Best Practice & Research Clinical Rheumatology 28 (2014) 663e672

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Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh

The concept of spondyloarthritis: Where are we

now?
Neha Garg a, Filip van den Bosch b, Atul Deodhar a, *
a
Division of Arthritis & Rheumatic Diseases (OP09), Oregon Health & Science University, Portland, OR, USA
b
Department of Rheumatology, University of Ghent, Ghent, Belgium

a b s t r a c t

Keywords: The term spondyloarthritis (SpA) encompasses a group of diseases

Ankylosing spondylitis characterized by inflammation in the spine and in the peripheral
Axial spondyloarthritis joints, and other clinical features such as uveitis, dactylitis, psori-
Non-radiographic axial spondyloarthritis
asis, inflammatory bowel disease, and association with human
ASAS classification criteria
leukocyte antigen (HLA) B27. The spectrum of SpA encompasses
axial spondyloarthritis (axSpA) and peripheral spondyloarthritis
including psoriatic arthritis (PsA), reactive arthritis (ReA), and in-
flammatory bowel disease-associated arthritis. In recent years,
there has been tremendous progress in understanding the natural
history and pathogenetic mechanisms underlying SpA leading to
the development of effective treatments. It has become imperative
to identify the disease early, and accurately, to avail patients of
effective treatments in a safe manner. The development of the
Assessment of SpondyloArthritis International Society (ASAS)
classification criteria has been a welcome advance in this regard.
This article provides a historical evolution of the concept of SpA,
from the Rome Criteria to the ASAS criteria, current issues and
barriers with the use of ASAS criteria, and the work that still needs
to be done moving forward.
© 2014 Elsevier Ltd. All rights reserved.

* Corresponding author.
E-mail address: deodhara@ohsu.edu (A. Deodhar).

http://dx.doi.org/10.1016/j.berh.2014.10.007
1521-6942/© 2014 Elsevier Ltd. All rights reserved.
664 N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672

Introduction

The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory diseases that share
common clinical and genetic features. These features include inflammation of the axial skeleton
(sacroiliac (SI) joints and spine); peripheral arthritis commonly occurring in a characteristic pattern,
that is, asymmetric, oligoarticular, and predominately in the lower extremities; enthesitis; dactylitis;
uveitis; psoriasis; inflammatory bowel disease (IBD); and association with the HLA-B27 gene. While
some diseases within the SpA group affect the axial skeleton predominantly, some conditions involve
the peripheral skeleton primarily. In its current understanding, SpA encompasses axial spondyloar-
thritis (axSpA) including non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spon-
dylitis (AS), plus peripheral spondyloarthritis (pSpA) including psoriatic arthritis (PsA), reactive
arthritis (ReA), and IBD-associated arthritis (Fig. 1). The past few years have witnessed considerable
progress in advancing our understanding of the disease process and the natural history and genetics of
patients with axial skeletal inflammation, some of whom may develop damage at the SI joints at a later
stage. This led to defining axSpA as an umbrella term, which includes AS plus patients with axial
inflammation who do not have the X-ray changes that currently define AS.
The estimated prevalence of SpA in Europe has been reported to be 1.2% and that of AS is 0.2e1.2%
[1e5]. According to a recent National Health and Nutrition Examination Survey (NHANES), the age-
adjusted prevalence of axSpA is estimated to be up to 1.4% in the USA [6,7]. The onset of axSpA typi-
cally occurs at a young age (usually <45 years), but due to the lack of a pathognomonic clinical feature
or laboratory test, early diagnosis is difficult. The average delay in diagnosis is estimated to be 8e11
years [8]. Without early diagnosis and with delayed treatment, axSpA imparts a tremendous symp-
tomatic burden and loss of function during the productive years of life.
With limited treatment options in the past, the need for early diagnosis and treatment was less
crucial, but with the availability of new effective treatment options (biologic agents blocking tumor
necrosis factor alpha (TNF-a), and possibly interleukin (IL)-17, IL-12, and IL-23) [9] and with the evi-
dence that early treatment may retard the radiological progression, it becomes imperative that we
make efforts to identify these patients and institute treatments as early as possible after the onset of
symptoms. The development of the Assessment of SpondyloArthritis International Society (ASAS)
classification criteria for both axSpA and pSpA has been a welcome advance in this regard after a long
hiatus. This article provides a historical evolution of the concept of SpA, current issues and barriers
with the use of ASAS criteria, and the work that still needs to be done moving forward.

Fig. 1. Current Concept of Spondyloarthritis.[42].

 N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672 665

Historical review

The term “ankylosing spondylitis” predates the term and concept of “spondyloarthritis.” The term is
derived from the Greek words ankylosis (bent or crooked) and spondylos (vertebra). In 1912, Raymond
described convincing illustrations of AS in mummies and graves of ancient Egypt [10]. Since then,
various Egyptian, French, and Danish descriptions have been presented. This contrasts with the first
accepted description of rheumatoid arthritis (RA) by Sydenham in 1848 [11]. Several separate de-
scriptions at the end of the 19th century promoted the general recognition of AS.

Evolution of the concept of SpA

The concept of SpA started with the understanding of AS as a separate disease, leading to the
proposal of the first classification criteria for AS at the European Congress of Rheumatology in Rome,
known as the “Rome criteria” in 1961 (Table 1). Soon after that, the New York (NY) criteria were
published in 1966 [12] providing more specific definitions of AS and providing a grading method of
sacroiliitis for the first time. Another seminal event occurred in 1974 when Moll and Wright identified
certain seronegative polyarthritides separate from RA with a relation to AS. These diseases with
manifestations now known to be key for the pSpA spectrum included PsA, ReA (known as Reiter's
syndrome at the time), arthritis associated with uveitis, and IBD [13,14]. Strong association with the
HLA B27 gene was identified around the same time, providing a strong evidence for the unified concept
[5]. The concept of inflammatory back pain (IBP) evolved in 1977 [15] to help differentiate it from the
more common chronic low back pain and led to the modification of the NY criteria in 1984 [16]. The
criteria for IBP have also been revised since [17] (Table 1).
Radiographic sacroiliitis, still considered the hallmark of AS, remains an integral part of modified NY
(mNY) criteria for the classification of AS. Radiographic sacroiliitis of grade 2 bilaterally or grade 3e4
unilaterally has been termed as “definite radiographic sacroiliitis.” For decades, sacroiliitis, as defined
by the mNY criteria, has formed the backbone of defining AS and, by extension, the whole SpA spec-
trum (Table 2). The Amor criteria and the European Spondyloarthropathy Study Group (ESSG) criteria
were developed in the 1990s [18,19] addressing for the first time the entire spectrum of SpA including
undifferentiated SpA. The ESSG criteria have entry conditions requiring the presence of IBP or synovitis.
The Amor criteria do not have mandatory features required for classification but provide different
significance to various SpA features. The Amor criteria perform better than ESSG for early SpA, which
may be attributable to the Amor inclusion of “response to NSAIDs” (NSAIDS, nonsteroidal anti-
inflammatory drugs) and HLA-B27 typing [20].

Evolution of the concept of axSpA and pSpA and development of ASAS classification criteria

The main limitation of mNY criteria, which mandate the presence of definite sacroiliitis, is their
failure to identify early disease. With the knowledge that sacroiliitis typical of AS may take years to
develop after the appearance of the initial symptoms of IBP or peripheral arthritis [21,22], as well as

Table 1
Inflammatory back pain criteria [15,17].

Feature Odds ratio

Age at onset <40 9.9

Insidious onset 12.7
Pain at night (with improvement upon getting up) 20.4
Improvement with exercise 23.1
No improvement with rest 7.7

Best trade-off if four or more of the above five parameters are fulfilled (sensitivity 79.6%;
specificity 91.7%).
Positive likelihood ratio ¼ 79.6/(100e72.4) ¼ 2.9.
 666
Table 2
History of criteria developed for AS and SpA.

N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672
Rome criteria 1961 New York 1966 Modified NY 1984 Amor criteria 1990 ESSG criteria 1991
Clinical: Clinical: Clinical: Diagnosis of an SpA requires Inflammatory spinal pain
 Low back pain and  Limitation of motion of  Inflammatory low a score of 6. or synovitis (asymmetric or
stiffness for >3 months, lumbar spine in all three back pain for 3 months Feature: Score predominantly in the lower limbs)
which is not relieved by rest planes e anterior flexion,  Limitation of lumbar motion  Lumbar pain at night or Plus
 Pain and stiffness in the lateral flexion, and extension  Limitation of chest expansion lumbar morning stiffness: 1 At least one of the following:
thoracic region  History or presence of pain Plus  Asymmetric oligoarthritis: 2  Positive family history
 Limited motion in the at dorsolumbar junction or Radiographic:  Buttock pain (or bilateral  Psoriasis
lumbar spine lumbar spine  Sacroiliitis grade 2 alternating buttock pain): 2  Inflammatory bowel disease
 Limited chest expansion  Limitation of chest expansion bilaterally or 3 unilaterally  Sausage-like toe or digit(s): 2  Urethritis, or acute diarrhea
 History or evidence of to 1 inch (2.5 cm), at fourth  Heel pain or other  Alternating buttock pain
iritis or its sequelae intercostal space well-defined enthesities: 2 Enthesopathy
Radiological: Radiological Grading:  Iritis: 2  Sacroiliitis as determined
 X-ray showing bilateral Definite AS  Nongonococcal urethritis/ from radiography
sacroiliac changes  Grade 3e4 bilateral sacroiliitis cervicitis within 1 month
characteristic of AS with at least one clinical criterion of onset: 1
(this would exclude bilateral  Grade 3e4 unilateral or  Acute diarrhea within 1 month
osteoarthritis of sacroiliac joints) grade 2 bilateral sacroiliitis of arthritis onset: 1
with clinical criterion 1 or  Psoriasis, balanitis or
with both clinical criteria 2 and 3 inflammatory bowel disease
Probable AS (Crohn's or ulcerative colitis): 2
 Grade 3e4 bilateral sacroiliitis  Sacroiliitis (bilateral grade 2
with no clinical criteria or unilateral grade 3): 2
 HLA-B27(þ) or (þ) family
history of a spondyloarthropathy: 2
 Rapid (<48 h) response to NSAIDs: 2
 N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672 667

with the increasing use of new imaging modalities to diagnose sacroiliitis early, there has been a
renewed interest in the development of new classification criteria for patients with axial inflammation.
In most early AS patients, SI joint inflammation can be detected by magnetic resonance imaging
(MRI) scans, which marked an important advance in the diagnostic imaging of the pre-radiographic
phase of AS [23e25]. Studies show that up to 80% of such patients with no definitive changes of
sacroiliitis on plain X-ray would progress to develop AS over the long term [21]. It is also known that
the sacroiliitis seen on plain radiographs does not fully explain the disease burden in these patients as
assessed by disease activity measures, patient global assessments, or its impact on the quality of life
[26]. It was argued that “pre-radiographic” (or “non-radiographic”) and “radiographic” sacroiliitis were
part of the same disease spectrum and that detection of sacroiliitis on plain radiographs should be
taken as a measure of chronicity or severity and not as an essential part of the diagnosis [22,26]. This
concept is in line with the concept of early RA, in which the presence or absence of erosions is
considered a measure of severity and not part of the diagnostic or classification criteria [19]. As axSpA
patients with or without radiographic sacroiliitis are considered to be part of a single disease entity,
combined with the difficulties in grading sacroiliitis reliably, it was thought that distinguishing the
lower grades (grade 1 and 2) from “definite” sacroiliitis (grade 3) was probably not important in the
clinical practice [27e32]. To address these issues, there was a strong need to develop new classification
criteria to include such patients with early axial inflammation.
As there can be considerable overlap (and change over time) between axial and peripheral mani-
festations of SpA, a need was felt to develop new criteria for patients with predominantly peripheral
manifestations of SpA, as the ESSG and Amor criteria were not developed specifically for pSpA but for
the entire group [20].
These considerations were central in the development of the ASAS criteria for SpA, published in a
series of papers from 2009 to 2011 (Table 3) [33e35]. The ASAS group proposed the term “axial
spondyloarthritis” (axSpA) for the first time to describe the full spectrum of axial disease, and the term
“peripheral spondyloarthritis” to describe the full spectrum of SpA diseases predominantly affecting
the peripheral skeleton.
The ASAS group has provided a new definition of IBP [17], a new set of classification criteria for
axSpA [33,34], and a definition of active sacroiliitis on MRI [36]. The axSpA classification criteria include
the presence of chronic low back pain in a patient <45 years of age plus a combination of the presence
of sacroiliitis, HLA B27, and various SpA features (Table 3). Patients with axSpA are subclassified as
“radiographic” versus “non-radiographic” based on the presence or absence of definite sacroiliitis
according to mNY criteria. In addition, patients without sacroiliitis on imaging can also be incorporated
under non-radiographic axSpA if they show the presence of HLA B27 plus 2 SpA features (Table 3).
The new criteria performed well in the validation study showing a sensitivity of 82.9% and a specificity
of 84.4% outperforming the ESSG and Amor criteria, even after incorporating “sacroiliitis on MRI” into
the earlier criteria [37].
The new ASAS pSpA classification criteria consist of a combination of peripheral arthritis (usually
lower limb predominant and asymmetric), enthesitis, dactylitis, and other SpA features including
psoriasis, IBD, preceding infection, HLA-B27, uveitis, and sacroiliitis on imaging (Table 3) [35]. These
criteria also performed better than modified Amor and ESSG criteria (modified to include MRI find-
ings), particularly in terms of sensitivity. In addition, a combination of axSpA and pSpA criteria was also
found to be superior to both ESSG and Amor criteria with a sensitivity of 79.5% and a specificity of
83.3%, compared with 79.1% and 68.8%, respectively, for the modified ESSG criteria, and 67.5% and
86.7%, respectively, for the modified Amor criteria.

Advantages and drawbacks of the ASAS axSpA criteria

One major advantage of the ASAS criteria for axSpA is the identification of “non-radiographic” SpA
patients so that the rheumatologist can institute treatment early. Inclusion of MRI to detect sacroiliitis
early in the course has been a crucial advance. MRI is highly sensitive in detecting SI joint inflammation
[36] and has been shown to predict the development of AS [38]. MRI also offers an advantage in dis-
tinguishing active inflammation (bone marrow edema) from chronic changes of previous inflammation
(erosions, fatty marrow change, sclerosis, and ankylosis).
668 N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672

Table 3
ASAS Classification Criteria of Axial and Peripheral SpA.

ASAS Classification Criteria for Axial Spondyloarthritis:

In patients with 3 months of back pain and age of onset <45 years
 Sacroiliitis on imaging* plus 1 SpA features**
OR
 HLA B27 plus 2 SpA features
*Sacroiliitis on imaging
 Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA
 Definite radiographic sacroiliitis according to modified NY criteria
**SpA Features
 Inflammatory back pain
 Arthritis
 Enthesitis (heel)
 Uveitis
 Dactylitis
 Psoriasis
 Chron's colitis
 Good response to NSAIDs
 Family history of SpA
 HLA B27
 Elevated CRP
ASAS Classification Criteria for Peripheral Spondyloarthritis:
Arthritis or Enthesitis or Dactylitis
Plus 1 of:
 Psoriasis
 Inflammatory bowel disease
 Previous infection
 HLA B27
 Uveitis
 Sacroiliitis on imaging (radiographs or MRI)
OR
Plus 2 of the remaining
 Arthritis
 Dactylitis
 Enthesitis
 IBP in the past
 Positive family history of SpA

The sensitivity and specificity of the entire set of ASAS criteria are quoted to be 83% and 84%,
respectively. However, the ASAS criteria have been criticized for the poor specificity of the clinical arm.
Inappropriate use of these classification criteria for diagnostic purposes e especially in the absence of
objective signs of inflammation (such as peripheral synovitis/uveitis/elevated C-reactive protein, or
presence of sacroiliitis on the MRI scan) e can lead to misdiagnoses in clinical practice. The ability to
classify patients with axSpA based on clinical features without imaging evidence of sacroiliitis is an
important advance, but at the same time it renders a significant potential for overdiagnosing SpA in
patients with chronic mechanical back pain or fibromyalgia. This risk is high in populations with a low
pretest probability of the disease and/or a high HLA B27 prevalence, such as the white non-Hispanic
population within the USA (with an HLA B27 prevalence of 7.5%), or in certain Native Americans
with an even higher HLA B27 prevalence. Bone marrow edema is not specific for SI inflammation and
can be seen in trauma or osteoarthritis of the SI joints [36]. Hence, false-positive MRI scan in a young
individual with mechanical back pain runs the risk of misdiagnosis.
The predictive value of the SI joint bone marrow edema for radiographic progression is not
consistent in all SpA patients [36]. Therefore, at present, it remains difficult to predict which patients
with IBP with or without bone marrow edema on MRI scans will progress to develop ankylosis
spondylitis. There still remains a subgroup of patients in whom IBP and bone marrow edema around
the SI joints spontaneously resolve (Fig. 2). Misdiagnosing SpA in these patients might lead to over-
treatment with medications that have potential risks.
 N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672 669

Fig. 2. Clinical Conceptualization of the Natural History of axSpA: An Emerging Model (published in Deodhar A. The Rheumatologist,
May 2014 issue [47], originally adopted from van Vollenhoven, R. F. Nat. Rev. Rheumatol. 7, 205e215 (2011)).

Lastly, the term “non-radiographic” axSpA remains unclear and confusing to many rheumatologists
[39]. The “non-radiographic” axSpA terminology includes patients with no changes of sacroiliitis on
any imaging, those with changes of sacroiliitis on MRI scan alone, plus those with changes of sacroiliitis
on plain radiographs that fail to fulfill the mNY criteria for “definite sacroiliitis.” Furthermore, the term
“non-radiographic” axSpA does not clarify that it is applicable to SI joints only and not to the spine
radiographs (but this confusion is also present with the mNY criteria, which do not allow the classi-
fication of patients as AS when there is only isolated spine involvement without definitive sacroiliitis).
Similarly, classifying patients with clear structural changes in SI joints on T1-weighted MRI scans as
“non-radiographic” SpA is another source of confusion. Hence, although ASAS has appropriately
allowed the presence of MRI-defined sacroiliitis to be classified as axSpA, the terms “radiographic”
versus “non-radiographic” add a layer of confusion.

Advantages and drawbacks of the ASAS pSpA criteria

The ASAS pSpA criteria have several notable advantages. The inclusion of monoarthritis and poly-
arthritis in addition to oligoarthritis, requirement of fewer clinical features to fulfill the criteria, in-
clusion of enthesitis and dactylitis as entry criteria, and the addition of HLA-B27 are some obvious
advantages increasing the sensitivity of the criteria. Clinical trials using new, targeted biologics for ReA
or IBD-associated arthritis are unlikely to be carried out by the pharmaceutical industry for economic
reasons. However, if these diseases are combined under the term “peripheral SpA,” the pharmaceutical
industry may be interested in carrying out such trials, which may pave the way for Food and Drug
Administration (FDA)-approved therapies for such patients [40].
However, the ASAS criteria for pSpA also raise questions. The organization of various pSpA diseases
(PsA, IBD-associated arthritis, and ReA) into a single group reignites the debate of “lumping” versus
“splitting.” [41,42] Backers of “lumping” would argue that, given the unifying features including as-
sociation with HLA-B27, similar clinical manifestations including dactylitis and uveitis, common
therapies employed (anti-TNF, anti-IL-12, and anti-IL-23 drugs), and potentially shared pathogenic
mechanisms, these diseases should be lumped. However, with advancing knowledge within all
670 N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672

medicine specialties, clinicians and researchers “split” diseases into specific subcategories, enabling
better understanding of the pathogenesis and prognosis, and also paving the way for drug trials tar-
geting a narrow spectrum of the disease e as would be argued by “splitters.” This raises, of course, the
question of how far one should go in “splitting diseases,” as it seems reasonable to speculate that
different pathogenetic mechanisms play a role in, for example, arthritis mutilans compared to spon-
dylitis, yet both manifestations are also “lumped” under the term “psoriatic arthritis”.
Indeed, there is reason to believe that the various diseases lumped together under “peripheral
SpA” are fundamentally different leading to substantially varied responses to certain therapeutic
agents (e.g., antibiotics for post-Chlamydia ReA would not work for any other member of pSpA).
“Splitters” believe that the differences between these diseases are significant enough to warrant
separate consideration in the classification criteria. Specifically, ReA with a proven recent gastro-
intestinal or genitourinary infection should probably be split because of the inherent risk that the
underlying infection could deteriorate with immunomodulatory drugs. PsA also deserves special
mention in this context, because it is the most well-studied disease among those in the “peripheral
SpA” spectrum. Various criteria have been published for classifying PsA, such as the Moll and
Wright criteria, and the more recent CASPAR criteria [43], with much better specificity [44,45]. In
the setting of the clinical trials for pSpA, it would be challenging to interpret the outcome measures
validated for one subset of pSpA and not others, and treatment outcomes may be misinterpreted.
Emerging data on the treatment of individual disease entities (e.g., combination antibiotics for post-
Chlamydia ReA [46]) may be overlooked and not addressed in clinical trials designed to study pSpA
as a broad group [42]. Lastly, the entry criteria allow for enthesitis, which is difficult to distinguish
from fibromyalgia tender points or the mechanical causes of enthesitis, contributing to a low
specificity.

Summary

The concept of SpA is a work in progress. On the one hand, we would like to diagnose patients with
SpA early, and, on the other, we would like to avoid overdiagnosis by erroneously including patients
with mechanical back pain (or patients with fibromyalgia). ASAS criteria have been a major advance in
furthering the understanding of SpA, paving the way for the highly needed research in this group of
disorders. Several questions remain unanswered.

Future perspectives

The most appropriate terminology to describe the disease and its subsets continues to be debated.
One could envision diagnosing patients as “SpA” alone with subsequent description of other charac-
teristics such as predominantly axial or peripheral, presence or absence of structural changes on ra-
diographs or MRI (for axial disease), and presence of psoriasis, uveitis, IBD or antecedent
gastrointestinal or genitourinary infection, etc. The natural history of patients with inflammatory low
back pain remains unclear. How many of those patients actually progress to develop AS, what are the
predictors of such progression, and how to focus treatment to those with a higher risk of progression
are some other areas in need of future research. Modification of the current criteria to improve
specificity would help to avoid the misdiagnosis of mechanical back pain as axSpA. A slightly different
method of reporting SpA by first diagnosing SpA and then adding descriptive terms such as pre-
dominantly axial or peripheral, with or without psoriasis, IBD or uveitis, radiographic or not, and with
or without recent infection (in the case of ReA) might be more appealing.

Future research agenda

Modification of the current classification criteria to improve the specificity of axSpA, development
of a consensus terminology for various subsets of spondyloarthritides, and conducting epidemiologic
studies to assess the natural history of IBP and nr-axSpA are some of the important needs. These needs
should be considered in any future research agenda on this topic.
 N. Garg et al. / Best Practice & Research Clinical Rheumatology 28 (2014) 663e672 671

Practice points:

1. The average delay in the diagnosis of axial spondyloarthritis (axSpA) is estimated to be 8e11
years. Without early diagnosis and with delayed treatment, axSpA imparts a tremendous
symptomatic burden and loss of function during the productive years of life.
2. The main limitation of modified NY criteria, which mandate the presence of definite sac-
roiliitis, is their failure to identify early disease. The new Assessment of SpondyloArthritis
International Society (ASAS) classification criteria for axial spondyloarthritis can be used to
classify patients early, before they develop definitive sacroiliitis on radiographs.
3. Using “classification criteria” for diagnosis in clinical practice needs to be avoided. Inap-
propriate use of the ASAS classification criteria for diagnosis can lead to overdiagnosis and
inappropriate treatment.
4. The ASAS classification criteria for “peripheral spondyloarthritis” lump together separate
disease entities such as psoriatic arthritis, reactive arthritis, and arthritis associated with
inflammatory bowel disease. This “lumping” may help in clinical trials, although it may not
help in targeting therapy.

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