1. MBBS, MMed (Int Med), FAMS (Rheum), FACR, RhMSUS, RMSK
STATE-OF-THE-ARThritis Axial Spondyloarthritis (Ankylosing Spondylitis)
Dr Eugene Lim
Rheumatologist
MBBS, MMed (Int Med), FAMS (Rheum), FACR, RhMSUS, RMSK

2. Content Disease Burden: Does AS Matter?
Pathogenesis: T-helper 17 Pathway
Anti-IL17A Therapy: Cosentyx (Secukinumab)
Diagnosis & Pitfalls
Window-of-Opportunity: Does Treatment Matter?
Treat-to-Target: Preventing Damage & Disability
Metrology: Measuring Disease Activity
ASAS-EULAR Treatment Guideline
Personal Experience & Practice

3. Disease Burden Does AS Matter?
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4. Ankylosing Spondylitis is a progressive painful disease that leads to significant, irreversible bone damage and loss of spinal mobility
Ankylosing Spondylitis affects between 0.1% and 1.4% of the general population globally
Reference:
1. Dean L et al., Rheumatology 2014;53: (Abstract results section)

5. Ankylosing Spondylitis is a progressive painful disease that leads to significant, irreversible bone damage and loss of spinal mobility
A significant proportion of AS patients report problems with sleeping, driving, dressing and getting in and out of chairs, all of which negatively impacts patients’ physical function and QoL
Reference: 1. Dagfinrud H et al., J Rheumatol 2005;32:516–23 (Figure 2)

6. Ankylosing Spondylitis affects mostly young people substantially impacting their quality of life and ability to function
Over half of patients experience disease onset before the age of 30 in the prime of their life significantly impacting patients’ social, working and psychological life
Select measure of interest
Reference:
Feldtkeller E et al., Current Opinion in Rheumatology 2000, 12:239–247 (Table 1)
Kucharz et al., Rheumatol Int. 2013; 33(11): 2899–2901. (Results and Discussion section)
4. Ozgül A et al., Curr Rheumatol Rep Oct;12(5): (Abstract, Table 2)

7. The disease is associated with severe comorbidities and an increased mortality risk
Patients with AS have an increased standardized mortality ratio of up to 87% greater than the general population
Select measure of interest
Reference:
1. Mok C et al., Arthritis & Rheumatism Vol. 63, No. 5, 2011, pp 1182–1189 (Table 2)
2. Kaprove, et al 1980 (Mentioned in GVD not in reference pack)
3. Bakland G et al., Ann Rheum Dis 2011;70:1921–1925. (Table 1)
4. Lehtinen 1993 (Mentioned in GVD not in reference pack)
5. Radford, Doll and Smith 1977 (Mentioned in GVD not in reference pack)

8. The disease is associated with severe comorbidities and an increased mortality risk
Patients with AS have a higher risk of developing serious comorbidities involving the cardiovascular, skeletal, pulmonary, gastrointestinal systems and psychological wellbeing
Reference:
1. Lautermann D et al., Clin Exp Rheumatol 2002; 20 (Suppl. 28) S11-S15 (Page 1 bottom right)
2. Dincer U et al., Tohuko J. Exp. Med., 2007,212, (Abstract)
3. Ghozlani M et al., Bone 44 (2009) 772–776 (Abstract osteoporosis)
4. Montala N et al., J Rheumatol 2011;38:893–7 (Abstract results)
5. Braun J et al., Rheumatol 2002; 20 (Suppl. 28): S16-S22 (page 1 right column)
6. Shen B et al., Rheumatol Int (2013) 33:1429–1435 (Page 4)

9. Pathogenesis T-helper 17 Pathway
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10. HLA-B27 Misfolding and Ankylosing Spondylitis Colbert RA, Tran TM, Layh-Schmitt G. Mol Immunol January 2014, Pages 44-51
HLA-B27 heavy chain misfolding
Inefficient peptide loading
Endoplasmic reticulum associated degradation (ERAD)
ER stress
Unfolded protein response (UPR)
Cytokine activation:
lL-23  Th17 pathway
IFNβ
lL-1α

11. What is Th17/IL17?

12. Th17 Housekeeping & Proinflammatory Roles

13. Pathogenic Th17 drives SpA Pathology1
The natural history of ankylosing spondylitis is characterized by new bone formation in the sacroiliac joint and spine2
1. Lories RJ, McInnes IB. Nature Medicine 2012;18:1018–19; 2. Louie GH, Ward MM. Curr Opin Rheumatol. 2014;26:145–50

14. Anti-Interleukin 17A Therapy Cosentyx (Secukinumab)

15. A fully human IgG1k monoclonal antibody targeting IL17A
What is Secukinumab?
A fully human IgG1k monoclonal antibody targeting IL17A

16. ASAS Working Group Criteria for Response & Partial Remission
ASAS 20 Working Criteria
Improvement of ≥ 20% and absolute improvement of ≥ 10 units on a 0 to 100 scale in ≥3 of the following domains:
Patient Global Assessment (VAS global)
Pain Assessment (VAS global + nocturnal pain)
Function (BASFI)
Inflammation (2 BASDAI morning stiffness questions)
Absence of deterioration in potential remaining domain
Partial Remission Criteria
Value of ≤ 20 in each of the four domains
Andersen JJ et al, Arthritis Rheum, 2001: 44 –
Public

17. Subjects Achieving ASAS20 Response (%)
Effect of TNF & IL17A Inhibitors on ASAS20 Responses (Anti–TNF-naïve Subjects)
ASAS20 response rates at Week 16 for secukinumab, Week 24 for infliximab,
Week 14 for golimumab and at Week 12 for adalimumab and etanercept
Subjects Achieving ASAS20 Response (%)
*5 mg/kg i.v. infusion at Weeks 0, 2, 6, 14, and 22
TNF, tumor necrosis factor; PBO, placebo; ASAS20, ≥20% improvement in Assessment of Spondyloarthritis International Society
1. van der Heijde, D, et al. Arthritis Rheum. 2006;54:2136–46; 2. Davis Jr JC, et al. Arthritis Rheum. 2003;48:3230–6;
3. Inman RD, et al. Arthritis Rheum. 2008;58:3402–12; 4. van der Heijde, D, et al. Arthritis Rheum. 2005;52:582–91;
5. Landewe R, et al. Ann Rheum Dis. 2014;73:39–47
6. Baeten D, et al Arthritis Rheum. 2014;66(Suppl):S360:Abstract 819
7. Sieper J, et al. Arthritis Rheum. 2014;66(Suppl):S232. Abstract 536
N=138
N=138
N=201
N=208
N=107
N=139
N=140
N=78
N=78
N=90
N=92
N=89
N=45
N=45
N=45
40 mg
q2w
PBO
25 mg
BIW
PBO
50 mg
q4w
100 mg
q4w
PBO
5 mg/kg
iv*
PBO
iv q2w 75 mg q4w
iv q2w 150 mg
q4w
PBO
75 mg qw
q4w
150 mg qw
q4w
PBO
Adalimumab
ATLAS1
Etanercept2
Golimumab
GO-RAISE3
Infliximab
ASSERT4
Secukinumab
MEASURE 15
Secukinumab
MEASURE 26

18. Subjects Achieving ASAS40 Response (%)
Effect of TNF & IL17A Inhibitors on ASAS40 Responses (Anti–TNF-naïve Subjects)
ASAS40 response rates at Week 16 for secukinumab, Week 24 for infliximab
and golimumab and at Week 12 for adalimumab
Subjects Achieving ASAS40 Response (%)
*5 mg/kg i.v. infusion at Weeks 0, 2, 6, 14, and 22
TNF, tumor necrosis factor; PBO, placebo; ASAS20, ≥20% improvement in Assessment of Spondyloarthritis International Society
1. van der Heijde, D, et al. Arthritis Rheum. 2006;54:2136–46; 2. Inman RD, et al. Arthritis Rheum. 2008;58:3402–12
3. van der Heijde, D, et al. Arthritis Rheum. 2005;52:582–91; 4. Baeten D, et al Arthritis Rheum. 2014;66(Suppl):S360:Abstract 819
5. Sieper J, et al. Arthritis Rheum. 2014;66(Suppl):S232. Abstract 536
N=138
N=201
N=208
N=107
N=140
N=78
N=78
N=90
N=92
N=89
N=45
N=45
N=45
40 mg
q2w
PBO
50 mg
q4w
100 mg
q4w
PBO
5 mg/kg
iv*
PBO
iv q2w 75 mg q4w
iv q2w 150 mg
q4w
PBO
75 mg qw
q4w
150 mg qw
q4w
PBO
Adalimumab
ATLAS1
Golimumab
GO-RAISE2
Infliximab
ASSERT3
Secukinumab
MEASURE 14
Secukinumab
MEASURE 25

19. MEASURE 3: Study Design
MEASURE 3: first randomized, double blind, placebo controlled first Phase 3 study assessing efficacy and safety of s.c. maintenance therapy with 300 mg or 150 mg secukinumab following i.v. loading
Pavelka et al. P1828. ACR2017

20. Secukinumab Sustained ASAS20/40 Rate through 2 years (MEASURE 3)
Pavelka et al. P1828. ACR2017

21. Secukinumab improvements seen regardless of prior anti-TNF Prespecified subanalysis by prior Anti-TNF use (MEASURE 3)
Anti–TNF-naïve
Anti–TNF-IR
% responders
ASAS20
% responders
ASAS40
Secukinumab 10 mg/kg i.v.→ 300 mg s.c.
Secukinumab 10 mg/kg i.v.→ 150 mg s.c.
Placebo
Pavelka et al. P1828. ACR2017

22. Does Secukinumab Inhibit Disease Progression of SpA?
| Presentation Title | Presenter Name | Date | Subject | Business Use Only

23. Rheumatologist score bony fusion using the mSASSS scoring method – giving points to squaring, erosions, slcerosis and syndesmophytes.
| Presentation Title | Presenter Name | Date | Subject | Business Use Only

24. Anti-TNF Therapy over 2 Years Does Not Inhibit Radiographic Progression in AS – Blinded Comparisons with a Historical Cohort

25. Mean mSASSS Change at Week 104 Higher in Patients With Elevated Baseline hsCRP (>5 mg/L)
Observed Data
mSASSS range: 0–72 High hsCRP: >5 mg/L; normal hsCRP: ≤5 mg/L n, number of patients with both baseline and Week 104 assessments
Braun, et al. OPO0001 presented at the 25th European League Against Rheumatism Congress. 2016, June ; London.

26. Mean mSASSS Change at Week 104 Higher in Patients With Syndesmophytes at Baseline
Observed Data
mSASSS range: 0–72 n, number of patients with both baseline and Week 104 assessments
Braun, et al. OPO0001 presented at the 25th European League Against Rheumatism Congress. 2016, June ; London.

27. Mean mSASSS Change at Week 104 in Anti–TNF-naïve and Anti–TNF-IR Patients
Observed Data
mSASSS range: 0–72 n, number of patients with both baseline and Week 104 assessments; IR, inadequate response
Braun, et al. OPO0001 presented at the 25th European League Against Rheumatism Congress. 2016, June ; London.

28. MEASURE 1: Sustained Low mSASSS Progression at Year 4
Approximately 80% of patients had no radiographic progression with Secukinumab*
Braun, et al. ID 3L. ACR 2017.

29. Favorable Safety & Tolerability through 2 years (MEASURE 3) Safety profile is consistent with that of other Phase 3 studies (MEASURE 1 & 2)

30. IL17 inhibitors have demonstrated a rapid onset of action and durable response over two years
*P < ; †P < 0.001; §P < 0.01 versus placebo. (P-values at Week 16 adjusted for multiplicity of testing). Nonresponder imputation used for missing data to Week 16. Observed data shown from Week 20 through Week 104 (from patients entering the long term extension). #MEASURE 1; Subject received intravenous loading doses of secukinumab 10 mg/kg at baseline Week 2 and Week 4, before receiving subcutaneous dosing every four weeks from Week Reference: 1. Baeten D, et al Arthritis Rheum. 2014;66(Suppl):S360:Abstract Novartis data on file (CSR MEASURE 1, Table , Table ) 3. Novartis data on file (CSR MEASURE 1, Table , Table ) 4. Baeten D, et al Arthritis Rheumatol. 2015; 67 (suppl 10).

31. IL17 inhibitors have demonstrated a rapid onset of action and durable response over two years
Biologic-naive
Biologic experienced
‡P<0.05 vs. Placebo. Data from the overall population enrolled in the randomized, double-blind, placebo-controlled Phase 3 study, MEASURE 1; Subjects received intravenous loading doses of secukinumab 10 mg/kg at baseline Week 2 and Week 4, before receiving subcutaneous dosing every four weeks from Week 8. n , number randomized. Week 16 data shown is non-responder imputed. Observed data shown at Weeks 52 & 104 (from patients entering the long term extension)
Reference: 1. Novartis data on file (CSR MEASURE 1: Table ) 2. Novartis data on file (CSR MEASURE 1: Table ) Beaten D et al. Arthritis Rheumatol. 2015; 67 (suppl 10).

32. Conclusions
Secukinumab is a highly effective, new treatment option for AS with a good safety profile
Possible favourable outcome in terms of lesser new bone formation and lower risk of TB reactivation in patients with latent TB
Trend towards more improvement with time

33. Diagnosis & Pitfalls
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35. Diagnostic Pitfalls Missed diagnosis misdiagnosis Obesity Female
Non (pre)-Radiographic AxSpA
MRI with STIR sequence
Thoracic-only syndesmophytes
Low-dose whole-spine CT
Sacroiliitis
Osteoarthritis
Crystal arthropathy
Infection
Exercise-induced (1 in 4 MRI+)
Negative imaging & HLA-B27
IBP
Family history of SpA
Good response to NSAID
Elevated ESR/CRP
Enthesitis

36. Presence of multiple spondyloarthritis (SpA) features is important but not sufficient for a diagnosis of axial spondyloarthritis: data from the SPondyloArthritis Caught Early (SPACE) cohort ZE Zaitouni, PAC Bakker, M Lunteren et al. Ann Rheum Dis 2017;76:

37. Window of Opportunity Does Treatment Matter?
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38. Pathology: Inflammation (Spondylitis) and New Bone Formation (Ankylosis)
Higher disease activity leads to more structural damage in the spine in ankylosing spondylitis: 12-year longitudinal data from the OASIS cohort
Ramiro S, van der Heijde D, van Tubergen A, et al. Ann Rheum Dis 2014;73:

39. TNF inhibitors have not demonstrated inhibition of radiographic progression in the long term
* Patients represented as "not TNFi treated" were enrolled in the Outcome Assessment in Ankylosing Spondylitis International Study (OASIS). The OASIS study was an international observational study on outcome in AS patients from 3 different countries (Belgium, France, and The Netherlands). It included consecutive patients who were followed up for 10 years according to a predefined protocol, including assessment of radiographs of the cervical and lumbar spine at baseline, at 1-year and 2-year followup, and every 2 years thereafter. Patients were treated according to common practice guidelines including the use of NSAIDs, analgesics, and regular exercise therapy., **Etanercept treated; Values are the mean SD change from baseline. There were no statistically significant differences between groups in the mean change in score. ; mSASSS = modified Stoke Ankylosing Spondylitis Spine Score
Reference:
1. van der Heijde D et al., ARTHRITIS & RHEUMATISM Vol. 58, No. 5, May 2008, pp 1324–1331 (Table 2, Abstract Conclusion)
Public

40. Can early treatment prevent ankylosis?
Evaluation of the change in structural radiographic sacroiliac joint damage after 2 years of etanercept therapy (EMBARK trial) in comparison to a contemporary control cohort (DESIR cohort) in recent onset axial spondyloarthritis
Dougados M, Maksymowych WP, Landewé RB, et al. Ann Rheum Dis doi: /annrheumdis
2 years' use of Etanercept in AS patients with disease duration averaging 2.4 years resulted in far less damage progression compared to a control cohort with disease duration averaging 1.5 years.
Modification of structural lesions on MRI of the sacroiliac joints by etanercept in the EMBARK trial: a 12-week randomised placebo-controlled trial in patients with non-radiographic axial spondyloarthritis
Maksymowych WP, Wichuk S, Dougados M, et al. Ann Rheum Dis doi: /annrheumdis
There were even hints of "backfill" of lesions (ie repair) in the Etanercept treated cohort, after just 12 weeks of treatment.

41. Can late treatment retard ankylosis?
TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort
Molnar C, Scherer A, Baraliakos X, et al. Ann Rheum Dis doi: /annrheumdis
In this 10-year observational study of AS patients with longstanding active disease averaging 14 years, those in clinical remission or very low disease activity had virtually no radiographic progression. The longer the duration of treatment (4 years compared to 2), the higher the probability of not having further radiographic progression (68% vs 42%).
Reduction in Spinal Radiographic Progression in Ankylosing Spondylitis Patients Receiving Prolonged Treatment With Tumor Necrosis Factor Inhibitors
Maas F, Arends S, Brouwer E, et al. Arthritis Care & Research, 69: 1011–1019. doi: /acr.23097
In this 8-year follow-up of a Dutch cohort of AS patients who received anti-TNF treatment and had clinical and Xray evaluation every 2 years, the rate of radiographic progression declined steadily the longer anti-TNF was used, with virtual arrest of progression evident from Year 4 onwards.

42. Treat-to-Target Preventing Damage & Disability
Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force
Smolen JS, Braun J, Dougados M, et al. Ann Rheum Dis 2014;73:6-16
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43. T2T Recommendations
A major treatment target should be clinical remission/inactive disease of musculoskeletal involvement (arthritis, dactylitis, enthesitis, axial disease), taking extra-articular manifestations into consideration.
The treatment target should be individualised according to the current clinical manifestations of the disease.
Clinical remission/inactive disease is defined as the absence of clinical and laboratory evidence of significant inflammatory disease activity.
Low/minimal disease activity may be an alternative treatment target.
Disease activity should be measured on the basis of clinical signs and symptoms, and acute phase reactants.
The choice of the measure of disease activity and the level of the target value may be influenced by considerations of comorbidities, patient factors and drug-related risks.

44. T2T Recommendations
Once the target is achieved, it should ideally be maintained throughout the course of the disease.
The patient should be appropriately informed and involved in the discussions about the treatment target, and the risks and benefits of the strategy planned to reach this target.
Structural changes, functional impairment, extra-articular manifestations, comorbidities and treatment risks should be considered when making clinical decisions, in addition to assessing measures of disease activity.
Validated composite measures of disease activity such as the BASDAI plus acute phase reactants or the Ankylosing Spondylitis Disease Activity Score (ASDAS), with or without measures of function such as BASFI, should be performed and documented regularly in routine clinical practice to guide treatment decisions; the frequency of the measurements depends on the level of disease activity.
Other factors, such as axial inflammation on MRI, radiographic progression, peripheral musculoskeletal and extra-articular manifestations, as well as comorbidities may also be considered when setting clinical targets.

45. Metrology Measuring Disease Activity
Business Use Only

46. + 0.07 × Peripheral Pain/Swelling + 0.58×Ln(CRP+1)
Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores Machado P, Landewé R, Lie E, et al. Ann Rheum Dis 2011;70:47-53
ASDAS-CRP (the preferred version):
0.12 × Back Pain × Duration of Morning Stiffness × Patient Global
× Peripheral Pain/Swelling ×Ln(CRP+1)
Clinically important worsening defined as an increase in ASDAS of at least 0.9 points.

47. Measurement and Treatment of Radiographic Progression in Ankylosing Spondylitis: Lessons Learned from Observational Studies and Clinical Trials Louie GH, Ward MM. Curr Opin Rheum 2014 Mar; 26(2):
Given its higher sensitivity to detect change, the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) has been used in clinical studies to evaluate the effectiveness of treatments to slow radiographic progression.
The anterior corners of the cervical and lumbar vertebrae are scored for erosions, sclerosis, squaring (scored as 1), syndesmophytes (scored as 2), or bridged syndesmophytes (scored as 3), with a possible range of 0 (normal) to 72 (complete bridging of both the cervical and lumbar spine).
Group mean mSASSS of the historical OASIS (Outcome Assessments in Ankylosing Spondylitis International Study) cohort increased approximately 1 unit per year

48. ASAS-EULAR Treatment Guideline
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49. Algorithm based on the ASAS-EULAR recommendations for the management of axial spondyloarthritis. ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; bDMARD, biological disease-modifying antirheumatic drug; TNFi, tumor necrosis factor inhibitor; IL17-inhibitor, interleukin-17 inhibitor. *Either BASDAI or ASDAS, but the same outcome per patient.
Désirée van der Heijde et al. Ann Rheum Dis doi: /annrheumdis
©2017 by BMJ Publishing Group Ltd and European League Against Rheumatism

50. Algorithm based on the ASAS-EULAR recommendations for the management of axial spondyloarthritis. ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; bDMARD, biological disease-modifying antirheumatic drug; TNFi, tumor necrosis factor inhibitor; IL17-inhibitor, interleukin-17 inhibitor. *Either BASDAI or ASDAS, but the same outcome per patient.
Désirée van der Heijde et al. Ann Rheum Dis doi: /annrheumdis
©2017 by BMJ Publishing Group Ltd and European League Against Rheumatism

51. Algorithm based on the ASAS-EULAR recommendations for the management of axial spondyloarthritis. ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; bDMARD, biological disease-modifying antirheumatic drug; TNFi, tumor necrosis factor inhibitor; IL17-inhibitor, interleukin-17 inhibitor. *Either BASDAI or ASDAS, but the same outcome per patient.
Désirée van der Heijde et al. Ann Rheum Dis doi: /annrheumdis
©2017 by BMJ Publishing Group Ltd and European League Against Rheumatism

52. Personal Experience & Practice
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53. Current Treatment Options for AS management

54. Personal Experience & Practice (1)
Non-radiographic AxSpA treated like established AS, perhaps more urgently and aggressively
Full dose NSAID/coxib is first-line for pure axial disease
Sulfasalazine is preferred csDMARD in peripheral and extra- articular involvement
Steroids, if needed, preferably intra-articular
Targeted therapies:
TNF inhibitor as first (and possibly second) line
Primary non-responder: switch class (monoclonal vs soluble receptor)
Secondary non-responder: switch drug
Anti-IL17 as second (and possibly first) line
JAK inhibitor (Tofacitinib)

55. Personal Experience & Practice (2)
Anti-IL17A (Secukinumab):
Most were switches from TNF inhibitors:
Primary or secondary inadequate responder
Developed or worsening psoriasis
Refractory dactylitis or enthesitis
Recurrent infections (URTI)
First line use:
IGRA-positive LTBI
High infection risk (elderly, immunocompromised)
Radiographic new bone formation or MRI fatty corners evident at diagnosis

56. Personal Experience & Practice (3)
Continuing NSAID upon starting biologic to reduce ankylosis?
Secondary anti-TNF failure:
Anti-biologic antibodies
Dysbiosis: silent ileitis in 50-80%; stool calprotectin, ASCA
Obesity
Tapering to longterm maintenance vs on-demand treatment
70% flare within 6 months off biologic
Flare triggers: infection, trauma, entheseal strain
Targeting prevention/retardation of radiographic progression:
2 years remission in early disease (1-3 years from symptom-onset)
4 years remission in established disease, or damage evident at Dx