Key words Achilles tendon - axial spondyloarthritis - sonoelastography - strain index
Schlüsselwörter Axiale Spondyloarthritis - Achillessehne - Sonoelastographie - Strain index
Introduction
The term spondyloarthritis (SpA) represents a condition characterised by a broad
spectrum of clinical manifestations, laboratory abnormalities and imaging features;
in particular, SpA is an inflammatory condition in which both peripheral and axial
joints might be affected [1 ].
Enthesitis, that is the inflammation of insertions of tendons, ligaments and capsules
into the bone, is the characteristic sign of ankylosing spondylitis (AS) and related
pathologies, which are commanly regrouped as axial(ax)-SpA [2 ]. Clinical assessment of enthesitis is
performed by eliciting tenderness at the affected entheseal site. Clinical diagnosis
of enthesitis, however, is neither sensitive nor specific and it often relies on
typical abnormalities seen in imaging studies [3 ]. Considering entheses involvement as critical in ax-SpA, it would be
useful to develop reliable tools to assess enthesitis in order to improve the
management of patients. Ultrasound (US) has a greater sensitivity than clinical
examination and other imaging techniques for the detection of peripheral involvement
of ax-SpA [4 ].
Sonoelastography (SE) is a method that can assess the mechanical properties of soft
tissue qualitatively and quantitatively through US imaging techniques [5 ]. SE has demonstrated feasibility in the
diagnosis of cancers of the breast and liver, and in some preliminary work, in
several musculoskeletal disorders. It is based on the principles that the
compression of soft tissue produces strain that is greater in tissues that are
softer and more elastic than in harder, more rigid tissues. Pathological and healthy
tissues can present with similar echogenicity and morphology on conventional US.
However, alterations in tissue elasticity often occur with degeneration or other
pathological changes that involve the sof tissues [6 ].
The clinical utility of SE for the diagnosis of common tendinopathies and plantar
fasciitis has been reported previously in the literature [7 ]
[8 ]
[9 ]. The SE findings of Achilles
tendon in patients with AS compare to healthy subjects have been reported only Turan
et al. [10 ]. However, to the best of our
knowledge, there is no report evaluating the association of strain index (SI) with
disease related parameters in patients with ax-SpA. The aims of this study were to
assess semiquantative SI provided during the SE examination compared to healthy
controls and to evaluate the association of SI with spinal pain, disease activity,
functional status, or enthesitis index in patients with ax-SpA.
Material and Methods
This prospective observational cross-sectional study was approved by the local ethics
committee of our institution and performed in accordance with the principles of the
Declaration of Helsinki. Written informed consent was obtained from all participants
prior to the study.
Sixty-four ax-SpA patients without clinical symptom of enthesitis, who was admitted
to outpatient clinic of physical therapy and rehabilitation between September 2015
and June 2016, were included in the study. All patients fulfilled the Assessment of
Spondyloarthritis International Society (ASAS) classification criteria [11 ] for nonradigraphic ax-SpA and/or
Modified New York diagnosis criteria for AS [12 ]. None of the patients had achilles tendon enthesitis within the 3
months prior to the study and psoriasis vulgaris. Patients with a known history of
metabolic or endocrine diseases and sports-related or traumatic injuries were
excluded from the study. A total of 30 volunteers who did not have any tendon
complaint or systemic inflammatory disorders that might influenced the results were
matched with the study subjects according to age and gender, and were included as
controls.
Clinical evaluation
The demographic and clinical characteristics of all participants were recorded.
Disease activity was measured via the self-administered 6-question Bath
Ankylosing Spondylitis Disease Activity Index (BASDAI) (0: no disease activity,
10: the highest disease activity) [13 ].
Patients with a BASDAI ≥ 4 were defined as having active disease.
Functional capacity was measured via the self-administered 10-question Bath
Ankylosing Spondylitis Functional Index (BASFI) (0: lowest activity, 10: the
highest activity) [14 ]. Weight and height
were measured and body mass index (BMI) was calculated by dividing weight in
kilograms by height in meters squared. Spinal pain intensity was evaluated
visual analog scale (VAS).
The Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was
used to assess the severity of enthesitis [15 ]. This index was calculated by the evaluation of following 16
enthesitis sites: the greater trochanter right/left (R/L),
quadriceps tendon insertion into the patella (R/L), patellar ligament
insertion into the patella and tibial tuberosity (R/L), Achilles tendon
insertion (R/L), plantar fascia insertion (R/L), medial and
lateral epicondyles (R/L) and the supraspinatus insertion (R/L).
Tenderness at each site was quantified on a dichotomous basis:
0=non-tender and 1=tender.
Sonoelastography
Toshiba (Toshiba Medical Systems Corporation, Otawara, Japan) Aplio 500 US device
and 12-MHz linear probe was used for SE examinations. The Achilles tendons were
examined axially and longitudinally by a radiologist who was experienced in
musculoskeletal US and blinded to the clinical data while the patient was lying
in the prone position with the foot hanging over the edge of the examination
table in a relaxed position. During US examination, the anterior-posterior
thickness and width of the tendon was determined by measuring the diameter in a
transverse view at the level of the medial malleolus. SE images of the tendon
were obtained in the longitudinal plane in the same position. The transducer was
perpendicular to the tendon in order to avoid anisotropy. The compression and
decompression were applied to the area of examination by the probe. Light
repetitive compressions were performed to obtain elastography images using a
free-hand technique. Repetitive compressions cause sinusoidal waves. If the
pressure of compression and decompression is periodic and regular, symmetric
sinusoidal wave can be obtained. If the symmetric sinusoidal wave could not be
obtained, compression and decompression should be performed again. The
compression phase was observed above the baseline and the decompression phase
was observed below the baseline. The measurements were performed during the
decompression phase. Region of interest (ROI) was placed on the Achilles tendon
and adjacent Kager’s fat pad. The software calculates the SI (tendon
strain/Kager’s fat pad strain) based on the displacement using
the ratio of the lesion and adjacent Kager’s fat pad. All patients
scanned by the same sonographer. The SE imaging of ax-SpA patient is
demonstrated in [Fig. 1 ].
Fig. 1 Sonoelastography image of the Achilles tendon of a 35 years
old male patient with axial spondyloarthritis. The monitor is divided
into two windows. The right windowis longitudinal gray-scale ultrasound
image, left window is colour-coded sonoelastography image.Below these
windows is the sinusoidal wave of compression and decompression.The
strain index (tendon strain/Kager’s fat strain) was calculated
as 3.45.
Statistical Analysis
All statistical analyses were performed using the Statistical Package for the
Social Sciences (SPSS), version 22>, for Windows (SPSS, Chicago, IL,
USA). Continuous variables were expressed as mean±standard deviation and
categorical variables were expressed as percentage. Compliance of the variables
with normal distribution was assessed by the Kolmogorov-Smirnov test.
Inter-group analyses were performed with Student’s t-test for normally
distributed variables and the Mann-Whitney U test for non-parametric variables.
The Chi-square test was used for the analysis of categorical variables. To
determine the correlation between the variables, Spearman’s rank or
Pearson’s correlation analyses were performed according to the
distribution of the data. A P value of<0.05 was considered as
statistically significant.
Results
The demographic and clinical characteristics of the patients are presented in [Table 1 ]. No significant difference was
observed between the groups in terms of age, gender, and BMI (age: 39.7±10.8
vs. 37.2±5.8 years, P=0.289; female/male: 27/37 vs.
15/15, P=0.522; BMI: 28.1±4.6 vs. 27.8±3.8,
P=0.184, respectively). The mean disease duration in patients with ax-SpA
was 5.11±5.0 years. The mean BASDAI and BASFI scores were 3.7±2.2,
3.2±2.5 respectively. HLA-B27 positivity was observed in 65.6% of
the patients with ax-SpA. In addition, 21 patients were receiving non-steroidal
anti-inflammatory drugs (NSAIDs) and 43 patients were receiving biological agents.
The biological agents used consisted of adalimumab in 19 patients, etanercept in 12
patients, infliximab in 9 patients, and golimumab in 3 patients.
Table 1 Demographic and clinical characteristics of patients
with axial spondyloarthritis.
ax-SpA patients
(n=64)
Age (years), mean±SD
39.7±10.8
Sex (Female/male) n (%)
27/37 (42.2/57.8)
BMI (kg/m2 ), mean±SD
28.1±4.6
Disease duration (years), mean±SD
5.11±5.0
History of peripheral arthritis n (%)
13 (20.3)
History of uveitis n (%)
14 (21.9)
HLA-B27 positivity n (%)
42 (65.6)
ESR mm/h, mean±SD
18.8±13.6
CRP mg/dL, mean±SD
0.82±0.9
BASDAI, mean±SD
3.7±2.2
BASFI, mean±SD
3.2±2.5
SPARCC, mean±SD
2.5±4.1
Medication n (%)
NSAID
21 (32.81)
ETN
12 (18.8)
INF
9 (14)
ADA
19 (29.69)
GOL
3 (4.69)
ax-SpA axial spondyloarthritis, SD Standard deviation,
BMI body mass index, ESR erythrocyte sedimentation rate,
CRP C-reactive protein, BASDAI Bath Ankylosing Spondylitis
Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional
Index, SPARCC Spondyloarthritis Research Consortium of Canada, NSAID
non-steroidal anti-inflammatory drugs, ETN etanercept, INF
infliximab, ADA adalimumab, GOL golimumab.
The US examination findings of the patients and controls are presented in [Table 2 ]. Although the mean anterior-posterior
thickness and width of left Achilles tendon did not significantly differ between the
patients and the controls (4.8±2.1 vs. 4.4±0.5 mm,
P=0.184; 15.9±2.5 vs. 15.1±1.2 mm, P=0.088,
respectively), the mean anterior-posterior thickness and width of right Achilles
tendon were significantly higher in ax-SpA patients than in the controls
(5.02±2.6 vs. 4.44±0.46 mm, P=0.033;
16.3±2.7 vs 15.3±1.1 mm, P=0.042). Ax-SpA patients
had significantly higher right and left SI than the controls (2.96±0.94 vs.
1.90±0.45, P<0.001; 2.95±0.95 vs. 1.92±0.48,
P<0.001, respectively). When the patients were classified into two subgroups
according to the types of medication they received (NSAIDs: 21 patients, biological
agents: 43 patients), there were no significant differences between these groups in
terms of BASFI, ESR, CRP, and SI (P>0.05 for all). However, the mean BASDAI
score was significantly higher in the NSAIDs group than in the biological agent
group (4.7±2.1 vs. 3.3±2.2, P=0.02). There was no
significant difference in righ and left Achilles SI between male (n=37) and
female (n=27) ax-SpA patients (2.93±1.01 vs 2.99±0.84,
p=0.759; 2.92±1.02 vs 2.98±0.86, P=0.807,
respectively).
Table 2 The ultrasonography and sonoelastography examination
findings of the patients and controls.
ax-SpA patients (n=64)
Controls (n=30)
P value
Age (years), mean±SD
39.7±10.8
37.2±5.8
P=0.289
Sex (Female/male) n (%)
27/37 (42.2/57.8)
15/15 (50/50)
P=0.522
BMI (kg/m2 ), mean±SD
28.1±4.6
27.8±3.8
P=0.184
Left AP thickness (mm), mean±SD
4.8±2.1
4.4±0.5
P=0.184
Right AP thickness (mm), mean±SD
5.02±2.6
4.44±0.46
P=0.033
Left width (mm), mean±SD
15.9±2.5
15.1±1.2
P=0.088
Right width (mm), mean±SD
16.3±2.7
15.3±1.1
P=0.042
Left strain index, mean±SD
2.95±0.95
1.92±0.48
P<0.001
Right strain index, mean±SD
2.96±0.94
1.90±0.45
P<0.001
ax-SpA axialspondyloarthritis, SD Standard deviation,
BMI body mass index, AP anterior-posterior.
The correlations of SI with disease related parameters are presented in [Table 3 ]. In ax-SpA patients, SI of right and
left Achilles tendons showed significantly positive correlations with spinal VAS,
BASDAI, BASFI, and SPARCC enthesitis index (for right side; P=0.016,
r=0.300; P=0.001, r=0.408; P=0.001, r=0.401;
P=0.002, r=0.378, respectively; for left side; P=0.004,
r=0.357; P<0.001, r=0.452; P<0.001, r=0.451;
P=0.007, r=0.336, respectively). However, there were no significant
correlation between SI and age, sex, ESR, CRP, BMI, or mean disease duration (for
all P>0.05).
Table 3 The correlation of strain index with disease related
parameters.
Right Strain index
Left Strain index
r
P value
r
P value
Age (years)
0.078
0.538
0.093
0.466
BMI (kg/m2 )
0.197
0.119
0.174
0.169
Disease duration (years)
0.134
0.291
0.133
0.296
BASDAI
0.408
0.001
0.452
<0.001
BASFI
0.401
0.001
0.451
<0.001
sVAS
0.300
0.016
0.357
0.004
SPARCC
0.378
0.002
0.336
0.007
CRP (mg/dL)
0.027
0.831
0.148
0.243
ESR
0.049
0.700
0.029
0.823
BMI body mass index, BASDAI Bath Ankylosing Spondylitis Disease
Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index,
sVAS spinal visual analog scale, SPARCC Spondyloarthritis
Research Consortium of Canada, CRP C-reactive protein, ESR
erythrocyte sedimentation rate.
Discussion
Our study results demonstrated that ax-SpA patients had higher SI of Achilles tendon
compared to healthy subjects and SI was significantly associated with spinal pain
score, disease activity, functional status, and enthesitis index.
One difficulty faced by clinicians is the inability to establish early diagnosis due
to poor specifity symptoms of ax-SpA [3 ]. With
the introduction of novel effective therapies for ax-SpA that can reduce disease
activity and improve quality of life, early correct diagnosis, and classification
of
patients presenting with symptoms suggestive of ax-SpA becomes crucial. Peripheral
enthesitis, an important feature that can be observed in all forms of ax-SpA,
usually manifests as isolated pain or tenderness at physical examination [16 ]. The reliability and accuracy of the
clinical examination to assess entheses are not satisfactory, so imaging technigues
have potential use in their objective assessment [17 ]. X-rays and computed tomograpy only detect and evaluate structural
bone changes that correspond to past episodes of activity or injury and do not
inform us of the presence of inflammatory activity in enthesis at the time of
examination. Thus, more sensitive methods, such as US and magnetic resonance imaging
(MRI) are often used. However, MRI is limited by its costs, accessibility,
inconvenience to the patient, and the inability to image multiple entheseal sites
simultaneously [3 ].
Sonoelastography is a relatively new US-based imaging technique that provides
information on the elastic properties and stiffness of various tissues and lesions
[18 ]. SE is based on the principle that
tissue displacement in response to external compression produces strain within the
tissue and the strain is lower in harder tissue than in softer tissue. This strain
information can be presented either as a visual map (gray scale or color coded,
depending on the user’s preference) or semiquantitative measurement of
strain ratio [19 ]. To date, several clinical
studies applying SE in differential diagnosis of breast, thyroid, and prostat
cancers and characterization of lymph node have been reported in literature
previously [20 ]
[21 ]
[22 ]
[23 ]
[24 ]. It has been demonstrated that healthy
Achilles tendons showed mainly hard structered pattern on SE; however, mild
softening was found in 12.1% of the tendons in the study by Zordo et al.
[25 ].
Using conventional US, it is sometimes difficult or even imposible to distinguish
pathological changes from surrounding healthy tissue, as they often present with the
same echogenicity [26 ]. In such cases, SE
could detect or differentiate abnormalities, which are thought to correspond to
sub-clinical changes not yet evident on B-mode evaluation, providing suplementary
information useful for diagnostic, therapeutic (US guided procedures) and follow-up
purposes [9 ]. In the study by Klauser et al.,
it has been demonstrated that SE showed a better histologic agreement when compared
with conventional B-mode US in Achilles tendon of cadavers [27 ]. Galletti et al. found that a case series
of patients with negative or inconclusive US exam where SE allowed to show tendon
pathologies in an observational study evaluating the value of SE in the diagnosis
of
tendinopathies [9 ]. In an another study, it
has been also demonstrated that the diagnostic accuracy of B-mode US, SE and color
Doppler US in confirming clinically symtomatic Achilles tendinopathy was
94.7%, 97.8%, and 82.5% respectively [19 ].
In the present study, the stiffness of Achilles tendon in patients with ax-SpA was
evaluated by the measurement of SI. SI calculates the strain differences between the
two user-defined areas in an elastogram, hence providing more objective estimation
of the tissue strain properties compared to color-coded images of the SE method
[7 ]. The SI can be used as a comparative
index among different subjects rather than as an absolute strain measurement [28 ]. Although the patient with symptomatic
Achilles tendons were excluded from the present study, there were statistically
significant differences in SI between patients and healthy controls. Also,
significant correlations of SI with disease activity, functional status, enthesitis
index, and spinal VAS score were demonstrated in this ax-SpA population. To the best
of our knowledge, no study in the literature has investigated the association of SI
with such disease related parameters in ax-SpA patients. But, there was no
correlation between SI and age, sex, disease duration, ESR, or CRP in patients with
ax-SpA. However, it is known that elevated CRP levels and ESR are frequently absent
in AS [29 ]. In the study by Turan et al., B
mode and SE findings had moderate to good correlation in the assessment of Achilles
tendon abnormalities and SE abnormalities were more common in the distal third of
the Achilles tendons in the AS group when compared to the controls. However, the
association of SE findings with disease activity, enthesitis index, or functional
status were not evaluated in that study. Recently, Zardi et al. have demonstrated
no
diffences in the Achilles tendon stiffness ratio between AS patients and controls
in
their study [30 ]. But, only 11 AS patients and
13 controls with an older mean age were included in that study. Also, they did not
report any information about the relationship of stiffness ratio with disease
related clinical parameters in that study. We also assessed the effect of biological
treatment on SE findings, but we found no significant differences between the
patients on NSAID and on biological treatment.
However, because of the cross-sectional study design, we could not evaluate the SE
findings before and after biological treatment. The study by Ooi et al. has also
demonstrated that patients with symptomatic Achilles tendinopathy had significantly
higher SI than the healthy volunteers [19 ].The
present study has some limitations. Firstly, we did not asses the presence of
calcaneal spur and the level of physical activity of participants which may have
affected the SE findings. Also, the patients with symptomatic Achilles tendon were
excluded from the study. So, we could not compare SI between patients with
symptomatic and asymptomatic Achilles tendons. In addition, power doppler USG was
not performed to confirm SE findings. Finally, the patients were on various drug
treatments and the results could have been affected by these treatment regimes.In
conclusion, SE may be a useful tool for the evaluation of subclinical enthesitis in
patients with ax-SpA in clinical practice. However, prospective longitudinal studies
with sufficiently large samples are required to characterize the specifity and the
prognostic value of SE in patients with ax-SpA.
