Update in

Axial Spondyloarthritis

and Ankylosing Spondylitis

Sergio Schwartzman, MDFranchellie M. Cadwell

Associate Professor of Medicine

Weill Medical College of Cornell University

The Hospital for Special Surgery

New York Presbyterian Hospital

New York, NY

The Hospital for Special Surgery

Disclosures

• Consultant:

– Abbvie, Antares, Genentech, Janssen, Lilly, Novartis, Pfizer, Regeneron, Sanofi,

UCB

• Speaker:

– Abbvie, Janssen, Genentech, Pfizer, UCB, Crescendo, Novartis

• Board Member:

– Crescendo Biosciences

– National Psoriasis Foundation

Objectives

• Understand the evolving definition,

immunology, genetics and classification of

ankylosing spondylitis (AS) and axial

spondyloarthritis (SpA)

• Comprehend established and new

therapies for AS and axial spondyloarthritis

Agenda

• Background –Group of Overlapping

Diseases

• Classification

• Genetics (HLA-B 27) and Potential

Causes

• Treatment

Spondyloarthritis:A Family of

RelatedDiseases

UndifferentiatedSpondyloarthritis

ReactiveArthritis(Reiter’s

Syndrome)

JuvenileSpondyloarthritis

ArthritisAssociated with

InflammatoryBowel Disease(Enteropathic

Arthritis)

PsoriaticArthritis

AnkylosingSpondylitis

Overlapping Illnesses - Now Termed

Spondyloarthritis

Spondylitis Association of America.

Entheses –Attachment of a Tendon or a

Ligament o Bone

Lories RJ, McInnes IB. Nat Med. 2012;18(7):1018-1019Schett G, et al. Nat Rev Rheumatol. 2017;13:731-741

Spondyloarthritis

Natural History Ankylosing Spondylitis

Reproduced with permission from: Little, H, Swinson, DR, Cruickshank, B. Upward subluxation of the axis in

ankylosing spondylitis: a clinical pathologic report. Am J Med. 1976;60:279. Copyright © 1976 Elsevier.

Causation

• In the correct genetic host and with the correct

precipitants Malfunctioning of the Innate and

Adaptive immune response

• Three overlapping elements:

• Enthesitis

• Bone erosion

• Inappropriate bone formation Syndesmophyte formation and

fusion

• IL23, IL-17 and TNF

– Enthesitis occurs via the IL-23/IL-17 axis

– TNF direct effects on bone erosion

– IL-17 direct effects on bone formation and bone erosion

Infection

Genetics - HLA B-27

• In the United States, approximately 6% of the

population is HLAB-27 positive

• Approximately 5% of patients with HLAB-27 develop

AS

• Heritability for >90% in AS – twin studies

Stolwijk C, et al. Epidemiology of Spondyloarthritis Rheum Dis Clin N Am 38. (2012) 441-476.

Epidemiology

• Prevalence: Varies by country

and background

• Gender ratios of around 2:1

(male:female)

Stolwijk C, et al. Arthritis Care Res (Hoboken). 2015 Dec 29. doi:10.1002/acr.22831. Akkoc N. Curr Rheumatol Rep. 2008. Braun

J, et al. Arthritis Rheum. 1998;41:58-67. Brewerton D. Lancet.1973;301:904-907. Braun J, et al. Lancet. 2007;369:1379-1390.

How Does HLA B27 Cause Spondyloarthritis

• Molecular Mimicry virus or bacteria copies the body

• Inability to Clear Infectious Agents

• Misfolding in the ER – inflammatory peptide

• Microbiome

Comparison of AS, SpA and RA

1. Saraux A, et al. Ann Rheum Dis 2005;64:1431-1435. 2. Guillemin F, et al. Ann Rheum Dis

2005;64:1427-1430. 3. Hunter TM, et al. Rheumatoid Int. 2017;37:1551-1557. 4. Reveille JD,

Weisman MH. Am J Med Sci. 2013;345(6):431-436. 5. Adomaviciute D, et al. Scand J

Rheumatol. 2008;37:113-119.

Natural History -

van der Linden, et al. Arthritis Rheum. 1984;27(4):361-8.

The Spectrum of Axial SpA

Pre-Radiographic Stage

(MRI abnl,

undifferentiated SpA)* Modified New York Criteria (1984)*

Time (years)

Radiographic Stage

Back Pain Back Pain Back Pain

Radiographic

SacroiliitisSyndesmophytes

Van der Linden, et al. Arthritis Rheum. 1984;27(4):361-8

NON RADIOGRAPHIC - Spectrum of Axial

Spondyloarthritis

*Clinical arm if non-radiographic axial SpA; **Radiographic evidence of inflammatory spinal changes, including

for example, syndesmophytes, fusion, or posterior element involvement.

Sieper J, et al. Arthritis Rheum. 2013;65(3):543-551.

Radiographic Stage

X-ray-positive sacroilitis

Time

Radiographic Stage

X-ray-positive sacroilitis

and/or spinal changes**

Non-Radiographic Stage

X-ray-negative

Patients with chronic back pain ≤3 months and age of onset <45 years

Axial SpA (ASAS criteria)

Ankylosing spondylitis (modified New York criteria)

The Spectrum and Natural History of SpA

Symptoms

• Onset of back pain before the age of 45 that persists over 3 months, that is at its worst in the mornings and during the night. It improves with exercise

• Tendinitis and fasciitis

• Fatigue, fever, loss of energy

• Eye inflammation - Uveitis

Delay in Diagnosis - Age at Onset of Symptoms

and Age at Diagnosis in AS

Feldtkeller E, et al. Z Rheumatol. 1999;58:21-30. Feldtkeller E, et al. Rheumatol Int. 2003;23:61-66.

From first symptoms to diagnosis: 5-10 yrs

Age at

Onset of Symptoms

Age at

Diagnosis

Age (years)

Pa

tie

nts

(%

)

n=1396

0

20

40

60

80

100

920 Males

476 Females

7050403020100 60

Outcome Measures

Garrett S, et al. J Rheumatol. 1994;21(12):2286-2291.

BASDAI

1.How would you describe the overall level of fatigue/tiredness you have experienced?

NONE ______________________________________ VERY SEVERE

2.How would you describe the overall level of AS neck, back or hip pain

you have had?

NONE ______________________________________ VERY SEVERE

3.How would you describe the overall level of pain/swelling in joints other

than neck, back, hips you have had?

NONE ______________________________________ VERY SEVERE

4.How would you describe the overall level of discomfort you have had

from any areas tender to touch or pressure?

NONE ______________________________________ VERY SEVERE

5.How would you describe the overall level of morning stiffness you have

had from the time you wake up?

NONE ______________________________________ VERY SEVERE

6.How long does your morning stiffness last from the time you wake up?

_________________________________________________________

0 hrs ½ 1 1½ 2 or more hours

• Aortic

regurgitation,

ascending

aortitis,

aortic valve

incompetence,

conduction

abnormalities,

cardiomegaly,

and

pericarditis

• Apical

pulmonary

fibrosis

LungHeartSkin

Psoriasis

Gut

Enteric

Mucosal Lesions

• Ileal and

colonic mucosal

ulcerations

• May affect 40%-

50% of patients

Eye

Acute

Anterior Uveitis

AS Spectrum Comanifestations and Comorbidities

Van der Linden S, et al. Ankylosing Spondylitis. In: Kelley’s Textbook of Rheumatology, 6th ed:1039-1053.

Bulkley BH, et al. Circulation. 1973;48:1014. Boushea DK, et al. Semin Arthritis Rheum. 1989;18:277. Gratacos

J, et al. J Rheumatol. 1993;20:1613. Lance NJ, et al. J Rheumatol. 1991;18:100.

Osteoporosis Cardiovascular Ds

Fibromyalgia

Optic Nerve

Uveitis in Spondyloarthritis

Hamideh F, et al. Semin Arthritis Rheum. 2001;30(4):217-241

http://www.geteyesmart.org/eyesmart/diseases/uveitis/.

• 30% to 40% of patients with AS over

their lifetime develop anterior uveitis

• Often unilateral presentation but can be

bilateral

• Anterior, Acute and Recurrent

Association Between Inflammatory Bowel

Disease and SpA

• Familial Clustering

• Genetic - HLA-B27, NOD2/CARD15, and IL-

23R

• Cytokines - TNF–α, IL-12, IL-23, and IL-17?

• Microbiome Associations

• Similar precipitants – infection, trauma,

“stress”

• Overlapping Treatments

SpA prevalence rates between 17 to 39% have been reported in IBD

SpA Prevalence in IBD/IBD Prevalence in

SpA

• SpA prevalence rates between 17 to 39% have been

reported in IBD

• In patients with different forms of SpA approximately

60% have gut inflammation “microscopic colitis ”

• 5 - 12% of SpA patients will develop overt IBD

• Routine screening is not recommended as only a small

percentage develop overt IBDSimenon G, Van Gossum A, Adler M, et al. Macroscopic and microscopic gut lesions in seronegative spondyloarthropathies. J Rheumatol. 1990;17(11):1491–4.

De Vos M, Mielants H, Cuvelier C, et al. Long-term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology. 1996;110(6):1696–703.

Treatment: AS and Bowel Disease

• Differential effects of anti-TNF therapies

• Infliximab, certolizumab, golimumab and

adalimumab are used in treating clinical

symptoms, inducing and maintaining remission,

and mucosal healing

• Can NSAIDs exacerbate IBD?

Rudwaleit M, et al. Best Pract Res Clin Rheumatol. 2006;20(3);451-471.

Molto A. Front Med (Lausanne). 2018; 5: 62.. doi: [10.3389/fmed.2018.00062]

Wach J J Rheumatol. 2016 Nov;43(11):2056-2063. Epub 2016 Sep 15.

Comorbidities

• Osteoporosis - Prevalence between 19 and 50% -

Inflammation and immobilization

• Cardiovascular - Age-adjusted and sex-adjusted HR of

1.60 accounting for 34.7% of all deaths

• Fibromyalgia - BSRBR-AS, (AS and AxSpA) 1,504 (68% male)-

20.7% met the 2011 research criteria for FM

Treatment Recommendations

Recommendations

• Strongly Recommend NSAID continuously, conditionally

recommend on-demand

• Strongly recommend TNFi – allowances for IBD and Uveitis

• Strongly recommend against systemic steroids

• Conditionally recommend against SAARDs

• Strongly recommend Physical Therapy

• Strongly recommend THR

• Conditionally recommended treating nr-AxSpA with TNFi

• Tendon injections should be avoided

Efficacy of Sulfasalazine

(Cochrane Meta-Analysis)

• Conclusion:

Patients with early disease, with higher levels of ESR,

and peripheral arthritis may benefit

Chen J, Liu C. Cochrane Database Syst Rev. 2005;(2):CD004800.

Some Evidence of Benefit No Evidence of Benefit

• ESR

• Morning stiffness

• Peripheral arthritis

(2 trials)

• Physical function

• Pain

• Spinal mobility

• Enthesitis

• Patient and physician

global assessment

11 Randomized Controlled Trials

Efficacy of Methotrexate

(Cochrane Meta-Analysis)

• Conclusions:

– MTX demonstrated no statistically significant benefit

– Additional randomized controlled trials with larger

samples,

longer duration, and higher MTX dosages are needed

Chen J, Liu C. Cochrane Database Syst Rev. 2004;(3):CD004524.

OutcomesMTX + Naproxen

vs Naproxen

MTX

vs Placebo

• Function

• Pain

• Peripheral arthritis/enthesitis

• Morning stiffness

• PGA

• CRP and ESR

No significant difference

between intervention groups

2 Randomized Controlled Trials (N=81)

Do NSAIDs really reduce radiographic

progression AS patients…and how should these

be administered ?

Do NSAIDs really reduce radiographic progression

AS patients…and how should these be

administered ?

NSAIDs on-demand treatment group (n=104)

vs. continuous treatment group (n=111) over 2

years1

Radiographic progression was 0.41.7 in the

continuous treatment group vs. 1.52.5 in the

on-demand treatment group (p=0.002)1

Probability Plot of mSASSS* Progression Over 24 months1

ENRADAS TrialProbability Plot of mSASSS* Progression

Over 24 months2

NSAIDs (diclofenac) on-demand treatment group (n=60) vs. continuous treatment group (n=62) over 2 years2

Radiographic progression was 1.28 in the continuous treatment group vs. 0.79 in the on-demand treatment group. The difference was numerical higher in the continuous group, but not statistically significant2.

*Modified Stoke AS Spine Score. NS: Not significant; GI: Gastrointestinal

1. Wanders et al. Arthritis Rheum 2005;52:1756-65. 2Sieper et al. Ann Rheum Dis 2016;75:1623-9.

Clinical improvements in AS after 24 weeks

of TNF inhibitor treatment

Van der Heijde, et al. Arthritis Rheum. 2005;52:582-591. Davis J, et al. Arthritis Rheum. 2003;48:3230-3236. van der Heijde, et al.

Arthritis Rheum. 2006;54:2136-2146. Inman et al. Arthritis Rheum 2008.589:3402-3412. Braun et al. EULAR 2008. #OP0032.

Landewe et al. Ann Rheum Dis 2014;73:39-47.

Response after 24 weeks of TNF inhibitor treatment in AS

Placebo

Infliximab

Etanercept

Adalimumab

Golimumab 50mg

Golimumab 100mg

Certolizumab 200mg

Certolizumab 400mg

*Different studies, not head to head comparisons

IL-17 Secukinumab in AS

Braun J, et al. ACR Annual Meeting. November 3-8, 2017, San Diego, CA

Secukinumab Secukinumab

MEASURE 2

IL-17 Ixekizumab - COAST V - Results

IL-17 COAST W – Objective Outcomes

Newer Therapies

• Tofacitinib

• Baricitinib

• IL-17 Ixekizumab

• Tildrakrisumab

Tofacitinib for Biologic-Naïve

Patients with AS

• Randomized, double-blind, placebo-controlled, dose-ranging

phase 2 trial

• Tofacitinib: oral JAK inhibitor

• Baseline characteristics

– Mean disease duration: 1.5-4.1 years; mean BASDAI total score, 6.3-7.0

– Concomitant DMARDs: 27.5%-44.2%

van der Heijde D, et al. ACR/ARHP 2015. Abstract 5L.

Biologic-naïve

adult AS patients

with IR or

intolerance

to NSAIDs

(N=208)*

Tofacitinib 10 mg BID

(n=52)

Tofacitinib 2 mg BID

(n=52)

Tofacitinib 5 mg BID

(n=52)

Placebo

(n=51)

Week 12

Follow-up

to

Week 16

Tofacitinib for AS: Results

• Tofacitinib treatment also associated with improvements in

ASDAS, SPARCC MRI (joint and spine)

*Primary endpoint. †P<.001 vs PBO. ‡P<.05 vs PBO.

Week 12, %Tofacitinib PBO

(n=51)2 mg (n=52) 5 mg (n=52) 10 mg (n=52)

ASAS20 response

(Emax model)*

Difference vs PBO

(95% CI)

56.0

15.8

(5.0-30.3)

63.0

22.9

(8.4-37.7)

67.4

27.3

(10.7-43.4)

40.1

–

ASAS20 (observed) 51.9 80.8† 55.8 41.2

BASDAI 50 46.2‡ 42.3‡ 42.3‡ 23.5

DC for AE 0 1.9 1.9 5.9

TEAEs 44.2 53.8 51.9 43.1

SAEs 0 1.9 1.9 3.9

• Apremilast - Posture Study - ASAS20 Response at Week 16: Placebo (164) 36.6%

Apremilast (163) 32.5%1

• Abatacept – Pilot study, in TNF naïve and TNFi IR. Week 24, ASAS40 was reached by

13% of group TNF naive and 0% of group TNF Exp; ASAS20 was reached by 27% and

20%, respectively3

• Ustekinumab - Study 1 [anti-tumor necrosis factor (TNF)-naïve]; Study 2 [anti-TNF

refractory], and Study 3 non-radiographic axSpA2

• Risankizumab - Wk 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the

18 mg, 90 mg and 180 mg compared with 17.5% Placebo

• Guselkumab – No studies being done

• Tocilizumab – ASAS 20 Wk 12, 37.3% vs 27.5 % placebo ASAS40 11.8% vs 19.6%

placebo4

1.https://clinicaltrials.gov/ct2/show/resASAS 20 ults/NCT01583374?view=results 2 Deodhar A, Arthritis Rheumatol. 2018 Sep 18. doi:

10.1002/art.40728. 3. Song I, of the Rheumatic Diseases 2011;70:1108-1110. 4. Sieper J et al. Ann Rheum Dis 2014;73:95–100

Unsuccessful Therapies

C-axSpA - Certolizumab for nr-Axial SpA

317 Pts axSpA without radiographic evidence AS400 mg dose of subcutaneous CIMZIA or placebo at baseline and at 2 and 4 weeks, followed by 200 mg of CIMZIA every 2

weeks thereafter

ASDAS-MI; defined as ASDAS decrease from

BL ≥2.0 points or reaching lowest possible valueDeodhar AA. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/ nct02552212/

Drug-Free Remission with Anti-TNF Therapy

Clinical response to discontinuation of anti-TNF therapy in patients with

ankylosing spondylitis after 3 years of continuous treatment with infliximab

Cumulative percentages of Retreatment after discontinuation of infliximab in AS

41/42 patients responded and reached a disease state similar to when treatment was discontinued

Baralaiakos. Arthritis Res Ther. 2005; 7(3): R439–R444.

Conclusions

• Axial Spondyloarthritides are joint and enthesial diseases

that have a predilection for affecting the axial skeleton.

There are distinctive clinical presentations and extra-

articular manifestations.

• The new axial and peripheral SpA criteria have broadened

our view of this group of diseases

• The genetics and immunology are being increasingly

understood

• Therapies targeting SpA have dramatically affected the lives

of patients and provided therapeutic choices

• Research into new therapy and biomarkers continues to

evolve