773726

review-article2018
TAB0010.1177/1759720X18773726Therapeutic Advances in Musculoskeletal DiseaseF Proft and D Poddubnyy

Therapeutic Advances in Musculoskeletal Disease Review

Ankylosing spondylitis and axial

Ther Adv Musculoskel Dis

2018, Vol. 10(5-6) 129­–139

spondyloarthritis: recent insights and DOI: 10.1177/

https://doi.org/10.1177/1759720X18773726
https://doi.org/10.1177/1759720X18773726
1759720X18773726

impact of new classification criteria

© The Author(s), 2018.
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Fabian Proft and Denis Poddubnyy

Abstract:  Development of the Assessment in Spondyloarthritis International Society (ASAS)

classification criteria for axial spondyloarthritis (SpA) was one of the major breakthroughs in
the field over the past decade. Despite some concerns related to the specificity of the criteria,
they stimulated research into the early stage of the disease. This resulted in major advances
in the understanding of the course of the disease, revealing predictors of progression,
improvement in early diagnosis and treatment in axial SpA. In this review, we summarize the
recent developments resulting from the introduction of the ASAS classification criteria for
axial SpA and the implications for research and clinical practice.

Keywords:  Axial spondyloarthritis, ankylosing spondylitis, ASAS, classification criteria, diagnosis

Received: 22 December 2017; revised manuscript accepted: 6 April 2018

Introduction Current classification criteria Correspondence to:

A group of chronic inflammatory diseases is sub-
sumed under the generic term ‘spondyloarthritis’
(SpA) (Figure 1). They share common clinical,
genetic and pathophysiological features,1–3 such as
involvement of the axial skeleton (sacroiliac joints
and spine), characteristic peripheral manifestations
(dactylitis, enthesitis and asymmetric mono- or
oligoarthritis predominantly affecting the lower
extremities) and particular extra-articular manifes-
tations, such as anterior uveitis, psoriasis and
inflammatory bowel disease,1,2 as well as association
with the major histocompatibility complex class I
human leucocyte antigen-B27 (HLA-B27).1,4,5
Depending on the leading manifestation, two
major SpA groups are defined: axial SpA with
predominant involvement of the sacroiliac joints
and/or spine, and peripheral SpA with predomi-
nant peripheral manifestations such as arthritis,
enthesitis and dactylitis (Figure 1). In this review,
we will focus on recent developments resulting
from the introduction of the Assessment in
Spondyloarthritis International Society (ASAS)
classification criteria for axial SpA,6,7 and the
implications for understanding, diagnosing and
treating the disease.
Denis Poddubnyy
In the early years of this century, the concept of Department of
Gastroenterology,
axial SpA as one disease with two subsets has Infectiology and
arisen: with radiographic changes in the sacroiliac Rheumatology, Campus
Benjamin Franklin, Charité
joints (ankylosing spondylitis [AS] or radiographic Universitätsmedizin
axial SpA) and without (nonradiographic axial SpA Berlin, Hindenburgdamm
30, 12203 Berlin, Germany
[nr-axSpA]).8–11 With the introduction of new and denis.poddubnyy@charite.
effective treatment options, such as tumour necro- de
sis factor (TNF) blockers,12–16 it has become cru- Fabian Proft
Department of
cial to identify the disease as early as possible to give Gastroenterology,
patients these opportunities in the early course of Infectiology and
Rheumatology, Charité
the disease. As the commonly used classification Universitätsmedizin
criteria, the modified New York (mNY) criteria for Berlin, Berlin, Germany
AS,17 were not able to capture individuals with
early disease (i.e. without structural damage in the
sacroiliac joints on X-rays) and evidence of the abil-
ity of magnetic resonance imaging (MRI) to detect
active inflammation of the spine and sacroiliac
joints early in the disease course emerged,11,18–21
the new ASAS classification criteria were devel-
oped and published in 2009.6,7 They enabled clas-
sification of patients as having axial SpA even
before relevant structural damage in the sacroiliac
joints occurred. According to the new ASAS clas-
sification criteria,6 at an early disease stage this is
possible either by using the ‘imaging’ arm with
signs of active sacroiliitis in MRI with at least one

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Therapeutic Advances in Musculoskeletal Disease 10(5-6)

Spondyloarthris

Axial Peripheral
manifestaons manifestaons

Undifferenated
peripheral SpA
Reacve
Arthris

Non-radiographic Radiographic
axial SpA axial SpA Psoriac arthris

SpA
associated
with IBD

Figure 1.  The spectrum of spondyloarthritis (SpA) and overlap (cross-sectional and longitudinal) between
different SpA forms.
IBD, inflammatory bowel disease.

other SpA feature or by using the ‘clinical’ arm,
where the presence of HLA-B27 is mandatory with
an additional two or more SpA features (Figure 2).
Furthermore, classification is also possible at a later
stage when already advanced chronic changes of
the sacroiliac joints can be seen in the conventional
radiograph according to the mNY 17 and at least
one other SpA feature is present. These criteria
showed a sensitivity of 82.9% and a specificity of
84.4%, clearly outperforming the original European
Spondyloarthropathy Study Group22 and Amor
criteria.23 Focusing on the so-called ‘imaging arm’
alone, the ASAS classification criteria showed a
sensitivity of 66.2% and a specificity of 97.5%.
Moreover, when these criteria were applied to other
cohorts and tested against the rheumatologist’s
diagnosis as the gold standard, acceptable results
for sensitivity and specificity were shown. These
were comparable to the initial results with a sensi-
tivity between 68% and 87% and a specificity
between 62% and 95%.24–27 At follow up of the ini-
tial cohort6 after 3–5 years by the treating rheuma-
tologist, the positive predictive value that patients
who initially fulfilled the criteria would still be diag-
nosed with axial SpA was excellent with 93.3%.28
These classification criteria have been accompa-
nied by a new definition of inflammatory back
pain,29 a new definition of active sacroiliitis on
MRI30 and new classification criteria for peripheral
SpA and SpA in general.2
Controversial appraisal of the ASAS
classification criteria of axial SpA
The development of the new axial SpA classifica-
tion criteria6 was a significant step towards a

130 journals.sagepub.com/home/tab
 F Proft and D Poddubnyy

Figure 2.  Assessment in Spondyloarthritis International Society (ASAS) classification criteria for axial
spondyloarthritis (SpA).6
*Sacroiliitis on imaging refers to definite radiographic sacroiliitis according to the modified New York criteria or active
sacroiliitis on magnetic resonance imaging according to the ASAS consensus definition.
CRP, C-reactive protein; HLA-B27, human leucocyte antigen-B27; IBD, inflammatory bowel disease; NSAIDs, nonsteroidal
anti-inflammatory drugs.

better understanding, definition and unification
of the disease concept. Undoubtedly, these clas-
sification criteria draw attention to an early stage
of the disease and stimulated interventional trials
that resulted in approval of effective drugs for
patients who had had no approved therapeutic
options in the past. However, the concept of axial
SpA as one disease and the terminology used,
especially when it comes to the term ‘nonradio-
graphic axial SpA’, is still a matter of debate.3,31–33
First, it has to be pointed out that the assessment
of conventional X-rays of the sacroiliac joints is
challenging34 and high relevant inter- and intra-
observer variations have been reported.35–38 The
inter-observer variability was even more pro-
nounced when the grading from local readers and
trained central readers was compared,39,40 but
was also evident between central readers.41,42 The
highest variability was observed in the evaluation
of grades 1 and 2.34 This may be clinically impor-
tant, as the difference in the grading of one sacro-
iliac joint between grade 1 and grade 2 can change
the diagnosis from nr-axSpA to AS and vice versa,
with potentially prognostic and therapeutic
implications. Surprisingly, the reproducibility of
assessing radiographic sacroiliitis could not be
substantially improved by training.34 Interestingly,
in a follow up of the previously described ASAS
cohort, which was used to develop the ASAS clas-
sification criteria, a net progression from nr-
axSpA at the baseline visit to AS of 5% was seen
after a mean follow up of 4.4 years (range: 1.9–
6.8).43 However, cross-tabulation revealed that
more than every second patient (36 out of 62),
who was assessed mNY positive at baseline was
classified as mNY negative at the radiological fol-
low up, while 54 out of 295 mNY negatives at

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Therapeutic Advances in Musculoskeletal Disease 10(5-6)
baseline ‘progressed’ to the radiological form at
follow up.43 The explanation of Sepriano and col-
leagues is that the subtle radiographic changes
cannot reliably be discriminated from measure-
ment errors.43
Second, the term nr-axSpA indicates that no radi-
ographic changes are seen on the conventional
radiograph, but this does not always have to be
the case. There can be minor but obvious radio-
graphic changes in the sacroiliac joints (e.g. scle-
rosis and few small erosions of the right sacroiliac
joint = grade 2 and suspicious changes in the left
sacroiliac joint = grade 1), which are just not
enough to fulfil the radiological part of the mNY
criteria and therefore would still be labelled as
mNY negative and thereby classified as nr-axSpA,
although unambiguous changes are present. On
the other hand, it can be the case – even though
rare – that in the absence of radiographic sacroili-
itis there are clear radiographic changes of the
spine attributable to AS (e.g. syndesmophytes or
complete ankylosis). In this case, the classifica-
tion term would be still nr-axSpA.
The third point is related to the use of classifica-
tion criteria as an aid in the diagnostic process.
The sensitivity and specificity of the ASAS clas-
sification criteria for axial SpA were estimated to
be 82.9% and 84.4%, respectively.6 This was dif-
ferent for separate analysis of the ‘imaging’ arm
(sensitivity of 66.2% and specificity of 97.3%)6
and the ‘clinical’ arm (sensitivity of 56.6 % and
specificity of 83.3%).44 Thus, the multi-arm con-
struct of the ASAS criteria increases the sensitiv-
ity of the criteria, at the price of a decrease in
specificity (as compared with the imaging arm).
In the absence of diagnostic criteria for axial SpA,
the ASAS classification criteria may be used by
physicians in the clinical routine to diagnose axial
SpA in their patients. Hence, it has to be stressed,
that just ‘ticking boxes on a checklist’ of the
ASAS classification criteria for making a diagno-
sis means an inappropriate use of these criteria,45
which, like all classification criteria, should be
applied to patients with an established diagnosis
only. Classification criteria, in contrast to the
diagnostic approach, give a ‘yes’ or ‘no’ answer
with a certain sensitivity and specificity (instead
of disease probability with a diagnostic approach),
do not consider negative results of diagnostic tests
and do not take other explanations of symptoms/
differential diagnoses into account. As a result, a
young patient with unspecified back pain, who is
HLA-B27 positive, could be misdiagnosed with
132 journals.sagepub.com/home/tab
axial SpA because of other subjective items like a
‘good response to nonsteroidal anti-inflammatory
drugs (NSAIDs)’ or heel pain suggesting enthesi-
tis, for instance. The same is, however, also true
for the imaging arm of the criteria, which requires
the presence of bone marrow oedema on the MRI
scan of the sacroiliac joints in combination with
one additional SpA parameter.
Finally, in the first years after publication of the
ASAS classification criteria, the specificity of the
‘clinical’ arm was the main target of criticism.31,32
In the last years, the focus changed to the ‘imag-
ing’ arm and the specificity of ‘positive’ MRI,46–50
that led to an update of the ASAS definition of
active sacroiliitis on MRI,51 stressing the impor-
tance of the contextual interpretation of bone
marrow oedema as ‘highly suggestive of SpA’ if
used for classification. Despite the limitations
related to specificity, MRI still remains the most
important imaging method, especially for the
early diagnosis of axial SpA.
In order to address these concerns, to test the per-
formance of the ASAS classification criteria in a
large prospective cohort of patients including those
recruited in North America, and finally to modify
the classification criteria (if needed) in order to
increase the specificity, ASAS and the SpA
Research and Treatment Network (SPARTAN)
have recently announced the CLASSIC
(Classification of Axial SpondyloarthritiS Inception
Cohort) study that is going to start recruitment in
2018.52
Similarities and differences between
nr-axSpA and AS
nr-axSpA and AS share common epidemiological,
genetic and clinical characteristics4,16,27,53–56 that
support the concept of axial SpA as one disease
with two stages.1,53 The prevalence of nr-axSpA is
comparable with the prevalence of AS, each with
0.3–0.6% in the population.4,27 The ratio of nr-
axSpA to AS in patients first diagnosed with axial
SpA is close to 1:1.57–60 Cohort studies suggest
similar characteristics for age, prevalence of HLA-
B27, occurrence of peripheral manifestations and
extra-articular symptoms as well as disease activity
parameters (based on patient-reported outcomes)
and burden of the diseases.9,55,56 However, AS is
characterized by a significantly higher prevalence
of men and higher C-reactive protein (CRP) levels
in comparison with nr-axSpA.9,55,56 This might be
explained by the fact that female patients and
 F Proft and D Poddubnyy

Figure 3.  Treatment algorithm for axial spondyloarthritis (SpA) based on the Assessment in Spondyloarthritis
International Society/European League Against Rheumatism65 and American College of Rheumatology/
Spondylitis Association of America/SpA Research and Treatment Network64 recommendations.
bDMARDs, biologic disease-modifying antirheumatic drugs; csDMARDs, conventional synthetic disease-modifying
antirheumatic drugs; IL-17A, interleukin-17A; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumour necrosis factor.

patients with lower activity of inflammation (low
CRP, less inflammation on MRI) are less likely
develop radiographic changes, and therefore
might sustain at the nonradiographic stage.53 This
implies the existence of a certain subgroup of
patients with axial SpA with a rather mild, non-
progressive disease course.1,53 Approximately 12%
of the patients with nr-axSpA progress to AS over
a period of 2 years, with elevated CRP levels and
active sacroiliitis on MRI being the strongest pre-
dictors for this progression41,42. Concerning the
response to anti-TNF-alpha treatment, there
seems to be no significant difference between the
two groups when the level of active inflammation
at baseline is comparable.16,54,56,61
spondylitis, while phase III studies for nr-axSpA
are still ongoing.
In the last years, the major treatment target in
SpA was defined as clinical remission/inactivity
of musculoskeletal (arthritis, dactylitis, enthesi-
tis, axial disease) and extra-articular manifesta-
tions.62 The current versions of the leading
international management recommendations for
axial SpA (ASAS and the European League
Against Rheumatism recommendations from
201763) and treatment recommendations (from
the American College of Rheumatology/
Spondylitis Association of America /SPARTAN
from 201664) are similar (Figure 3).

According to these recommendations, first-line

Treatment of axial SpA
Axial SpA is at present a ‘hot topic’ in the field of
rheumatology and new therapeutic options are in
the pipeline and will be available in the near future.
The exact role of new therapies in the treatment
algorithm in axial SpA still has to be defined.
NSAIDs and TNF blockers are well-known
effective treatment options in patients with axial
SpA. With secukinumab, a monoclonal antibody
against interleukin-17A (IL-17A), a new com-
pound has been available since 2015 as an impor-
tant treatment option for patients with ankylosing
therapies for patients with symptomatic axial SpA
are NSAIDs, including selective cyclooxygenase-2
(COX-2) antagonists, together with exercise/phys-
iotherapy and education of the patients.65 Therapy
with conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs) such as sul-
phasalazine may have some beneficial effect in
patients with peripheral joint involvement, but are
not effective in the majority of patients with axial
involvement.66–68 If these patients have a poor
response to NSAIDs, contraindications or intoler-
ance for NSAIDs, the only effective treatment cur-
rently available is therapy with biological DMARDs

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Therapeutic Advances in Musculoskeletal Disease 10(5-6)

Figure 4.  (a) Approval status and year of approval for biological disease-modifying antirheumatic drugs
(bDMARDs) by the European Medicines Agency for axial spondyloarthritis (SpA) in the EU and a number of
other countries. (b) Approval status and year of approval for bDMARDs by the US Food and Drug Administration
for SpA in the USA.

(bDMARDs): TNF-alpha inhibitors65 or with
secukinumab, the recently introduced monoclonal
antibody against IL-17A.65
Currently there are five TNF inhibitors (inflixi-
mab,12 etanercept,14 adalimumab,13 golimumab15
and certolizumab pegol16) and one monoclonal
antibody against IL-17A (secukinumab69)
approved for the treatment of patients with AS in
the EU, the USA and most other parts of the world.
In the EU, four TNF inhibitors (etanercept,70 adal-
imumab,71 golimumab72 and certolizumab pegol16)
also have approval for the treatment of nr-axSpA
after failure of the standard treatments, whereas
the label is restricted to such patients with objec-
tive signs of active inflammation: elevated CRP or
active sacroiliitis on MRI (Figure 4).
The European Medicines Agency (EMA) further
demanded a therapy-withdrawal trial design to
investigate whether patients with nr-axSpA can
achieve a disease state of ‘drug-free remission’
after a treatment cycle like an ‘induction therapy’.
These trials are still ongoing.

134 journals.sagepub.com/home/tab

Contrary to the EMA decision, the US Food and
Drug Administration rejected the approval for
TNF inhibitors for nr-axSpA, due to questions
about the specificity of the ASAS criteria and the
natural history of the disease entity, hinting that a
significant proportion of these patients may show
spontaneous remission and therefore might not
require the costly and potentially harmful anti-
TNF therapy.73
There is some evidence that NSAIDs, in particu-
lar celecoxib, might possess not only a sympto-
matic efficacy but also disease-modifying
properties in AS, retarding the progression of
structural damage (syndesmophytes and ankylo-
sis) in the spine if taken continuously.74 However,
for diclofenac, a nonselective COX inhibitor, such
an effect was not proven in a recently published
trial.75 The data on the effect of TNF inhibitors
on radiographic spinal progression in ankylosing
spondylitis, despite their high anti-inflammatory
efficacy, remains controversial. While some stud-
ies could not show a retardation of radiographic
spinal progression in AS over a period of 2 years76–
78 or 479 years, three observational studies sug-
gested that it may take more than 4 years to detect
such an effect80–82 and that early (within the first 5
years or 10 years of the disease) initiation of anti-
TNF therapy might play a key role.81,82 Also,
achievement of sustained remission with TNF
inhibitors was associated with retardation of radi-
ographic spinal progression within a 2-year time
frame as shown in a recent analysis of an observa-
tional cohort study.83 However, no prospective
controlled trials have been conducted so far to
confirm these observations.
Concept of axial SpA in the context of other
inflammatory diseases
In many other systemic inflammatory-rheumatic
diseases, patients classified as one generic diagnosis
might present with relevant prognostic variations
among subgroups. This is obviously the case for
rheumatoid arthritis, with or without anti-citrulli-
nated protein antibodies, where no one would sep-
arate this heterogeneous patient cohort and limit
the existing effective treatment options, for exam-
ple, for patients without radiographic erosions. It is
generally true that capturing inflammatory disease
(such as rheumatoid arthritis, psoriatic arthritis,
Crohn’s disease, etc.) at an early stage implies a
broader spectrum of possible outcomes including
both milder forms with no or only slow progression
of structural damage and more severe forms with a
journals.sagepub.com/home/tab 135
F Proft and D Poddubnyy
rather more rapid progression of structural
damage.
A higher heterogeneity of the nr-axSpA subgroup
compared with AS is also acknowledged in the
wording of the current approval of TNF inhibi-
tors for nr-axSpA in the EU: in addition to the
lack of response to NSAIDs, objective signs of
inflammation (elevated CRP and/or positive
MRI) are required to start the treatment. So far,
only one phase III trial with a bDMARD (a TNF
inhibitor certolizumab pegol) has been per-
formed in patients with axial SpA (both nonra-
diographic and radiographic) fulfilling the ASAS
classification criteria. In this study, all patients
were required to have objective signs of inflam-
mation (positive CRP or active sacroiliitis on
MRI). As a result, the response rates in both sub-
groups (nr-axSpA and AS) were very similar sup-
porting again the concept of axial SpA as one
entity.16 We expect that the number of clinical
trials including the entire population of axial SpA
will increase in future.
Conclusion
Development of the ASAS classification criteria
for axial SpA has been one of the major break-
throughs in the field over the past decade. Despite
some concerns related to the specificity of the cri-
teria and some uncertainties around new nomen-
clature, the criteria stimulated research related to
the early stage of the disease. This resulted in
major advances in understanding the course of
the disease, revealing predictors of progression,
and improvement in the early diagnosis and treat-
ment of axial SpA.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare no conflict of interests in
preparing this article.
ORCID iD
Denis Poddubnyy https://orcid.org/0000-00
02-4537-6015
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