Diagnosis and Management of SpA

2
3
 Spondyloarthritis (SpA)
The SpA are a group of related
disorders that share distinctive clinical,
Undifferentiated radiographic and genetic features:
SpA • Sacroiliitis and spinal
inflammation
Juvenile SpA /
ERA Psoriatic • Peripheral arthritis and
Ankylosing Arthritis enthesitis
spondylitis (AS) (PsA) • Extra-articular manifestations
Arthritis / • Strong association with Human
spondylitis Leukocyte Antigen (HLA-B27)
associated with Reactive
IBD Arthritis (ReA) Spondyloarthritis can also be divided into:
Patients with predominantly axial and
predominantly peripheral SpA
IBD: Inflammatory Bowel Disease
Linden VD, et al. Chapter 10. In: Firestein, Budd, Harris, McInnes, Ruddy and Sergent, eds. Kelley’s Textbook of Rheumatology:
Spondyloarthropathies. 8th ed. Saunders Elsevier; 2009. p.1170.
Sieper J. Arthritis Res Ther 2009;11:208.
Spondyloarthropathies (SpA)
Inflammatory Back Pain (IBP)

• Back pain in SpA is frequently but not invariably has

inflammatory nature.

• According to the Assessment of SpondyloArthritis

international Society (ASAS) criteria, IBP typically exhibits at
least 4 of the following 5 features-
• Age of onset <40 years
• Insidious onset
• Improvement with exercise
• No improvement with rest
• Pain at night
Longer Symptom Duration is Associated with
More AS
Ratio of nr-AxSpA to AS in axSpA Patients in Relation to Symptom Duration at the Time of Diagnosis

Poddubnyy et al. Ann Rheum Dis 2012;71:1998-2001.

Diagnostic and Classification Criteria

• Diagnostic criteria ≠
classification criteria

• Classification criteria
should only be used to
include patients in
clinical studies or after
diagnosis

• No diagnostic criteria are

available for SpA

Deodhar. Clin Rheumatol 2014;33:714-747.

Diagnostic and Classification Criteria

• Gold standard for a clinical diagnosis should always be the

clinical judgement guided by full range of signs and
symptoms, laboratory and imaging results

• This kind of approach gives a subjective probability for a

diagnosis according to the physician's experience
Modified New York Criteria (1984)
 ASAS Classification Criteria for Axial SpA (2009)
In patients with back pain ≥3 months and age at onset <45 years
Sacroiliitis on imaging* HLA-B27
plus plus
OR
≥1 SpA feature** ≥2 other SpA features**

*Sacroiliitis on imaging: **SpA features:

• Active (acute) inflammation on • Inflammatory back pain
• Arthritis
MRI highly suggestive of
• Enthesitis (heel)
sacroiliitis associated with SpA
• Uveitis
or • Dactylitis
• Psoriasis
• Definite radiographic sacroiliitis • Crohn’s disease/ulcerative colitis
according to modified New York • Good response to NSAIDs
criteria 1984 • Family history for SpA
• HLA-B27
• Elevated CRP or ESR
**Elevated CRP is considered a SpA feature in the context of chronic back pain
Rudwaleit et al. Ann Rheum Dis 2009;68:777–83.
Spondyloarthritis (SpA)

Ax-SpA

Radiographic ax-SpA Non- Radiographic

Ankylosing Spondylitis (AS) (nr-axSpA)

Features of SpA Features of SpA

+ +
Sacrolilitis on X Ray Normal X Ray
+
Sacroilitis on MRI
Non-radiographic Axial SpA (nr-axSpA)
• Nr-axSpA includes pts that fullfill the ASAS axial SpA criteria,
but not the modified New York criteria for AS

• Unclear whether AS and nr-axSpA represent distinct but

overlapping disorders

• Or simply different points in the severity or chronology of

illness along a single spectrum
 Spectrum of Axial Spondyloarthritis: From Inflammation
to Structural Damage
Patients with chronic back pain ≥3 months and aged <45 years
Axial SpA (ASAS criteria)
Non-radiographic stage
X-ray-negative Ankylosing Spondylitis (modified New York criteria)
Estimated proportion of affected individuals*

MRI positive
sacroiliitis Radiographic stage
X-ray-positive sacroiliitis

Radiographic stage
X-ray-positive sacroiliitis and/or
spinal changes***

MRI negative,
HLA-B27-positive**

Time
*Heights of the images reflect an estimate of the proportions of patients in each group, an assumption as the exact numbers are not
currently known; **Clinical arm if nonradiographic axial SpA; ***Radiographic evidence of inflammatory spinal changes, including for
example, syndesmophytes, fusion, or posterior element involvement.
Sieper & van der Heijde. Arthritis Rheum 2013;65:543-51.
 About 20 % nr-axSpA will develop radiographic
sacroiliitis of AS after about 5 years of follow-up
Clinical features- differences between AxSpa and
nr-AxSpa

Axial Spa Nr Axial Spa

Gender M>F F>M
Uveitis More common Less common
HLA B27 More common Less common
CRP Higher Lower
Inflammation on MRI More Less

• Similar prevalence of peripheral articular and extraarticular disease

Diagnostic Challenges in Axial SpA
• No diagnostic criteria are available
• In clinical practice, a more flexible approach is needed than
“ticking boxes” according to the classification criteria
• Recognition of inflammatory back pain
• Differential diagnosis
– Sarcoiliitis on X-ray
– Reading MRIs (varying expertise, extensive training needed)
– Other pathologies may result in reactive lesions that appear as
inflammation on MRI
• For example: degenerative disease, lymphoma, bacterial infection
– Which patients benefit from Spinal MRI – more useful in patients with nr-
axSpA
“Can’t rely just on the imaging arm,
need to look at the whole context”
Sieper et al. Ann Rheum Dis 2009;68:ii1-ii44. Solmaz et al. Clin Rheumatol 2014;33:1475-1479.
Role of MRI
MRI SIJ
MRI SIJ

A. shows the T1 sequence. B. shows the STIR sequence. The bright white areas in
STIR, which are not seen in the T1, are the areas of bone marrow edema (arrows).
The corresponding areas in the T1-weighted images appear dark.
 ASAS/OMERACT: Definition of a Positive MRI of the
Spine in Axial SpA - Inflammatory Changes

ASAS definition of
‘positive MRI’ of the spine
(inflammation):

Evidence of anterior/
posterior spondylitis in 3
or more sites is highly
suggestive of axial SpA.
*
T1 T1-post-Gd STIR

Hermann KG et al. Ann Rheum Dis 2012; Epub 14MAY doi:10.1136/ard.2011.150680.

Predictors of radiographic progression

Arthritis Rheum 2012; 64 (5): 1388-98.

Keys to Early Diagnosis
• Evaluate IBP
• Look for other axSpA features - arthritis, dactylitis, enthesitis,
tenosynovitis, typical postural changes, restriction of spinal
mobility
• Extra-articular manifestations - uveitis, psoriasis and IBD
• Family history of SpA
• Response to previous treatments, such as NSAIDs
• CRP, the test should be repeated after 4 weeks
• Early referral
Role of imaging in the early diagnosis
• MRI is the only imaging technique capable of
detecting both active (inflammatory) and chronic
(structural) lesions as well as their anatomical dis-
tribution

• Correlates with histological findings in axSpA

• Predictor of response to therapy and can be used to

monitor disease activity over time
Role of imaging in the early diagnosis

• Inflammation on MRI of the SIJ is also highly

predictive of structural radiographic SIJ progression

• Identifies patients who could benefit from better

disease control
Recent advancement
MRI Lesion Combinations
• Improve the ability to differentiate axSpA from other
conditions
• 204 participants - Danish prospective cross-sectional MASH
study
• axSpA, lumbar disc herniation, postpartum buttock/pelvic
pain and healthy control groups

Sengül Seven et al. Rheumatology. April 2020

Recent advancement
• Bone marrow edema adjacent to the joint space was present
among all

• The edema score was highest in patients with axSpA

• Bone marrow edema adjacent to fat lesions or erosion with

cutoff score of ≥3 (fat lesions) and ≥4 (erosion) were exclusive
to axSpA

Sengül Seven et al. Rheumatology. April 2020

Benefits of Early diagnosis
• Early diagnosis and appropriate treatment of axSpA is
of utmost importance because
– 1) reassurance and knowledge to patients about their
disease, avoiding unnecessary investigations and
treatments
– 2) associated with better treatment responses, namely to
biologic treatments
– 3) prevent the development/ progression of structural
damage
– 4) early diagnosis and intervention will have positive
impact in work productivity
Diagnostic delay

• Despite recent advances, delay in diagnosis of SpA

still persists.

• An average diagnostic delay of 8.8 years was

described in women and 6.5 years in men
Measuring the disease activity
Composite scores

• BASDAI
• BASFI
• BASMI
• ASDAS-ESR
• ASDAS-CRP
Disease assessment

BASDAI (Bath Ankylosing Spondylitis Disease Activity Index )

• The gold standard for measuring and evaluating disease

activity in Ankylosing Spondylitis is the BASDAI.

• The questions are answered on a 10 cm VAS

Disease assessment
• BASDAI - Each question relates to how you have felt in the
past week.
Disease assessment

ASDAS (The Ankylosing Spondylitis Disease Activity Score)

• ASDAS is a new composite index to assess disease activity in
Ankylosing Spondylitis
• It combines five disease activity variables
• Better truth (validity), enhanced discriminative capacity and
improved sensitivity to change
• The two ASDAS formulas: ASDAS-CRP (preferred) and ASDAS-
ESR (alternative).

0.12 x Back Pain + 0.06 x Duration of Morning Stiffness + 0.11 x

ASDAS-CRP                   Patient Global + 0.07 x Peripheral Pain/Swelling + 0.58 x
Ln(CRP+1)

ASDAS-ESR 0.08 x Back Pain + 0.07 x Duration of Morning Stiffness + 0.11 x

Patient Global + 0.09 x Peripheral Pain/Swelling + 0.29 x √(ESR) 
Disease assessment
Management Guidelines
Goal of Management

• Relief of symptoms – Eliminate or reduce pain, stiffness, and

fatigue
• Maintenance of function
• Prevention of spinal deformities
• Minimization of extraspinal and extraarticular manifestations
• Maintenance of effective psychosocial functioning – To
preserve social participation, prevent job loss, and improve
health status and function
General principles of management
• Expert care - Rheumatologist, Dermatologist for psoriasis,
Gastroenterologist for inflammatory bowel disease (IBD), and
an Ophthalmologist for uveitis.

• Disease activity should be regularly measured and therapy

adjusted accordingly to improve outcome

• Patient education, physical therapy and exercise,

encouragement to participate in support groups, and
encouragement and support of smoking cessation.

• Pharmacologic treatment of the axial and peripheral articular

manifestations
Nonpharmacologic interventions 

• Patient education

• Need for a lifelong exercise and posture-training program

• Importance of regular follow-up and management of
comorbidities 

• Smoking cessation
Physical therapy

• Exercises include postural training, range of motion

exercises, stretching, recreational activities, and sometimes
hydrotherapy

• Spinal manipulation should be avoided in patients with

spinal fusion or advanced spinal osteoporosis
 
Pharmacological Therapy

• Pre - treatment evaluation 

• All patients - Baseline complete blood count, serum

creatinine, liver function tests, erythrocyte sedimentation
rate (ESR), and C-reactive protein (CRP).

• Hepatitis B and C screening – Must be done before

starting DMARDs.

• Testing for latent tuberculosis – Mantoux or IGRA

(interferon-gamma release assay ) test must be done
before starting all biologic DMARDs
Pharmacological Therapy

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs)
• Biological (bDMARDs).

• Unlike rheumatoid arthritis, oral (low-dose)

glucocorticoids have no role in AS, but intraarticular
injections may be helpful to selected patients.
 NSAIDs Are an Effective Treatment in SpA
ASAS20 responses at Week 61 Reduction of Radiographic Progression3
NSAIDs on-demand (n=104) vs continuous
80 *p<0.001 vs. placebo (n=111) over 2 years
Percentage of Patients (%)

64.75
60
52.5

40

20.4
20

0
Etoricoxib Naproxen Placebo
90/120 mg (n=99) (n=93)
(n=195)

Effectiveness of NSAID non selective and Radiographic progression was 0.41.7 in the
COX-2 selective for pain control and for continuous treatment group vs 1.52.5 in the
function2 on-demand treatment group (p=0.002)
1
Van der Heijde D, et al. Arthritis Rheum 2005;52:1205-1215. 2Sidiropoulos PI, et al. Rheumatology 2008;47:355-361. 3Wanders
et al. Arthritis Rheum 2005;52:1756-176.
NSAIDs Usage
European Medicines Agency (EMA) and Food and Drug
Administration (FDA) recommendation: Due to concerns about
safety of long term NSAIDs therapy  The lowest effective dose for
the shortest possible duration should be used with either non-
selective NSAIDs or COX-II selective inhibitors
Side effects (data from COX-II selective NSAIDs) are mainly:
• Cardiovascular
• Gastrointestinal (increase the risk of serious GI events by 5-10 fold)
• Renal
Taking into account the relatively young age and the low comorbidity in AS patients,
serious adverse events (SAEs) can be expected to occur in ≤1% of patients per year if
patients are treated with a full dose of a NSAID

Song et al. Arthritis Rheum 2008;58:929-938.

bDMARDs (Biologicals)

• TNF alpha antagonist – Infliximab, Etanercept,

Adalimumab, Golimumab, Certolizumab
bDMARDs (Biologicals)

• IL-17 antagonists
– Secukinumab, Ixekizumab
Braun Study
Infliximab in AS: Braun J. et al.

70 Patients with Active AS

(modified NY criteria and BASDAI of ≥ 4 and Spinal Pain ≥ 4 on a 10-cm VAS)
DMARDs and Steroids Not Allowed;
NSAIDs allowed

Randomized 1:1, Double-Blind; Placebo-Controlled through Week 12

Placebo Infliximab
at 0, 2, and 6 weeks* 5 mg/kg at 0, 2, and 6 weeks*

Primary Endpoint: > 50% improvement in BASDAI by Week 12

*Open-label follow-up: IFX 5 mg/kg q6w

Braun et al. Lancet. 2002;359:1187-93

BASDAI 20 and 50 responses up to week 12

Percentage of Patients With Improvement of:

BASDAI 20% BASDAI 50%

100
% of Patients Responding

100

% of Patients Responding
*P < 0.01 Primary **P < 0.0001
* endpoint
* 80
80 *

60 60 ** **
**
40 40

20 20

0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
Weeks Placebo Infliximab Weeks

Braun et al. Lancet. 2002;359:1187-93

Efficacy of TNF alpha inhibitors
• Metanalysis of 20 studies with data from 3096 patients.

• 15 studies with AS patients, 4 with nr-axSpA patients and one

with both.

• For AS patients, TNFαblockers showed better efficacy than

placebo for BASDAI, BASFI and ASAS40 response.

• TNFαblockers improve disease activity and functional capacity

clinically meaningful for both AS and nr-axSpA patients.

Ann Rheum Dis. 2015

GO-RAISE

Efficacy : ASAS Response Rates (Golimumab)

ASAS responses at Week 14 ASAS responses at Week 24
100
Patients Achieving ASAS Response (%)

100
*p<0.001
*p<0.001
80
80

60
50.0 60
*
44.9 * 49.3
40 43.5
40
23.2
*
20 15.4
20 15.4
7.7 12.8
5.1

0
0
ASAS40 ASAS5/6
PBO (n=78)
PBO (n=78) GLM 50 mg (n=138)
Adapted from Inman et al. Arthritis Rheum 2008;58:3402-12.
Braun et al. EULAR 2008. OP0032.
Treatment Recommendations

– As per 2019 update of the American College of

Rheumatology/ Spondylitis Association of
America/Spondyloarthritis Research and Treatment
Network
Treatment Recommendations

– RECOMMENDATIONS FOR ADULTS WITH ACTIVE AS

• NSAIDs > No treatment

• No preferred NSAID
• Active disease despite NSAIDs, consider TNFi > IL 17
inhibitors
• No preferred TNFi
• If TNFi unavailable or contraindicated may use IL 17
inhibitors
• If biologicals are unavailable or contraindicated
sulfasalazine or methotrexate esp in peripheral arthritis
Treatment Recommendations

– RECOMMENDATIONS FOR ADULTS WITH ACTIVE AS

• Active AS despite treatment with the first TNFi used,

conditionally recommend treatment with a different TNFi
over treatment with a non-TNFi biologic

• Strongly recommend against treatment with systemic

glucocorticoids
Treatment Recommendations

– RECOMMENDATIONS FOR ADULTS WITH ACTIVE AS

• Isolated active sacroiliitis, active enthesitis (except

Achilles, patellar, and quadriceps tendons) and active
peripheral arthritis despite treatment --> local steroids
Treatment Recommendations

– RECOMMENDATIONS FOR ADULTS WITH ACTIVE AS

• Strongly recommend treatment with physical therapy

over no treatment with physical therapy

• Active physical therapy interventions (supervised

exercise) over passive physical therapy.
Treatment Recommendations

– RECOMMENDATION FOR ADULTS WITH STABLE AS

• On-demand treatment with NSAIDs over continuous

treatment with NSAIDs

• TNFi + NSAIDs +/- cs DMARDs then may discontinue

NSAID, then csDMARDs

• Continue physical therapy

Treatment Recommendations

– RECOMMENDATIONS FOR ADULTS WITH AS-RELATED

COMORBIDITIES

• Uveitis
• Psoriasis
• Inflammatory bowel disease

– Involve Specialist of corresponding speciality

Summary of the main recommendations (2019)
Summary of the main recommendations (2019)
Summary of the main recommendations (2019)
Approvals for nr Ax SpA
• In Europe if elevated CRP and active inflammation on MRI
Biologics- Certolizumab, adalimumab, etanercept and
golimumab

• US FDA aproved Cimzia (certolizumab pegol) when objective

signs of inflammation present (March 2019)

• US FDA approved ixekizumab and secukinumab in people who

have objective signs of inflammation (June 2020)
 ASAS/EULAR Recommendations
for the Management of AS
D

I
S
Non-steroidal anti-inflammatory drugs (NSAIDs)
E
A
S
Education, A E
Axial Peripheral n
exercise, physical
disease disease a
therapy, P
rehabilitation, l S R
O
patient Sulfasalazine (SSZ) g u G
associations, e r R
self-help groups Local s g E
corticosteroids S
i e S
c r I
TNF blockers/IL 17 blockers s y O
N

ASAS: Assessment in AS Zochling J, et al. Ann Rheum Dis 2006;65:442-452.

EULAR: European league against rheumatism Braun J, et al. Ann Rheum Dis 2011;70:896-904.
ASAS Working Group Criteria for Response
• Patients will be categorized as an ASAS 20 responder if the patient achieves the
following:
– >20% improvement from baseline and absolute baseline
improvement of >10 (on a
0-100mm scale) in at least 3 of the following 4 domains:
• Patient global assessment
• Spinal pain
• Function (BASFI)
• Inflammation
– Average of the last 2 BASDAI questions concerning level and
duration of morning stiffness
– No deterioration from baseline (>20% and absolute
change of at least 10 on a 0-100 mm scale) in the
potential remaining domain
Anderson JJ, et al. Arthritis Rheum. 2001;44(8):1876–1886.
AS Patients with a History of IBD:
Relative IBD Flare Rate Lowest with infliximab
Incidence of IBD flares or new-onset disease according to TNF-inhibitor treatment
received
3
Per 100 patient-years

2.3 2.2
2

1.3

0.2
0
Remicade
Infliximab Humira
Adalimumab Enbrel
Etanercept Placebo
Placebo
n=366;Y:618 n=295;Y:132 n=419;Y:625 n=434;Y:150

*Calculations are based on a relatively small number of patients. Y: patient years

Adapted from: Elewaut et al. Rheumatology 2009;48:1029-1035

6
Summary

• Early diagnosis of SPA is essential

• Treat to target and remission is the goal
• Informed and shared decision
• Anti-tnf therapy major role in halting disease
progression
• Long term use is safe with monitoring

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