1. 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

2. 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):

3. 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

4. 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)

5. 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 ( )
2.8 ( )
2.1 ( )
2.3 ( )
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)

6. 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 ( )
5.2 ( )
5.6 ( )
5.2 ( )
0.303
BASFI (0-10)a
5.1 ( )
5.1 ( )
5.0 ( )
3.7 ( )
0.891
ASDAS-CRP a
3.5 ( )
3.5 ( )
3.4 ( )
3.4 ( )
0.743
CRP (mg/dl)
1.5 ( )
1.1 ( )
0.9 ( )
0.6 ( )
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 ( )
5.1 ( )
4.4 ( )
4.7 ( )
HAQ (0-3)b
0.9 ( )
0.8 ( )
0.241
Flouri I, et al. (under revision)

7. 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)

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

9. 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)

10. 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)

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

12. 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 ( )b
0.57 ( )b
TNFi agent used: INF (reference)
1.00 (ref)
ETA
2.67 ( )c
0.52 ( )a
ADA
1.74 ( )a
0.34 ( )b
GOL
3.53 ( )c
0.24 ( )b
Previous csDMARDs (yes)
0.68 ( )a
Methotrexate co-therapy (yes)
0.60 ( )a
Peripheral disease (yes)
1.91 ( )b
VAS global (>60)
1.47 ( )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)

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

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

15. Patients with axial disease
60-70% responders ASDAS innactive or moderate
Months
(* analysis in censored cases)

16. Patients with peripheral disease
6 months months months
(* analysis in censored cases)

17. 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

18. 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 ( )a
0.62 ( )a
0.66 ( )
TNFi agent used (ETA versus MAbs)
1.68 ( )b
1.88 ( )a
Previous csDMARDs (yes)
0.68 ( )b
0.64 ( )a
0.71 ( )
Peripheral disease (yes)
1.47 ( )b
BASDAI-50 (yes)
0.49 ( )c
ASDAS-ID (yes)
0.33 ( )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 ( )c
0.74 ( )
TNFi agent used (ETA versus MAbs)
1.45 ( )a
1.92 ( )b
1.62 ( )a
1.65 ( )a
Methotrexate co-therapy (yes)
0.65 ( )b
0.73 ( )
0.65 ( )a
CRP (>1.2 mg/dl)
0.76 ( )
TJC-28 (>3)
1.32 ( )
1.84 ( )a
1.82 ( )b
1.81 ( )b
DAS28 baseline (>4.5)
0.61 ( )
DAS28-remission (yes)
0.35 ( )c
EULAR-good response (yes)
0.41 ( )c
ACR70 (yes)
0.29 ( )c
a: p<0.05; b: p<0.01; c: p<0.001
Flouri I, et al. (under revision)

19. 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.

20. 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

21. 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