Dr Jon Packham discusses the latest therapies and evidence for Spondyloarthropathies treatment

1. It’s the Keele difference.
Research Institute for Primary
Care & Health Sciences
Keele University
Delivering high quality multidisciplinary research in primary care.

2. It’s the Keele difference.
What’s new in
spondyloarthropathy?
Dr Jon Packham
Honorary Senior Lecturer – Keele University
Consultant rheumatologist – Haywood Hospital
Delivering high quality multidisciplinary research in primary care.

3. New classification criteria
New management guidance
• New NICE guidance on spondyloarthropathies
Latest therapies
• New guidance
• Forthcoming therapies for PsA and AS
Biosimilars
• New guidance
• Safety and efficacy data
• Switching
Overview

4. New classification criteria

5. It’s the Keele difference.Delivering high quality multidisciplinary research in primary care.
AS is dead
Long live AS

10. Ankylosing Spondylitis is dead
Long live
Axial Spondyloarthropathy

14. +

20. 57.
1
68.
2

21. 29.
8
29.
5

27. “An onset after 45 years of age is exceptional”

28. “An onset after 45 years of age is exceptional”

29. .
Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results
of a randomised placebo-controlled trial (ABILITY-1)
J Sieper et al Ann Rheum Dis. 2013 Jun; 72(6): 815–822
• Adalumimab ASAS 40 response at week 12
– (A) Full analysis set
– (B) Symptom duration <5 years or ≥5 years.
– (C) Age <40 years or ≥40 years.
– (D) CRP normal/elevated at baseline.
– (E) HLA-B27 +ve / -ve.
Predictors of biologic response
(indicator of ‘true’ axial inflammation?)

30. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All Sx < 5
years
Sx > 5
years
Age
<40
Age
>40
Placebo
Adalumimab

31. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All Sx < 5
years
Sx > 5
years
Age
<40
Age
>40
Placebo
Adalumimab

32. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All Sx < 5
years
Sx > 5
years
Age
<40
Age
>40
Placebo
Adalumimab

33. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All CRP
normal
CRP
raised
B27 -ve B27
+ve
Placebo
Adalumimab

34. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All CRP
normal
CRP
raised
B27 -ve B27
+ve
Placebo
Adalumimab

35. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All CRP
normal
CRP
raised
B27 -ve B27
+ve
Placebo
Adalumimab

36. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All SPARCC <2SPARCC >2
Placebo
Adalumimab

37. ABILITY-1 ASAS 40 response %
0
10
20
30
40
50
60
All SPARCC <2SPARCC >2
Placebo
Adalumimab

38. Ability-1 conclusions
• Good predictors of treatment response to
adalimumab
– Objective evidence of active inflammation at baseline
• positive MRI
• elevated CRP level
• Little evidence to support treatment of
‘clinical arm’ axial SpA with normal CRP

39. Diagnosis of non-radiographic axial spondyloarthritis divided people into 3
groups:
1/ people with MRI changes
2/those with no MRI changes but elevated C-reactive protein levels
3/ those without MRI changes and without elevated C-reactive protein
For people with symptoms of non-radiographic axial spondyloarthritis,
but without objective signs of inflammation
No recommendations for treatment with TNF-alpha inhibitors X
NICE Axial SpA TA (25/9/15)

40. Ankylosing
spondylitis
‘Real’ diagnostic groups
under ASAS criteria

41. Ankylosing spondylitis
MRI +ve SIJs +
1 SpA feature
‘Real’ diagnostic groups
under ASAS criteria

42. Ankylosing spondylitis
MRI +ve SIJs +
1 SpA feature
‘Real’ diagnostic groups
under ASAS criteria
MRI +ve spine +
1 SpA feature

43. Ankylosing spondylitis
Back pain + HLA B27 +
↑CRP + 1 SpA feature
MRI +ve SIJs +
1 SpA feature
‘Real’ diagnostic groups
under ASAS criteria
MRI +ve spine +
1 SpA feature

44. Back pain with
no inflammation
?No disease stage
Ankylosing spondylitis
Back pain + HLA B27 +
↑CRP + 1 SpA feature
MRI +ve SIJs +
1 SpA feature
Back pain + HLA B27
+ 2 SpA features
‘Real’ diagnostic groups
under ASAS criteria
MRI +ve spine +
1 SpA feature

46. B27 +ve clinical arm SpA
– what is it?
HLA-B27 +ve in 9.7% of population
Axial inflammation in <1% of population
>90% of B27 +ve patients do not have axial SpA
True axial
inflammation
Fibromyalgia Mechanical
back pain

47. Mechanical low back pain
• Third of all adults
• Commonly progresses to ‘chronic pain’
• In relatives of HLA-B27 +ve SpA patients
– ASAS clinical criteria
relatively easy to meet

48. Clinical axial SpA
• 20 year old son of AS patient with 3/12 LBP
• HLA-B27 +ve (50% likelihood)
• Family history (100%)
• + 1 from:
– Arthritis / dactylitis / enthesitis
– Inflammatory back pain
– Uveitis / psoriasis / colitis
– Raised CRP
– NSAID response

50. New NICE referral and management
spondyloarthropathy guidelines 2017

51. New NICE guidance on SpA covers
the whole patient journey
NICE, National Institute for Health and Care Excellence
NICE Guideline NG65: Spondyloarthritis in over 16s: diagnosis + management: https://www.nice.org.uk/guidance/ng65. Feb
2017.
Recognition,
referral and
diagnosis
Pharmacological
management
Non -
pharmacological
management
Surgical
interventions
Organisation of
long term care and
monitoring
Information for people with
SpA
This guideline covers diagnosis and management of suspected or confirmed spondyloarthritis in adults
aged 16 years or older
These guidelines are available at:
www.nice.org.uk/guidance/ng65
If a diagnosis of
peripheral
spondyloarthritis
is confirmed,
offer plain film
X-ray of the
sacroiliac joints

52. New guidance increasingly covers EAMs in SpA
NICE: Spondyloarthritis in over 16s: diagnosis and management. Guideline Feb 2017 over 16s: diagnosis + management:
https://www.nice.org.uk/guidance/ng65. Feb 2017, p6, 12, 14, 17, 23.
Information
Organisation
of long term
care and
monitoring
Surgical
interventions
Non-
pharmacology
management
Pharmacology
management
Recognition,
referral and
diagnosis
Raise HCP
awareness of
SpA
NSAIDs Only if spinal
deformity
severe +
affecting QoL
Ensure cross-
disciplinary
communication
is supported
Ensure
tailored +
appropriateConsider
EAMs
Exercise
program
Consider
hydrotherapy
Consider
physical aids
Access to
specialist care
Consider
EAMs
Advise on
flares +
management
Advise on
EAMs
Recognise
risk
factors/early
signs +
symptoms
Consider
EAMs
CONSIDER
SKIN, GUT, EYES
See sections 1.1.2, 1.3.3, 1.4.5, 1.4.18, 1.9.3

53. Referral for suspected axial spondyloarthritis
NICE SpA guidleines 2017 (Braun 2013 >=4)
If a person has low back pain that started before age 45 years > 3 months:
Refer the person to a rheumatologist for a spondyloarthritis assessment if
4 or more of the following additional criteria are also present:
– low back pain that started before the age of 35 years
(increased likelihood that back pain is due to spondyloarthritis compared with
low back pain that started between 35 and 44 years)
– waking during the second half of the night because of symptoms
– buttock pain
– improvement with movement
– improvement within 48 hours of taking non-steroidal anti-inflammatory drugs
(NSAIDs)
– a first-degree relative with spondyloarthritis
– current or past arthritis
– current or past enthesitis
– current or past psoriasis.
• If exactly 3 of the additional criteria are present,
perform an HLA-B27 test.
If HLA-B27 positive,
refer to a rheumatologist for a spondyloarthritis assessment

54. Referral for suspected axial spondyloarthritis
NICE SpA guidleines 2017 (Braun 2013 >=4)
If a person has low back pain that started before age 45 years > 3 months:
Refer the person to a rheumatologist for a spondyloarthritis assessment if
4 or more of the following additional criteria are also present:
– low back pain that started before the age of 35 years
(increased likelihood that back pain is due to spondyloarthritis compared with
low back pain that started between 35 and 44 years)
– waking during the second half of the night because of symptoms
– buttock pain
– improvement with movement
– improvement within 48 hours of taking non-steroidal anti-inflammatory drugs
(NSAIDs)
– a first-degree relative with spondyloarthritis
– current or past arthritis
– current or past enthesitis
– current or past psoriasis.
• If exactly 3 of the additional criteria are present,
perform an HLA-B27 test.
If HLA-B27 positive,
refer to a rheumatologist for a spondyloarthritis assessment

55. New therapies for PsA and AS
http://pathways.nice.org.uk/pathways/spondyloarthritis

56. DMARDs in PsA
Methotrexate
Leflunomide
Sulfasalazine en
Ciclosporin
Azathioprine

57. DMARDs in PsA
Methotrexate
Leflunomide
Sulfasalazine en
Ciclosporin
Azathioprine
(Hydoxychloroquine)
(Gold salts)

58. Other (NICE) treatment options in PsA
DMARDs (at least x2)
Etanercept
Adalumimab
Infliximab
Golumimab
If >3 active joints

59. Other (NICE) treatment options in PsA
DMARDs (at least x2)
Etanercept
Adalumimab
Infliximab
Golumimab
Aprelimast Ustekinumab
If >3 active joints

60. Expected NICE guidance on treatments in PsA
Secukinumab (after DMARDs)
Certolizumab pegol [ID579]2
Under final consultation summer 2017

61. Other (NICE) treatment options in PsA
DMARDs (at least x2)
Etanercept
Adalumimab
Infliximab
Golumimab
Aprelimast Ustekinumab
If >3 active joints

62. Other (NICE) treatment options in PsA
DMARDs (at least x2)
Etanercept
Adalumimab
Infliximab
Golumimab
Certolizumab
Aprelimast Ustekinumab
If >3 active joints

63. Other (NICE) treatment options in PsA
DMARDs (at least x2)
Etanercept
Adalumimab
Infliximab
Golumimab
Certolizumab
Aprelimast Ustekinumab Secukinumab
If >3 active joints

64. IL-17 inhibitors: considerations relating
to EAMs in patients with PsA
IBD, inflammatory bowel disease
1. Eli Lilly and Company. Taltz (ixekizumab). Summary of Product Characteristics. April 2016. Available at: https://www.medicines.org.uk/emc/medicine/32054.
Accessed: Jan 2017; 2. FDA Briefing Document BLA761032. July 2016. Available at: http://bit.ly/2lS0lV2. Accessed: Jan 2017; 3. Baeten D, et al. N Engl J Med.
2015;373:2534–48; 4. Hueber W, et al. Gut. 2012; 61: 1693–700; 5. Targan S, et al Am J Gastroenterol. 2016;111:1599–607; 6. Novartis Pharma. Cosentyx
(secukinumab). Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003729/WC500183129.pdf. Accessed: March 2017; 7. Dick AD, et al. Ophthalmology. 2013;120:777-87; 8. Hueber W, et al. Sci
Transl Med. 2010;2:52–72; 9. Letko E, et al. Ophthalmology. 2015;122:939–948.
IL-17 inhibitors have been associated with new and worsening IBD
in clinical studies1–5
Use with caution is suggested in patients with IBD1,6
Studies of IL-17 inhibitors have shown variable results in uveitis7–9

65. Forthcoming agents for PsA
Mechanism of action Drug name Development stage
TNF inhibitor Amgevita, Solymbic
(adalimumab)
EMA CHMP positive opinion, Jan 20171,2
JAK inhibitor Tofacitinib Phase III3
Upadacitinib (ABT-494) TBC
Fusion protein Abatacept Phase III4
IL-17 inhibitor Ixekizumab Phase III5–7
Brodalumab Phase III8
IL-23 inhibitor Guselkumab Phase II9
Risankizumab Phase II10
IL-6 inhibitor Clazakizumab Phase II11
Anti-PSGL-1 mAb Neihulizumab (AbGn-168H) Phase II12,13
1. EMA CHMP Summary of Opinion: Amgevita. Jan 2017; 2. EMA CHMP Summary of Opinion: Solymbic. Jan 2017; 3. Clinical Trials.gov: NCT01976364; 5. Clinical Trials.gov:
NCT01860976; 6. Clinical Trials.gov: NCT01695239; 7. Clinical Trials.gov: NCT02349295; 8. Clinical Trials. gov: NCT02584855; 10. Clinical Trials.gov: NCT02024646; 9. Clinical
Trials.gov: NCT02319759; 10. Clinical Trials.gov: NCT02986373; 11. Mease PJ, et al. Arthritis Rheumatol. 2016;68(9):2163-73; 12. Clinical Trials.gov: NCT02267642; 13. AbGenomics
Press Release: http://www.abgenomics.com/news_detail.php?NNo=24, 26.04.16.

66. Non pharmacological care of AS/AxSpA
Refer to a specialist physiotherapist for a structured
exercise programme:
stretching, strengthening and postural exercises
deep breathing
spinal extension
range of motion exercises for the spine
aerobic exercise
Consider hydrotherapy to manage pain and improve
function
Develop an individualised flare plan

67. NSAIDs in AS/AxSpA
Offer non-steroidal anti-inflammatory drugs
(NSAIDs) at the lowest effective dose
Monitoring of risk factors
Use gastroprotective treatment
If an NSAID taken at the maximum tolerated
dose for 2–4 weeks does not provide adequate
pain relief, consider switching to another NSAID
Etoricoxib – trial reduction of 90mg to 60mg
NSAID study metanalyses x2
Naproxen does NOT appear to carry additional
cardiovascular risk
Ibuprofen ??

68. Other (NICE) treatment options in AS/AxSpA
NSAIDs (no longer at least x2!)
Etanercept Etanercept
Adalumimab Adalumimab
Infliximab
Golumimab
Certolizumab Certolizumab
AS AxSpA
If BASDAI and pain VAS >4/10

69. Other (NICE) treatment options in AS/AxSpA
NSAIDs (no longer at least x2!)
Etanercept Etanercept
Adalumimab Adalumimab
Infliximab
Golumimab Secukinumab
Certolizumab Certolizumab
AS AxSpAAS
If BASDAI and pain VAS >4/10

70. Forthcoming agents for AS
Mechanism of action Drug name Development stage
JAK inhibitor Tofacitinib Phase III
IL-17 inhibitor Ixekizumab Phase III
Brodalumab Phase III
IL-23 inhibitor Guselkumab Phase II
Risankizumab Phase II
Anti TNF Golumimab Phase III
IL12/23 inhibitor Ustekinumab Phase III
IL-17 inhibitor Secukinumab Phase III
Phosphodiesterase 4
(PDE4) inhibitor
Aprelimast Phase III
Forthcoming agents for AxSpA

71. New guidance on biosimilars

72. Large molecule biosimilars authorised
by the EMA and launched in the UK
Reference1
A considerable number of anti-TNF biosimilars are due to enter
the UK market in coming years6,7
MSD
Remicade
(infliximab)
Hospira
Inflectra
(infliximab)
Napp
Remsima
(infliximab)
INFLIXIMAB
Reference4 Biosimilars5
Pfizer
Enbrel
(etanercept)
Biogen Idec
Benepali
(etanercept)
ETANERCEPT
Biogen Idec
Flixabi
(infliximab)
Biosimilars2,3

75. EMEA (and MHRA) statement on
biosimilars
“If biosimilarity has been demonstrated in one indication,
the EMA considers that extrapolation of efficacy and safety
data to all other indications of the reference product may be
acceptable with appropriate scientific justifications”
If a biosimilar study shows it works in one disease
(i.e. rheumatoid arthritis)
Then it is presumed that it will work similarly for all other
indications of the originator molecule

76. • Benepali (SB4; etanercept)
• Received marketing approval in Jan 20161
• Phase III RCT, moderate to severe RA,
Benepali (n=299) vs originator etanercept (Enbrel; n=297)
50 mg weekly in combination with methotrexate;
no prior treatment with biologic agents2
• ACR20 at Week 24 demonstrated equivalent efficacy; overall safety comparable
Benepali (etanercept) biosimilar licensed
for PsA in biologic-naïve patients
78.1 80.3
0
20
40
60
80
100
ACR20 at Week 24
n=247 n=234
Benepali Enbrel
Patients(%)

77. BSR provides five recommendations
around the use of biosimilars
BSR Position statement on biosimilar medicines.
http://www.rheumatology.org.uk/includes/documents/cm_docs/2017/r/revised_bsr_biosimilars_position_statement_jan_2017.pdf
Accessed February 2017 BSR, The British Society for Rheumatology.
Prescription by brand name
Prescription for clinical reasons:
•Biosimilars should be included as a treatment choice for new patients
•Switching patients currently receiving a reference product to a biosimilar should be on a case-
by-case basis until further data are available to support safe switching.
Substitution only with the consent of the prescribing
clinician
Decisions made in partnership with the patients
Registration with the BSR Biologic Registers
or other appropriate UK register
1
2
3
5
4

78. The effect of biosimilars on the
treatment landscape
1. American College of Rheumatology. Drug Safety : Hotline: Biosimilar Infliximab (Inflectra):
http://www.rheumatology.org/Learning-Center/Publications-Communications/Drug-Safety/Hotline-Biosimilar-Infliximab-
Inflectra, 14.12.16, viewed March 2017
Biosimilars in biologic-naïve
patients
Biosimilar use in stable
patients: non-medical switching
Non-medical switching is defined by the American College of Rheumatology as:
“no medical indication to change drugs”1

79. Current biosimilar switching RCTs/Extension
phases: rheumatology studies
AS, axial SpA; ACR, American College of Rheumatology; ADA, anti-drug antibody; AE, adverse event; ASAS, Assessment of SpondyloArthritis international Society; CD, Crohn’s disease; CDAI, clinical disease
activity index; DAS, disease activity score; ETN, etanercept; IFX, infliximab; OLE, open-label extension; RP, reference product; SDAI, simple disease activity index; SpA, spondyloarthritis; UC, ulcerative colitis
1. Park W et al. Ann Rheum Dis 2017;76:346–354; 2. Adapted from: Goll GL et al. Presented at ACR/AHRP Annual Meeting, Washington DC, Nov 15, 2016 (Abstract 19LB); 3. Smolen JS et al. Ann Rheum Dis
2016;75(Suppl 2):488; 4. Emery P et al. Arthritis Rheumatol.2016: 68 (suppl 10). 5. Yoo DH, et al. 2017 Feb;76(2):355-363
Study Statements from the published study*
PLANETAS
Extension Study1
(IFX; Remsima/Inflectra)
NOR-SWITCH2
(IFX; Remsima/Inflectra)
Smolen et al.3
(IFX; Remsima/Inflectra)
Emery et al.4
(ETN; Benepali)
PLANETRA
Extension Study5
(IFX; Remsima/
Inflectra)
.
CT-P13, IFX biosimilar; SB2, IFX biosimilar; SB4, ETN biosimilar
Study design: OLE in patients with AS (N=174) from randomised PLANETAS study (week 62-
102). Non-randomised switch from IFX to biosimilar; comparison with biosimilar maintenance.
Single switch.1
Study design: Randomised, double-blind, non-inferiority Phase IV study in SpA, RA, PsA, CD,
UC, psoriasis (N=481). Single switch; patients on stable IFX randomised 1:1 to receive
continued IFX or biosimilar; comparison with originator. Powered for pooled data, 52-week follow
up.2
Study design: Randomised double-blind Phase III transition study. Switch from IFX to
biosimilar in patients with RA (N=396); 1:1 for SB2 or IFX to week 46. Single switch. At Week
54, IFX patients re-randomised to receive SB2 or continue IFX; 78-week follow up.3
Study design: Extension from randomised double-blind study in patients with RA (N=245).
Patients continued to receive SB4, or switched from ETN to biosimilar (non-randomised); 100-
week follow up. Single switch. Patient-reported outcome measured by HAQ-DI.4
Study design: OLE in RA (N=302) from randomised PLANETRA study (week 62-102). Non-
randomised switch from Remicade to CT-P13 (Remsima, Inflectra), comparison with biosimilar
maintenance. Single switch.5
88 patients maintained on CT-P13, 86 switched to CT-P13. ASAS20 response rates at week 102
were 80.7% and 76.9% (maintenance and switch, respectively). ASAS40 and ASAS partial
remission were also similar between groups.
241 patients continued on IFX, 240 switched to CT-P13. Disease worsening seen in 53 (26.2%)
patients maintained on IFX, 61 (29.6%) switched patients. Switching from IFX to CT-P13 was
not inferior to continued treatment with IFX.
101 patients continued on IFX, 94 switched from IFX to SB2, 201 continued on SB2. Safety,
immunogenicity and efficacy profiles remained comparable up to Week 78.
126 patients continued to receive SB4; 119 switched from ETN to SB4. ACR responses were
comparable; also sustained in the extension period. At Week 100, a similar proportion of
patients achieved low disease activity based on DAS28, SDAI, or CDAI.
158 patients maintained on CT-P13, 144 switched to CT-P13. ACR20 response rates at week
102 were 71.7% and 71.8% (maintenance and switch, respectively). ACR50 and ACR70 were
also similar between groups.

80. New classification criteria have changed the spectrum of AS
New NICE guidance on SpA will cover the whole patient journey
• Focus on EAMs and cross-disciplinary practice
• Pelvic x-rays in PsA
• New axial SpA referral guidelines
Forthcoming agents for SpA with multiple mechanisms of action
Data on switching stable patients on anti-TNF is evolving
• Biosimilars probably similar efficacy to originator biologics
• Switching studies are required
Summary

81. It’s the Keele difference.
Acknowledgments

82. Thank you
Research Institute for Primary Care and
Health Sciences
David Wetherall Building
Keele University
Newcaslte-under-Lyme
ST5 5BG
Tel: 01782 733905
Fax: 01782 734719
www.keele.ac.uk/pchs