1. Update on non-TNFi therapies for spondyloarthritis
Tse Sau Mei
Tuen Mun Hospital

2. Pathogenesis of spondyloarthritis
A heterogeneous group of chronic inter-related inflammatory arthropathies affecting the synovium, entheses and certain extra-articular sites
Ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), enteropathic arthritis, juvenile SpA, undifferentiated SpA
Etiology is still largely unknown
Complex interplay of genetics and environmental factors
Histologically: infiltration of T cells ( CD4+ and CD8+), CD68+ macrophages, CD20+ B cells, proliferation of fibroblasts
Cytokines: TNFα, IL-6, IL-1, IL-17
Emerging role of Th17 cells, IL-23/IL-17 axis
EULAR Textbook on Rheumatic Disease
Autoimmunity Reviews 2014;13:64–69

3. Unmet need in SpA Axial SpA Mainstay of treatment: NSAIDs, anti TNF
Tolerability of NSAIDs
Up to 40% on anti TNF do not respond sufficiently due to intolerance or inefficacy
Lack of evidence on halting new bone formation
DMARDs are not effective in axial SpA

4. Non-TNF inhibitor therapies for SpA
Anti IL-12/23
Ustekinumab
Anti IL-17
Secuknumab
Brodalumab
PDE4 inhibitors
Apremilast
Bisphosphonates
Pamidronate, zoledonate, neridronate
Targeting T/B cells
Abatacept
Rituximab
Anti IL-6
Tocilizumab
Sarilumab

5. The IL-23/IL-17 axis
Nature 2007; 448;416

6. The IL-23/IL-17 axis in SpA Arthritis Rheum 2014;66(2):231–241
Schematic drawing depicting cells, effector cytokines, and possible contributions to spondyloarthritis (SpA) pathogenesis. Dendritic cells (DCs) and macrophages are major sources of interleukin-23 (IL-23), which is produced in response to microbes and their products signaling through pattern recognition receptors. Consequences of HLA–B27 misfolding and endoplasmic reticulum stress can augment IL-23 and IL-1 production, and CARD9 variants could affect production of this cytokine as well.
Cells of both the adaptive and the innate immune response are implicated in SpA pathogenesis. CD4 Th17 cell expansion has been reported, and killer cell immunoglobulin-like receptor 3DL2 Th17 cells may be triggered by surface HLA–B27 dimers on DCs and macrophages to produce IL-17.
Th17 development and survival may be influenced by variants of the IL-23 and IL-6 receptors (IL23R, IL6R), as well as IL-27 and Tyk-2– and STAT3-mediated cytokine responses. Tissue inflammation in SpA involves innate immune IL-17–expressing mast cells (synovium), neutrophils (facet joints), and CD3CD4CD8 entheseal-resident T cells. The latter produce IL-22, which can drive osteoproliferation in rodent models. Variants in IL6R, TYK2, and STAT3 may also affect tissue responses to cytokines.
IFN interferon-; TNF tumor necrosis factor; iNKT invariant natural killer T; GI gastrointestinal.
Arthritis Rheum 2014;66(2):231–241

7. Targeting IL-12/23 - Ustekinumab
A fully human monoclonal antibody directed against the p40 subunit shared by IL-12 and IL-23
Approved for treatment of moderate-to-severe psoriasis
In PsA, 2 phase 3 RCTs, PSUMMIT 1 and PSUMMIT 2 (n=927)
significantly better clinical efficacy at week 24 , response maintained to week 50
Peripheral joint count, psoriasis, dactylitis, enthesitis, axial symptoms (BASDAI)
Efficacy irrespective of MTX use
Better response in <100kg
Less improvement in TNFi experienced patients
Significantly inhibited radiographic progression of joint damage
UST (111)
PBO (61)
BASDAI20*
54·1%
26·2%
BASDAI50*
27·9%
13·1%
BASDAI70*
14·4%
0·0%
Lancet 2013; 382: 780–89
Ann Rheum Dis 2014;73:990–999
Ann Rheum Dis Published Online First

8. Ustekinumab – Axial SpA
Study
Subjects
Treatment groups
Results
TOPAS study
Open label single arm
28 weeks
20 Active AS
TNF-naive
UST 90mg at
week 0, 4, 16
ASAS40 response= 65%
Improvement in other clinical parameters and patient-reported outcomes
↓active inflammation on MRI
↓ NSAIDs intake
Overall well tolerated
Ann Rheum Dis 2014;73:817–823

9. Targeting IL-17 - Secukinumab
A fully human monoclonal anti-IL17 antibody
Demonstrated favorable safety and clinical efficacy in phase I and II studies in moderate to severe psoriasis
In PsA, proof on concept study showed trend towards clinical improvement
Ann Rheum Dis 2014;73:349–356

10. Secukinumab – Axial SpA
Study
Subjects
Treatment groups
Results
Proof of concept study
RCT
Phase 2
28 weeks
30 Active AS
(13 prior TNFi)
Secukinumab (2x10mg/kg on D1 and D22) VS
placebo
ASAS20 response rate at wk 6:
59.2% vs 24.5% *
Improved QoL
Decrease in CPR, ESR
Decrease in mean MRI scores
Lancet 2013; 382: 1705–13

11. Targeting IL-17 - Brodalumab
A human monoclonal antibody against interleukin-17 receptor A
Promising results in patients with active PsA at 12 weeks in a phase 2 RCT (n=106), efficacy sustained through week 52, irrespective of prior biologic use
Change in BASDAI in Brodalumab 280mg : -1.1 vs -0.2 (p<0.01)
Not tested in axial SpA yet
Ixekizumab – tested in PsO only
N Engl J Med 2014;370:

12. Small molecule – PDE4 inhibitors
Phosphodiesterases (PDEs) are enzymes responsible for the hydrolysis of cAMP, an intrinsic modulator of inflammatory responses
PDE4 is the predominant PDE in inflammatory cells
Inhibition of PDE4 elevates intracellular cAMP levels,
 downregulates the inflammatory response through TNF, IL-23, IL-12, and other inflammatory cytokines
Apremilast is a novel, orally available small molecule that specifically targets PDE4
In active PsA, RCTs ( including PALACE-1) confirmed efficacy including peripheral arthritis, enthesitis, psoriasis and physical function; irrespective of MTx use
Side effects: nausea, diarrhoea, headache
Arthritis Rheum 2012; 64(10):
Ann Rheum Dis 2014;73:1020–1026

13. Apremilast – Axial SpA Study Subjects Treatment groups Results RCT
(Phase 2 pilot study)
12 weeks
36 active AS
Activity on MRI
(3 with prior TNFi)
Apremilast 30mg bd Vs
Placebo
At week 12:
Change in BASDAI: vs -0.77
Numerically better improvement in BASFI, BASMI, fatigue, night pain
Continued improvement without peaking of effects
Acceptable safety profiles
Primary endpoint not met
Ann Rheum Dis 2013; 72:

14. Bisphosphonates Anti-inflammatory properties and analgesic effects
Act on cells from the monocyte/macrophage lineage and may modulate the generation of pro-inflammatory cytokines
Only intravenously administered bisphosphonates were used as a therapeutic agent in SpA as a high serum concentration and thus a more rapid response could be achieved
Pamidronate
Zoledronic acid
Neridronate
Curr Opin Rheumatol 2007;19(4):340-5

15. Bisphosphonates in SpA
Study
Subjects
Treatment groups
Results
RCT
6 months
84 AS
Pamidronate 60mg vs 10mg monthly infusion
↓in BASDAI: 2.22( 34.5%) vs 0.93(15%)*
 Dose dependent effects
6 open label trials
99 AS,
9 peripheral SpA
Pamidronate: mild and delayed clinical improvement (after 3rd infusion);
more evident with higher dosage and shorter interval
Placebo controlled trial
87 uSpA
Pamidronate 60mg monthly x 6 m Vs
placebo
Superior ASAS20 and BASDAI-50 response
Open label
11 AS with MRI osteitis
Zoledronic acid 5mg infusion
Improved MRI scores by 19-76%;
Improved clinical parameters
60 AS
Neridronate 10mg monthly infusion x 6
Standard infliximab therapy (5mg/kg)
Comparable reduction in BASDAI ( -1.72, -1.62), BASFI and axial pain
Arthritis Rheum 2002;46(3):776-73
Curr Opin Rheumatol 2007;19(4):340-5
Rheumatol Int 2012;32:3945–3950
Ann Rheum Dis 2014;73:1273–1274
Rheumatology 2014;53:90-94

16. Bisphosphonates in SpA
In a local 48-week randomized controlled trial comparing the clinical efficacy and radiological inflammation of pamidronate vs golimumab in 30 axial SpA patients
BASDAI improved in golimumab but not pamidronate; while pain relief occurred in both groups
P = NS
P <0.05
P < 0.01
P < 0.01
BASDAI
Spinal pain
Dr Mok CC

17. Targeting T cells and B cells
Immunohistiochemical stains of sacroiliac joint biopsies from SpA patients showed that T cells and macrophages were the most frequent infiltrates
The number of CD20+ B cells in the persistently inflamed joints from AS patients has been reported to be significantly higher than joints from controls or from AS patient without active inflammation
Ann Rheum Dis 2000;59:135-40
Arthritis Rheum 2006;54:

18. Abatacept
A fully humanized fusion protein that targets the co-costimulatory signal for full T-cell activation
Effective in active PsA in phase II RCT ( n=170)
Study
Subjects
Treatment groups
Results
Open label pilot study
24 weeks
30 active AS
(15 TNFi-naïve
15 TNFi-failure)
Abatacept 10mg/kg
on days 1, 15, 29 then Q28D
At week 24, ASAS40 reached in:
13% vs 0% in TNF naïve vs failure
ASAS20: 27% vs 20%
a major response was not observed
Open label study
7 active AS/uSpA
Who failed 2 TNFis
None achieved BASDAI50
1 patient: 49.3% reduction in BASDAI
IBP persisted
Enthesitis improved
 No strong efficacy in axial form
Arthritis Rheum 2011;63(4):939–48
Ann Rheum Dis 2011;70:
Joint Bone Spine 2012;79:47-50

19. Rituximab
A chimeric monoclonal antibody specific for human CD20 on mature B cells
Maybe effective in PsA in an exploratory study of 9 patients
Study
Subjects
Treatment groups
Results
RCT
Phase 2
24 weeks
20 Active AS
10 – TNF-naive
10 – TNF-failure
Rituximab 1g
on days 1 and 15
Higher response in TNF-naïve:
ASAS20 =50% vs 30%
maybe effective in TNFi-naïve patients
French Registry
(Auto-immunity and Rituximab)
26 cases:
AS – 10
uSpA – 7
PsA – 9
( 23 prior TNFi)
Mean number of rituximab course: 1.5
Efficacy was noted in 11 cases:
3/3 TNF-naïve patient responded
8/20 TNF-failure patient responded
No predictive factor of response (eg axial vs peripheral)  moderate efficacy, more marked if TNFi-naïve
Ann Rheum Dis 2012;71:
Arthritis Rheum 2010;62(5):
J Rheumatol 2012;39(12):

20. Targeting IL-6
Interleukin-6 (IL-6) is a pro-inflammatory cytokine found at elevated levels in serum and biopsy specimen from sacroiliac joint in AS patients
Levels correlate with disease activity
Clinical and radiological efficacy of TNF-blockade in AS is associated with significant reduction of IL-6 and CRP levels
Tocilizumab and Sarilumab - Monoclonal antibody to the human IL-6 receptor
Humanised vs fully human
Inflamm Allergy Drug Targets 2012;11:262–5
Rheumatol 2007;26:211–15
Ann Rheum Dis 2008;67:511–17
Arthritis Rheum 2011;63:3789–800

21. Tocilizumab and Sarilumab
Study
Subjects
Treatment groups
Results
Retrospective
study
N=21, TNFi failure
Axial and peripheral SpA
TCZ 4 or 8mg/kg monthly
Reduction in acute-phase reactants but failed to substantially improve axial SpA and was inconsistently effective in peripheral SpA
RCT
Phase 2/3
102 TNFi-naïve
active AS
TCZ 8mg/kg monthly Vs
placebo
Week 12 ASAS20 response: no significant difference
negative study ; terminated early
Phase 2
301 Active AS
Sarilumab
100, 150, 200mg SC biweekly
10, 150mg weekly
Or placebo
Week 12 no significant difference in ASAS20 response between placebo and any treatment groups
negative study
Arthritis Research & Therapy 2012, 14:R53
Ann Rheum Dis 2014;73:95–100
Ann Rheum Dis Published Online First: 18 Feb 2014

22. Summary √ (phase 3 RCTs) √ (proof of concept) √ (phase 2 RCT)
PsA
Axial SpA
Other
Ustekinumab
√ (phase 3 RCTs)
√ (proof of concept)
PSO, IBD
Secukinumab
√ (phase 2 RCT)
PSO, Uveitis, RA,
Brodalumab
√ (Phase 2 RCT) /
PSO
Apremilast
√ (phase 3 RCT)
Bisphosphonates
√ (Open label / RCT)
Abatacept
X (open label)
Rituximab
√ (exploratory)
√ (phase 2 RCT, registry)
Tocilizumab/
Sarilumab
X (RCT)

23. Conclusions Many of the non-TNFi biologics have proven efficacy in PsA
Subgroup analysis on those with axial involvement (using BASDAI) shows improvement in back pain as well in these studies 
For axial SpA patients, large scale studies are still lacking
Phase II trials seem to be promising for agents that targets IL-17 and IL-23

24. Thank you