as observed by MRI for patients treated for 1 year Haibel H. EULAR 2009 SAT0266

Adalimumab reduces SIJ inflammation in active pre-radiographic active axial SpA Baseline SAT0266 ADALIMUMAB REDUCES INFLAMMATION IN THE SACROILIAC JOINTS OF PATIENTS WITH ACTIVE SPONDYLOARTHRITIS WITHOUT RADIOGRAPHIC SACROILIITIS — RESULTS OF A PLACEBO-CONTROLLED, DOUBLE-BLIND CLINICAL TRIAL THROUGH 52 WEEKS H. Haibel1, X. Baraliakos2, M. Rudwaleit1, J. Listing3, R. Wong4, H. Kupper5, J. Braun2, J. Sieper*1 1Charité, University Medicine Berlin, Berlin, 2, Centre of Rheumatology, Herne, 3, German Rheumatism Research Centre, Berlin, Germany, 4, Abbott Laboratories, Parsippany, NJ, United States, 5, Abbott GmbH & Co KG, Ludwigshafen, Germany Background: Adalimumab is very effective in improving the signs and symptoms of active axial spondyloarthritis.1 No data are currently available on the course of the active inflammatory lesions in the sacroiliac (SI) joints as detected by magnetic resonance imaging (MRI) in patients with active spondyloarthritis without radiographic sacroiliitis. Objectives: We investigated SI joint inflammation at baseline, Week 12, and Week 52 in patients with active spondyloarthritis without radiographic sacroiliitis who were included in a placebo-controlled, double-blind trial of adalimumab. Methods: MRI investigations were conducted for patients at 2 centers in Germany enrolled in a 12-week, placebo-controlled trial with a 40-week, open-label extension. Adult patients with active SpA (BASDAI ≥4) and insufficient responses to ≥1 prior NSAIDs were included in this study. MRIs of the SI joints were performed at baseline, Week 12 and Week 52. Active inflammation in the SI joints was scored according to Hermann et al.,2 with each SI joint divided into quadrants and with modifications for additional points of intensity for each SI joint (range: 0–34). MRIs were scored independently by 2 readers blinded to time points of the MRIs. Mean scores of the 2 readings were included in the analysis. Results: Of the 37 patients with complete MRI data for the SI joints at baseline, 84% had a SI joint score ≥1; 78% had ≥2, and 24% had a score ≥10 (reflecting extended SI joint inflammation). Of the 19 patients with complete MRI data for baseline and week 12, mean SI joint score changed from 11.8 at baseline to 10.5 (median: 6.5 to 8.5) at Week 12 for the placebo group (n=9) and from 3.9 to 2.5 (median: 3.3 to 1.3) for the adalimumab group (n=10), p>0.05 (not significant) for both groups. Of 28 patients with complete MRI data for baseline and Week 52, the mean SI joint score changed from 10.1 to 4.3 (median: 6 to 2) for the initial placebo group (n=16), p=0.012, and from 4.8 to 3.0 (median: 3.25 to 3) for the adalimumab group (n=12), p>0.05 (not significant). For the pooled group, there was also a significant improvement from 7.9 at baseline to 3.8 (median: 5.3 to 3) at Week 52 (p=0.003). Of the pooled group of patients, 18% had a score of 0 at Week 52, reflecting no inflammation of the SI joints, and 54% had an MRI improvement of >50%. A score of ≥2 at Week 52 was found in 61% of patients. Inter-reader correlations were substantial: 0.88 at baseline, 0.91 at Week 12, and 0.88 at Week 52. Conclusion: Of patients with active axial spondyloarthritis without radiologic sacroiliits in this study, the majority had inflammatory lesions as detected by MRI in the SI joints, and a substantial number of patients also had extensive SI joint inflammation. Adalimumab therapy significantly improved inflammation as observed by MRI for patients treated for 1 year. References: 1Haibel H, et al. Arthritis Rheum. 2008;58:1981-91. 2Hermann KG, et al. Radiologe. 2004;44:217-28. Disclosure of Interest: H. Haibel, Abbott, Scherring Plough, Speakers fees X. Baraliakos, Abbott, Consultant M. Rudwaleit, Abbott, MSD, Schering-Plough, Pfizer, and Wyeth, Consultancies, speaking fees, honoraria J. Listing, Abbott, Consultant R. Wong, Abbott, Employee, stocks H. Kupper, Abbott, Employee, stocks J. Braun, Abbott, Schering-Plough, Wyeth, Centocor, Amgen, Reiumbursements, fees, grant J. Sieper, Abbott, Schering-Plough, Wyeth, Research grants, Abbott, BMS, Roche, Schering-Plough, Wyeth, Consulting fees or other remuneration, Abbott, Roche, Pfizer, Scheering-Plough, Wyeth, Speakers bureau Week 12 Week 52 Haibel H. EULAR 2009 SAT0266

Extraspinal manifestations Anti-TNF therapy in AS Extraspinal manifestations

Extra-articular Manifestations in AS Patients in Belgian Rheumatology Practices 58% AS 22% Uveitis 2% 6% Psoriasis ok 1% 2% 1% IBD 7% Vander Cruyssen et al. Ann Rheum. Dis 2007; 66(8): 1072-7

Data collection Placebo-controlled studies Infliximab (2 studies) Braun J et al, Lancet, 2002 359 (9313): 1187-93 Van der Heijde et al, Arthritis Rheum, 2005 52(2): 582-91 Etanercept (4 studies) Gorman N et al, Engl J Med, 2002 346 (18): 1349-56 Brandt J et al, Arthritis Rheum, 2003 48 (6): 1667-75 Davis J et al, Arthritis Rheum, 2003 48 (11): 3230-6 Calin A et al, Ann Rheum Dis, 2004 63(12): 1594-600 Adalimumab (2 studies) van der Heijde D et al, . Arthritis Rheum 2006;54(7):2136-2146. Haibel H, Arthritis Rheum 2006;54(2):678-681 Open studies Stone M et al, J Rheumatol, 2001 28(7): 1605-14 Braun J et al, Rheumatology (Oxford) 2005 44(5): 670-6 Baraliakos X et al, Arthritis Rheum, 2005 53(6): 856-63 Davis J et al, Ann Rheum Dis, 2005. 64(11): 1557-62 Braun J et al, Rheumatology (Oxford). 2005 May;44(5):670-6

Acute anterior uveitis in ankylosing spondylitis Prevalence: 30 - 40% Incidence: 10 - 20/100 patient years Clinical presentation: acute, unilateral Prognosis: generally good, some severe Conventional Therapy: corticosteroid eye drops

Incidence of acute anterior uveitis in AS patients on anti-TNF therapy /100 patient years pooled data n = 717 Braun J, Baraliakos X et al, Arthritis Rheum, 2005. 52(8):2447-51

Incidence of anterior uveitis in AS - double-blinded and open-label phases Infliximab: 3.4 flares / 100 patient years (CI: 1.1 – 8.0) Etanercept: 7.9 flares / 100 patient years (CI: 5.5 – 11.1) Placebo: 15.6 flares / 100 patient years (CI: 7.8 – 27.9) Statistical differences between incidences: Placebo vs. anti-TNFα : p = 0.01 Placebo vs. Infliximab: p = 0.005 Placebo vs. Etanercept: p = 0.05 Infliximab vs. Etanercept: p = 0.08 Braun J, Baraliakos X et al, Arthritis Rheum, 2005. 52(8):2447-51

Inflammatory bowel diseases (Crohn‘s disease and ulcerative colitis) in patients with AS Prevalence: 0.3 % Incidence: 10/100.000 / year Clinical appearance: recurrences, flares, periphal symptoms Prognosis: partly severe Conventional Therapy: Corticosteroids, Azathioprine

Low but different incidence of acute inflammatory bowel disease (IBD) in patients on anti-TNF therapy History of IBD in all patients 5.8 % n 2.3/100py (14 cases) 2.3/100py (3 cases) 1.3/100py (2 cases) 0.2/100py (1 case) 9 trials pooled data n = 1130 py = patient years n = 366 n = 419 n = 295 n = 434 INF vs. ETN p < 0.001, INF vs. ADA p = 0.02, ETN vs. ADA p = 1.0 Braun J, Baraliakos X et al, Arthritis Rheum. 2007 May 15;57(4):639-47

Summary Treatment with biologics is efficacious and safe in the long-term in patients with active AS Improvement of clinical, laboratory and imaging assessments of inflammation can be seen even in patients with total spinal ankylosis Discontinuation leads to clinical relapse but retreatment is safe and efficacious

Summary DMARDs do not provide and additional benefit AS patients treated with biologics Switching between biologics is safe and efficacious Choice of biologic compound should be done based on individual needs of patient Effect of biologic treatment on radiographic progression of patients with AS is still unclear

Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Thank you ! Dr. X. Baraliakos Rheumazentrum Ruhrgebiet, Herne Ruhr-University Bochum Germany 74