Comparative analysis of TNF-inhibitor survival in spondyloarthritis: data from the Hellenic Registry of Biologic Therapies P Sidiropoulos Rheumatology, Clinical Immunology and Allergy University of Crete, School of Medicine

Hellenic Registry for Biologic Therapies (in patients with chronic inflammatory arthritides) Independent organization (under the auspices of the Hellenic Rheumatology Society) Cooperation with the University of Lund, Sweden Structure Board of directors Investigators: eight Rheumatology Clinics in University & General State hospitals Center for data entry/analysis (University of Crete) Funding: unrestricted grants from pharma industry through the Hellenic Rheumatology Society Flouri I, et al. Semin Arthritis Rheum. 2014; 43(4): 447-57

Standardized evaluation protocol Patients with chronic inflammatory arthritides Data collection: Baseline, q6 months for the first 2 years, yearly thereafter 6 12 Data: Response -- Adverse events 28 joints -- Drugs VAS pain, global Physician’s global ESR, CRP HAQ EuroQuol BASDAI, BASFI

Comparative analysis of TNF-inhibitor survival in SpA: Hellenic Registry of Biologic Therapies Patients (≥18 years old) with a primary diagnosis of SpA (according to the treating physician) Initiating the first TNFi between 1/1/2004 and 31/12/2014 Primary outcomes: 10-year drug adherence (“drug survival”) (explore causes of therapy withdrawal and predictors) Secondary outcomes: drug survival according to the two major sub-diagnoses (AS, PsA) and to the presence of axial or peripheral arthritis relevant predictors Flouri I, et al. (under revision)

Baseline disease characteristics and activity (1077 SpA patients)   AS (n=561) PsA (n=375) uSpA (n=108) IBD-SpA (n=33) p- value Gender (male), N (%) 446 (80) 203 (54) 51 (47) 15 (46) <0.001 Age, years 41 (33-50) 49 (39-59) 41 (33-52) 43 (33-54) TNF inhibitor, N (%) Infliximab 382 (68) 49 (45) 21 (64) Etanercept 81 (14) 89 (24) 27 (25) 3 (9) Adalimumab 87 (16) 64 (17) 24 (22) 9 (27) 0.144 Golimumab 11 (2) 19 (5) 8 (7) 0 (0) 0.005 Follow-up, years 2.9 (1.0-7.3) 2.8 (1.0-5.4) 2.1 (0.7-4.5) 2.3 (0.9-3.9) 0.024 Axial inflammatory arthritis 561 (100) 121 (53) 70 (73) 22 (76) Peripheral arthritis 209 (46) 336 (94) 88 (87) No coadministered csDMARDs 0 (0-1) 1 (1-1) 1 (0-1) Methotrexate 100 (18) 232 (66) 62 (58) 11 (36) Monotherapy 417 (74) 86 (23) 32 (30) 12 (36) Ongoing corticosteroids 24 (5) 61 (17) 25 (24) 5 (16) Flouri I, et al. (under revision)

Baseline disease characteristics and activity (1077 SpA patients)   AS (n=561) PsA (n=375) uSpA (n=108) IBD-SpA (n=33) p- value Disease activity BASDAI (0-10) a 5.1 (3.8-6.4) 5.2 (4.2-6.2) 5.6 (4.3-7.2) 5.2 (4.1-6.9) 0.303 BASFI (0-10)a 5.1 (3.2-7.0) 5.1 (3.4-6.9) 5.0 (3.4-6.6) 3.7 (2.6-6.8) 0.891 ASDAS-CRP a 3.5 (2.8-4.1) 3.5 (2.5-4.1) 3.4 (2.4-4.2) 3.4 (3.0-3.8) 0.743 CRP (mg/dl) 1.5 (0.6-3.0) 1.1 (0.3-2.3) 0.9 (0.3-2.6) 0.6 (0.3-1.1) 0.001 ESR (mm/h) 29 (16-49) 30 (18-48) 25 (13-48) 24 (18-45) 0.545 VAS global (0-100) 60 (50-80) 65 (50-80) 70 (45-80) 70 (60-80) 0.213 VAS pain (0-100) 70 (50-80) 70 (58-80) 0.709 PhGA (0-4) 3 (2-3) 3 (3-3) 3 (2.8-3) Tender joint count 1 (0-3) 5 (2-11) 2 (0-5) 5 (0-11) <0.001 Swollen joint count 0 (0-1) 4 (1-8) 2 (1-4) 2 (0-6) DAS28-ESRb 3.8 (3.1-4.6) 5.1 (4.2-6.2) 4.4 (3.6-5.3) 4.7 (4.0-5.5) HAQ (0-3)b 0.9 (0.5-1.3) 0.8 (0.3-1.1) 0.241 Flouri I, et al. (under revision)

TNF-inhibitor discontinuations in patients with SpA   All (n=1077) AS (n=561) PsA (n=375) uSpA (n=108) IBD-SpA (n=33) % [per 100 patients-year] All discontinuations 38 [9.4] 35 [7.8] 40 [10.9] 49 [13.3] 55 [16.1] Due to inefficacy 43 [4.1] 36 [2.9] 47 [5.1] 55 [7.3] 61 [9.8] Primary inefficacy 21 [1.9] 17 [1.4] 22 [2.3] 36 [4.7] 11 [1.8] Secondary inefficacy 22 [2.2] 19 [1.5] 26 [2.8] 19 [2.5] 50 [8.0] Due to adverse events 39 [3.7] 46 [3.6] 36 [3.9] 26 [3.5] 28 [4.5] Other causes 17 [1.6] 18 [1.9] 87% of the stops occurred within the first 5 years Median time for d/c was 1.6, 1.4 and 1.1 years for AS, PsA and uSpA, respectively AS: ↑ AE-related discontinuations AEs: infusion reactions (n=61), psoriasis-like rash (n=18), malignancy (n=11), TB (n=9), other serious infections (n=8), demyelination (n=4) Flouri I, et al. (under revision)

TNF-inhibitor discontinuations: Adverse Events Flouri I, et al. (under revision)

5- and 10-year retention rates of the first TNFi therapy in SpA are 60% and 49%, respectively Drug survival: AS > PsA > uSpA > IBD-related “Early” divergence (2.5 years): AS > uSpA “Late” divergence (7 years): AS > PsA Flouri I, et al. (under revision)

Time-dependent drug retention according to the specific TNF-inhibitor ≤ 6 months: INF > ETA/ADA > 6 months: ADA > INF > ETA Causes of drug discontinuation Inefficacy: INF < ETA/ADA AE: ETA/ADA < INF Flouri I, et al. (under revision)

Higher TNF-inhibitor survival in patients with isolated axial disease Other predictors Male gender (increased retention) High CRP ( “ “) Flouri I, et al. (under revision)

Predictors of TNF-inhibitor discontinuation in SpA patients (Cox regression analysis) Discontinuations due to inefficacy Discontinuations due to adverse events Adjusted HR Gender (male) 0.60 (0.44-0.82)b 0.57 (0.40-0.81)b TNFi agent used: INF (reference) 1.00 (ref) ETA 2.67 (1.86-3.84)c 0.52 (0.30-0.89)a ADA 1.74 (1.13-2.68)a 0.34 (0.18-0.64)b GOL 3.53 (1.74-7.18)c 0.24 (0.04-1.69)b Previous csDMARDs (yes) 0.68 (0.47-0.99)a Methotrexate co-therapy (yes) 0.60 (0.39-0.91)a Peripheral disease (yes) 1.91 (1.25-2.90)b VAS global (>60) 1.47 (1.03-2.10)a a: p<0.05; b: p<0.01; c: p<0.001 The “protective effect” of MTX was most apparent in male patients and in those with peripheral disease MAbs had greater efficacy-related survival than etanercept in AS/uSpA but not in PsA Flouri I, et al. (under revision)

Predictors of TNF-inhibitor discontinuation in SpA patients (Cox regression analysis) Flouri I, et al. (under revision)

Predictors of TNF-inhibitor discontinuation in SpA patients (Cox regression analysis) Flouri I, et al. (under revision)

Patients with axial disease 60-70% responders ASDAS innactive or moderate Months 0 6 12 18 24 36 48 60 (* analysis in censored cases)

Patients with peripheral disease 6 months 12 months 24 months (* analysis in censored cases)

Does good clinical response predict long-term TNF-inhibitor survival? Axial arthritis Peripheral arthritis BASDAI 50 ASDAS-CRP Inactive Disease DAS28 remission EULAR Good Response ACR70 Response Cox regression analysis adjusting for baseline predictors & clinical response

Clinical response at 12 months is a strong predictor of long-term TNFi retention Αxial inflammatory arthritis (risk for drug discontinuation) Βaseline variables only Βaseline variables plus 1st year BASDAI-50 response Βaseline variables plus 1st year ASDAS-ID response Gender (male) 0.74 (0.56-0.98)a 0.62 (0.40-0.95)a 0.66 (0.43-1.02) TNFi agent used (ETA versus MAbs) 1.68 (1.24-2.28)b 1.88 (1.40-2.53)a Previous csDMARDs (yes) 0.68 (0.52-0.88)b 0.64 (0.42-0.96)a 0.71 (0.48-1.05) Peripheral disease (yes) 1.47 (1.12-1.93)b BASDAI-50 (yes) 0.49 (0.34-0.71)c ASDAS-ID (yes) 0.33 (0.26-0.41)c Peripheral arthritis (risk for drug discontinuation)   Baseline variables only Baseline variables plus 1st year DAS28-remission Baseline variables plus 1st year EULAR good response Baseline variables plus 1st year ACR70 response Gender (male) 0.63 (0.49-0.81)c 0.74 (0.52-1.06) TNFi agent used (ETA versus MAbs) 1.45 (1.09-1.93)a 1.92 (1.21-3.04)b 1.62 (1.05-2.50)a 1.65 (1.06-2.56)a Methotrexate co-therapy (yes) 0.65 (0.51-0.84)b 0.73 (0.50-1.05) 0.65 (0.46-0.93)a CRP (>1.2 mg/dl) 0.76 (0.57-1.02) TJC-28 (>3) 1.32 (1.00-1.75) 1.84 (1.10-3.06)a 1.82 (1.26-2.62)b 1.81 (1.26-2.59)b DAS28 baseline (>4.5) 0.61 (0.36-1.03) DAS28-remission (yes) 0.35 (0.24-0.50)c EULAR-good response (yes) 0.41 (0.29-0.58)c ACR70 (yes) 0.29 (0.21-0.40)c a: p<0.05; b: p<0.01; c: p<0.001 Flouri I, et al. (under revision)

Conclusions – key messages In this analysis of Greek SpA patients treated with the first TNFi, a rather favorable drug survival of 60% and 49% at 5 and 10 years respectively was found. Among the different baseline parameters assessed, having a diagnosis of AS and limited axial phenotype predicted longer drug adherence. The strongest independent predictor for long-term drug survival was achievement of a major response in axial or peripheral disease during the first year.

Limitations cohort design (missing data) No data on extra-articular manifestations No systematic data on HLA-B27 and smoking (possible disease modifiers) Radiographic data were not a prerequisite for patient recruitment

Acknowledgments Irini Flouri Theodora E. Markatseli Kyriaki A. Boki Paraskevi V. Voulgari Ioannis Papadopoulos Loukas Settas Dimitrios Zisopoulos Fotini N. Skopouli Alexios Iliopoulos Pierre Geborek Alexandros A. Drosos Dimitrios T. Boumpas Prodromos Sidiropoulos Medical School, University of Crete Medical School, University of Ioannina Sismanoglio Hospital, Athens General Hospital of Kavala AHEPA Hospital of the Aristotle University Medical School 424 General Army Hospital, Thessaloniki Harokopio University of Athens Veterans Administration Hospital Skȧne University Hospital, Lund, Sweden Supported by the Hellenic Rheumatology Society Funding from Pfarma industry: Abbvie, BMS, MSD, Phizer, Roche