Short-term effect of Ultrasound-Guided Low-Molecular-Weight Hyaluronic Acid Injection on clinical outcomes and imaging changes in Patients with Rheumatoid Arthritis of the Ankle and Foot Joints. A Randomized Controlled Pilot Trial

Abstract

To determine whether hyaluronic acid (HA) injection into rheumatoid arthritis ankles and feet can
achieve improvement in foot function and reduce synovial hyper-vascularization. Forty-four patients
with RA having unilateral or bilateral painful ankle and foot involvement ( N ¼ 75) were studied. All the
patients were randomized to receive HA ( N ¼ 40) or lidocaine (LI) ( N ¼ 35) injection at 2-week intervals;
Clinical assessments were performed using a visual analog scale (VAS) and foot function index (FFI total )
including subscales of pain (FFI pain) before injection at baseline, 4 weeks (first evaluation) and 12 weeks
(secondary evaluation). Imaging evaluation based on color Doppler ultrasound (CDUS) and synovitis
scores was performed simultaneously. HA injection improved the VAS score ( p ¼ .009), FFI pain ( p ¼ .041),
and FFI total ( p ¼ .032) considerably more than LI injections did at the first evaluation. The CDUS values
at first evaluation ( p ¼ .005) and secondary evaluation ( p < .001) decreased significantly compared with
the base line values. HA injections reduced the CDUS values of more than half of the joints (54%,
p ¼ .042) while the control group exhibited no change (20%, p ¼ .56). However, HA injection did not
reduce the CDUS values more than LI injection did. Regarding the evaluation of synovial hypertrophy,
no significant difference was observed between or within the groups in the synovitis scores. HA injec-
tion improved short-term foot function and pain reduction. HA injection may have a modest effect in
reducing synovial hyper-vascularization. Further large-scale study is warranted to confirm this result.

Full text

This is a post-refereeing final draft. When citing, please refer to the published version:
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Wang CC, Lee SH, Lin HY, et al. Short-term effect of ultrasound-guided low-molecular-
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weight hyaluronic acid injection on clinical outcomes and imaging changes in patients
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with rheumatoid arthritis of the ankle and foot joints. A randomized controlled pilot
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trial. Mod Rheumatol. Jan 06 2017:1-8.. DOI:10.1080/14397595.2016.1270496
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Short-term effect of Ultrasound-Guided Low-Molecular-Weight Hyaluronic Acid
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Injection on clinical outcomes and imaging changes in Patients with Rheumatoid
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Arthritis of the Ankle and Foot Joints. A Randomized Controlled Pilot Trial
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Chien-Chih Wanga,b*_, Si-Huei Leec,d* , Hsiao-Yi Lind,e*, Fu-Wei Liuf, Hong-Jen Chioud,g, Rai-Chi Chanc,d
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and Chen-Liang Chouc,d
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aDepartment of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital Yuli Branch,
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Hualien, Taiwan; bInstitute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan;
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cDepartment of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei, Taiwan;
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dSchool of Medicine, National Yang-Ming University, Taipei, Taiwan; eDepartment of Allergy ,
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Immunology and Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan; fDepartment of
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Physical Medicine and Rehabilitation, Taichung Veteran General Hospital Puli Branch, Nantou, Taiwan;
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gDepartment of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
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Correspondence
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Please address correspondence and reprint requests to: Dr Chen-Liang Chou, Department of Physical
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Medicine and Rehabilitation, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei
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112, Taiwan, R.O.C.
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Email: cl_chou@vghtpe.gov.tw
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Keywords: Hyaluronic acid, Ultrasound, Ankle,Foot, Rheumatoid arthritis, Synovitis
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Abstract:
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Objectives:
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To determine whether hyaluronic acid (HA) injection into rheumatoid arthritis ankles and feet can achieve
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improvement in foot function and reduce synovial hyper-vascularization.
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Methods:
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Forty-four patients with RA having unilateral or bilateral painful ankle and foot involvement (N=75) were
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studied. All the patients were randomized to receive HA(N=40) or lidocaine(LI)(N=35) injection at 2-
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week intervals; Clinical assessments were performed using a visual analog scale(VAS) and foot function
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index(FFItotal) including subscales of pain(FFIpain) before injection at baseline, 4 weeks(first evaluation)
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and 12 weeks(secondary evaluation). Imaging evaluation based on color Doppler ultrasound(CDUS) and
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synovitis scores was performed simultaneously.
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Results:
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HA injection improved the VAS score (P = 0.009),FFIpain (P = 0.041),and FFItotal (P = 0.032)considerably
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more than LI injections did at the first evaluation. The CDUS values at first evaluation (P = 0.005) and
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secondary evaluation (P< 0.001) decreased significantly compared with the base line values. HA
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injections reduced the CDUS values of more than half of the joints(54%,P = 0.042) while the control
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group exhibited no change(20%, P = 0.56). However, HA injection did not reduce the CDUS values more
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than LI injection did. Regarding the evaluation of synovial hypertrophy, no significant difference was
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observed between or within the groups in the synovitis scores.
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Conclusion:
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HA injection improved short-term foot function and pain reduction. HA injection may have a modest
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effect in reducing synovial hyper-vascularization. Further large-scale study is warranted to confirm this
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result.
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Introduction
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Rheumatoid arthritis(RA) is a chronic inflammatory disease mainly affecting the synovial joints. The
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inflammation reaction within the synovial membrane stimulates synovial overgrowth and
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neoangiogenesis, causing the progressive erosion of the joints.
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Damage to the ankles and feet is detrimental to independence and quality of life because of their essential
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role in weight-bearing and ambulation.1 Nevertheless, the anatomical complexities of ankle and foot
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joints hinder prompt diagnosis and treatment; thus, only approximately half of patients with RA receive
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specific foot treatment or a referral to a podiatric doctor.2 Furthermore, the inflammation reportedly
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progresses in more than 20% of cases involving foot synovitis even during clinical remission.3 These
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results suggest the need for further specific assessments and interventions for RA ankles and feet.
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Ultrasound(US) has been one of the most validated tools for assessing RA synovitis in recent years.4 For
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RA patients in remission status, US has been used for detecting ongoing synovitis.5 Previous studies have
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revealed that US with Doppler signals can detect early synovitis before clinical symptoms appear and
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distinguish between inactive and active synovitis according to the hyperemia grade,6 which is strongly
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related to joint destruction.7 These results indicate that US with Doppler can be a reliable imaging
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modality for measuring outcomes in patients with inflammatory arthritis.8 In addition, US-guided
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injection procedures can also provide precise and safe interventions, which is considered mandatory for
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proving the efficacy of local injection for treating ankle arthritis.9,10
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Local steroid injection is currently the most common and effective method of alleviating local
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inflammation in the synovial joint.11 ,1213 However, the adverse effects of corticosteroid injection include
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elevated blood sugar and a deleterious effect on surrounding tendons, indicating that other alternative
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types of treatment are crucial.9,14,15In recent years, hyaluronic acid (HA) has emerged as the most well-
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documented alternative therapy to corticosteroids for treating arthritis because of its anti-inflammatory
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effect.15-17 Although some studies have revealed the borderline efficacy of viscosupplementation, HA
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injections have been shown to be noninferior to steroid injections and to have longer-lasting effects in
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osteoarthritis(OA)knee treatment.18–19 HA has also been found to have high efficacy for treating RA
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synovitis.20 Several studies have revealed that HA injections can reduce pain and inflammatory mediator
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levels; moreover, when HA is used, patient satisfaction is equal to that produced when corticosteroids are
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used to treat RA in clinical settings, suggesting that HA may be a viable alternative for treating RA.17,21
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Although the application of HA injections into OA ankles and feet has yielded favorable results,22 no
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study has focused on the impact of injecting HA into painful RA ankles and feet. We hypothesized that
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injecting HA into RA ankles and feet can reduce pain, improve ankle and foot function, and reduce
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synovial hypervascularization simultaneously according to its anti-inflammatory effect.
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Patients and Methods
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Forty-eight patients attending the rheumatology outpatient clinic at Taipei Veterans General Hospital were
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studied. Ethical permission was obtained, and all patients provided written informed consent. Ethical
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approval for the study was obtained from the Ethics Committee of the hospital. Patients were included in
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the study if they had received a clinical diagnosis of RA in the Allergy Immunology Rheumatology
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outpatient clinic and a diagnosis of painful foot or ankle problems(with one or both legs involved). In
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addition, all the patients satisfied the following criteria: 1)received an RA diagnosis in accordance with the
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American College of Rheumatology (ACR) criteria23 for RA classification; 2)were >18years old; 3)had a
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disease duration of ≥1year;4)had no ankle or foot joint deformity or ankylosis; and 5)had no active disease
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flare-up or other substantial ongoing active disease,24 such as infections, and had a stable condition in the
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6 months prior to this study. The disease activity was measured using Disease Activity Score28
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(DAS28).The level of disease activity can be interpreted as remission (DAS28 ≤ 2.6), low
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(2.6 <DAS28 ≤ 3.2),moderate (3.2 < DAS28 ≤ 5.1), or high (DAS28 > 5.1),according to the European
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League Against Rheumatism(EULAR) response criteria.25
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Patients were excluded if their treatment needed to be adjusted immediately; if their treatment protocol was
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adjusted within 1 month prior to this study; if they had substantial active diseases, such as infections, or a
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history of allergy to lidocaine (LI) or HA injection; or if they had a history of traumatic ankle or foot injury
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with bone destruction.
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We conducted a prospective, double-blinded randomized controlled pilot study. Randomization of the
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patients was performed using sealed envelopes containing a randomized grouping of all patients in a
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numerical sequence. The independent clinical and imaging assessor was blinded to which patient group
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was assigned, and the patients receiving the injections were blinded to the injected drug. The patients in the
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intervention group were injected with low-molecular-weight HA(ARTZ Dispo[Seikagaku, Tokyo,
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Japan],MW: 0.5 × 106), whereas those in the control group received LI(2% xylocaine).
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Detailed physical examination and history taking were performed by a physiatrist. The ankle, midfoot, hind-
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foot, and forefoot joints were evaluated. The tibiotalar, subtalar(talocalcaneal joint), calcaneocuboidal,
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talonavicular, cuneonavicular, and tarsometatarsal joints were studied to determine the injection joint.
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Injection protocol
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Administration involved injecting a 2.5-mL preparation into the selected joint twice in 2 consecutive weeks.
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Injection was performed by a single physical medicine and rehabilitation physician with 5 years of
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experience in administering US-guided injections.
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.
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Determination of the injection joint
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The injection joint was selected according to the presence of synovitis on the basis of the clinical and
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imaging findings. First, painful joints were identified on the basis of clinical symptoms of synovitis with
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tenderness or spontaneous pain at the site of the joint and local swelling of the joint. Second, the joints with
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the most active synovitis under imaging (highest CDUS and/or more severe synovial hypertrophy) were
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selected. For example, if a patient had tenderness over the medial midfoot area, then one of the joints in
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this area, including the medial subtalar joint, ankle joint, or talonavicular joint, were selected according to
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the US and Doppler findings. The selected joint was recorded, and the physical medicine and rehabilitation
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physician finally performed the injection according to this record.
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During injection, the patients were placed in the supine position with the knee in a supported flexed
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position.26 The skin was disinfected through an aseptic technique before the injection. A US probe with a
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sterilized plastic covering was used to determine the appropriate entry site for the needle to avoid
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penetrating vessels or the hypertrophic synovium. A local analgesic injection of LI (1cc) was administered
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subcutaneously. Subsequently, ARTZ Dispo or LI was intra-articularly injected through a US-guided
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procedure (Figure 1).
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Measurement of outcome variables
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Outcomes were measured by an independent assessor at baseline before injection , 4 weeks(first evaluation)
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and 12 weeks(2nd evaluation) after injection. We assessed global pain daily by asking the patients about
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their average pain level on the assessment day by using a 100-mm visual analog scale(VAS).Foot function
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and pain related to ambulation and function were evaluated using the foot function index (FFI), which is a
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validated self-administered questionnaire for measuring RA foot and ankle pain and disability.27 It
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comprises three subscales: functional foot pain (FFIpain, nine items), functional disability (FFIdis, nine items),
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and functional limitation (FFIfl, five items). All items were rated using the100-mm VAS. The total FFI
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scores(FFItotal) were calculated by averaging the three subscale scores.
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We recorded the following demographic and clinical characteristics at baseline: age, sex, duration of foot
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and ankle pain, previous and current presenting history of RA, use of disease-modifying antirheumatic
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drugs and other therapies or drugs, and other medical and occupational history. Clinical variables included
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the DAS28, erythrocyte sedimentation rate (ESR), and C-reactive protein(CRP). The DAS28 were
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calculated according to the ACR remission criteria.28
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Each patient underwent US assessment of the entire painful ankle, for which gray-scale imaging and color
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Doppler techniques were used. The US examinations were performed by the author (H.J.C.), who has more
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than 20 years of experience in ultrasonography. The examinations were performed using a Siemens
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ACUSON X600 Ultrasound System equipped with a 6–18-Hz linear transducer, following the EULAR
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guidelines.29 We set the US gray scale to obtain maximal contrast and color gain according to the level at
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which color noise appeared. Subsequently, a spectral Doppler US was used to confirm that the color flow
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signal represented true blood flow rather than an artifact.
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The color flow Doppler values were evaluated through a semiquantitative technique30 consisting of a 0–3
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scale, where 0 = no Doppler signal (color pixel) or no flow, 1 = a single Doppler signal or low flow (three
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single spots or two single spots and one confluent spot), 2 = several Doppler signals (≤50% color pixels of
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the intra-articular area), and 3 = complete joint area with coherent Doppler signals or strong flow(≥50%
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color pixels of the intra-articular area).The responders were defined as the joints with CDUS that decreased
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by one grade after the injection and the responding rate was calculated in each group. Synovial hypertrophy
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was evaluated using a semiquantitative scoring method (the Leeds Score)27consisting of a 0–3 scale, where
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0 =no synovial hypertrophy, 1 =mild hypertrophy, 2 =moderate hypertrophy, and 3 =severe hypertrophy.
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Data analysis
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Statistical analysis and data evaluation were performed using SPSS Version 12 (SPSS, Chicago, IL). At
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baseline, an independent t test was used for continuous data, and a chi-square test was conducted for
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categorical data. The level of significance was set at P < 0.05. The improved scores were calculated (post
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evaluation scores− baseline scores) for a comparison between the groups. The improved scores of FFI and
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VAS were statistically analyzed using an analysis of covariance. The baseline data of FFI and VAS was
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covaried. Ordinal data such as CDUS values and laboratory data were analyzed using nonparametric tests
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(Mann–Whitney U and Kruskal–Wallis tests). The percentage of responders in different evaluation periods
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was assessed using the McNemar–Bowker test. Associations between the clinical and imaging
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improvements were identified through a Spearman’s correlation analysis.
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Results
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A total of 48 patients were recruited, four of whom could not be completely evaluated because the disease
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exacerbated during the evaluation period. A total of 44 patients completed the experimental protocol. The
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HA(n = 24)and LI(n = 20) groups did not differ significantly in clinical and ultrasound characteristics or
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baseline evaluation, except that there was a slight but significant difference in age(P =0.043)(Table 1).In
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total, 67% of the participants in the intervention group and 75% in the control group had bilateral painful
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feet. In total, 40 and 35 joints of the participants in the intervention and control groups were evaluated,
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respectively. Table 2 details the baseline evaluation of the foot and ankle joints.
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Outcome of clinical evaluation
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The change in FFItotal was significant in the second evaluation in the HA group compared with the LI
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group (P = 0.048), but not in the first evaluation (P = 0.11) (Table3). Regarding the FFI subscales, the HA
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group exhibited a greater reduction in FFIpain than the LI group did in both the first (P = 0.032) and
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second (P = 0.038) evaluations. The HA group exhibited a significantly greater reduction in global
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pain(VAS) in the second evaluation (P = 0.01) than did the LI group. Therefore, our result revealed that a
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single HA injection can alleviate global pain for a short duration through the placebo effect; additionally,
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two HA injections were required in order to ameliorate pain and improve function, suggesting the
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cumulative effect of HA.
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Outcome of US evaluation
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The HA group exhibited a significant reduction in CDUS values in both the first (1.3 ± 0.9, P = 0.005)
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and second (1.1 ± 0.9, P < 0.001) evaluations compared with the baseline (1.7 ± 0.9) in the intragroup
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comparison (Figure 2). By contrast, for the LI group, the reduction in CDUS values was nonsignificant in
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both the first (1.1 ± 0.7, P = 0.41) and second (1.0 ± 0.7, P = 0.8) evaluations compared with the baseline
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(1.2 ± 0.8) in the intragroup comparison. The intergroup comparison did not reveal a significant
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difference between the HA and LI groups (P = 0.42). Nevertheless, the responder percentage in the HA
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group indicated a significant difference between this group and the LI group in the second evaluation
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(54.1% and 20.0%, P = 0.005, respectively) but not in the first evaluation (33% and 10%, P = 0.112,
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respectively) (Figure 3). Among those responding to HA, 80% responders had high initial vascularity
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(Grades2 and 3) , suggesting the HA could attenuate the active synovitis .
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Regarding the evaluation of synovial hypertrophy, the Leeds scores in the HA group didn’t reveal
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significant difference between this group and LI group in the first evaluation (1.6 ±0.6 and 1.3 ±0.4,
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P=0.13 , respectively ) and in the second evaluation(1.4 ±0.7 and 1.2 ±0.4, P=0.48 ,respectively ) (Figure
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4).
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Correlation analysis
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To identify the predisposing factors contributing to clinical and imaging improvement, we performed a
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Spearman’s correlation analysis with baseline variables including age, duration, and DAS28; however, no
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significant correlation was observed. No other significant correlation was observed between functional
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improvement and the US evaluation.
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Discussion
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The findings of our study suggest that HA injection can improve foot function and reduce pain in RA
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ankles and feet in the short term. Studies have documented the effectiveness of HA injection for treating
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synovitis in patients with inflammatory joint disease, resulting in pain reduction and functional
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improvement. For example, Goto et al. reported that five consecutive HA injections to RA knees reduced
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ambulatory pain and suppressed PGE2 levels in synovial fluid.21 In an observational cohort study, Saito et
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al. also asserted that HA injection is preferable to steroid injection in RA ankles.20 However, these studies
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were not randomized controlled trials; hence, they could not eliminate the placebo effect, which has been
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reported to ameliorate pain and improve function by an average of 34%.31,32 In the present study, we
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compared the effects of HA injections in RA ankles and feet (intervention group) with those of LI
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injections (control group) and provide clear evidence of the effectiveness of HA injections in RA ankles
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and feet.
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Pain perception in patients with RA is multidimensional and mainly mixed with neuropathic and
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nociceptive-inflammatory elements.33 The global pain in our study revealed significant improvement after
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HA injections, which is consistent with a previous study that showed that using a hyaluronan solution
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reduces pain through the mechanism of reducing inflammatory mediator levels. Additionally, HA in our
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study was also revealed to reduce the functional pain associated with ambulation. This result may further
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prove that HA can reduce movement-evoked pain through desensitizing the overactive nociceptive nerve,
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which is not present in noninflamed joints.15,34, 35 The desensitizing effect may be derived directly from the
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elastoviscosity of HA acting as a mechanical filter that reduces both joint nociceptive activity and the
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firing rate of nerve endings in the synovium.15,35 Despites this rheological property that a higher
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molecular weight15,35 corresponds with higher elastoviscosity generating a more favorable analgesic
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effect, our study also reveals that low-molecular-weight HA can reduce both global and functional pain
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compared with LI, suggesting that low-molecular-weight HA may reduce the pain threshold through
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desensitizing overactive nociceptive and sensory nerves rather than through its temporal analgesic and
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anesthetic effects. This result may have been further speculated by previous findings that the lower-
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molecular-weight HA preparations can penetrate synovium more easily and thus enhance the interaction
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with inflamed synovial cells.36
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Estimating the level of inflammation according to synovial vascularity has been considered the most
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critical advancement of US.6,37 Our findings reveal that synovial hypervascularization was reduced after
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subsequent HA injections. This observation is similar to that of a study in which intra-articular steroid
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injections into small joints reduced the power of Doppler signals, suggesting that the anti-inflammatory
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effect attenuated the active synovitis.8 Although the reduction in the CDUS values did not a reveal
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significant difference in comparison with the LI injections, a greater increase in the proportion of joints to
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HA injections was observed, with 54% response rate after subsequent injections. This result, however,
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may be inferior to a previous study in which a single-dose steroid injection with a 90% response rate was
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reported in only 2 weeks of follow-up.8 Moreover, there was no regressive change in synovial
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hypertrophy, which is inferior to the results of a previous study in which steroids were used to normalize
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not only hyperemia but also synovial hypertrophy in juvenile idiopathic arthritis.38 Thus, it can be
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speculated that the anti-inflammatory ability of HA to suppress the imaging change in RA synovitis might
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not be as strong as steroids in short-term applications.8
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A reduction in CDUS values was also observed in two cases in the LI group, suggesting that the RA joints
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in patients in clinical remission may present regressive synovial hyperemia in the subsequent ultrasound
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follow-up. Moreover, it may be further speculated that the lidocaine solution could reduce the
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inflammation through diluting the inflammatory mediator, which is consistent with similar observations
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in previous studies.35,39 The small, close joint cavity in the ankles and feet was contended to contribute the
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prolongation of the dilution effect by up to 3 months.
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Our findings reveal that the reduction of CDUS is not associated with pain reduction or functional
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improvement. In other words, the improvement in clinical outcomes was markedly superior to the
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imaging changes. This result may contradict previous reports that have shown that using steroids in RA
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joints causes simultaneous clinical and imaging improvement.8 A possible explanation is that HA
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improves clinical outcomes not only through mitigating synovitis through an anti-inflammatory effect, but
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also through a simultaneous desensitizing neural effect, as mentioned earlier, which is not revealed by
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imaging evaluations. Moreover, the number of injections might also contribute to the reduced efficacy of
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reducing hypervascularization , in that two doses of HA may still be insufficient to decrease the level of
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inflammation.40 Although a previous study claimed that clinical assessment is subjective measure that
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might give a false impression of the response, our result may provide clear evidence of solid clinical
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improvement compared with the control group.40 By contrast, the reduced improvement in imaging
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studies may suggest a poor prognosis and further joint destruction, warranting more aggressive and
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systematic treatment.41
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The main limitation of our study was the lack of a formal control group injected with normal saline. This
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was due to ethical concerns regarding the injection of a nontherapuetic drug into inflammatory joints,
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although studies have shown that normal saline injections may also have therapeutic effects.39 Another
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limitation is that, because of the relatively short measurement duration and relatively small sample of
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patients, these results should be considered as preliminary findings. Future studies with a larger sample
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size and longer follow-up period are necessary to validate the findings of the current study. Finally,
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although the semiquantitative grading of color Doppler signals has been widely used and provides
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efficacious evaluations, it still does not enable the precise estimation of vascularity. Power Doppler with
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quantitative measurements could be adopted for further assessing the vascular pattern and providing
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objective parameters.42
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In summary, our preliminary results demonstrate that injecting HA into the painful ankles and feet of RA
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patients provides short-term pain alleviation and functional improvement. Despite the imaging changes
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not being associated with any clinical improvement, HA injections may provide a modest ability in
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normalizing hypervascularization in synovitis. The results further reveal the advantages of HA injection
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apart from anti-inflammation; such advantages include the neural effect, which is crucial to the weight-
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bearing function of ankle and foot joints. US has been shown to be a critical tool both in diagnosis and
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intervention in small joints such as the ankles and feet. Our results show that HA injections may be safe
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and efficacious in the short-term local management of RA ankles and feet and could be considered act as
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an adjunctive treatment in clinical practice.
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Declaration of Conflicting Interests
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Disclosure statement: None of the authors have any financial or scientific conflicts of interest with regard
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to the research described in this manuscript
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Funding
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No specific funding was received from any funding bodies in the public, commercial or not-for-profit
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sectors to carry out the work described in this article.
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15. Balazs EA. Analgesic effect of elastoviscous hyaluronan solutions and the
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18. Leighton R, Akermark C, Therrien R, et al. NASHA hyaluronic acid vs.
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19. Rutjes AW, Juni P, da Costa BR, Trelle S, Nuesch E, Reichenbach S.
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21. Goto M, Hanyu T, Yoshio T, et al. Intra-articular injection of hyaluronate (SI-
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36. Ghosh P, Guidolin D. Potential mechanism of action of intra-articular hyaluronan
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39. Chou WY, Ko JY, Wang FS, et al. Effect of sodium hyaluronate treatment on
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parallel-group, placebo-controlled study. Arthritis Rheum. 2006;54(5):1401-
482

1409.
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41. Pereira DF, Natour J, Buosi AL, Ferreira FB, Fernandes Ada R, Furtado RN. Is
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painless synovitis different from painful synovitis? A controlled, ultrasound,
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radiographic, clinical trial. Clinics (Sao Paulo). Feb 2014;69(2):93-100.
486
42. Wu MH, Chen CN, Chen KY, et al. Quantitative analysis of dynamic power
487
Doppler sonograms for patients with thyroid nodules. Ultrasound Med Biol.
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2013;39(9):1543-1551.
489
490

491
Figure 1.A.US-guided procedure in the talocalcaneal joint by using the posterior–lateral approach. B.
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TA= talus; CA = calcaneus; arrows = the needle
493
494

495
Figure 2. US evaluation at baseline and postinjection with gray-scale US and CDUS in the talocrural joint
496
in one of the patients in the HA group. A and B. Gray-scale of the talocalcaneal joint with the hypoechoic
497
pannus within the joint and Grade 3 vascularity under CDUS at baseline. C. CDUS decreased to Grade 2
498
vascularity at the first evaluation. D. Grade 2 vascularity at the second evaluation.
499
500
501

502
Figure 3. Comparison of the responder percentage between the HA and LI groups.
503
504

505
Figure 4. Comparison of the Leeds scores between the HA and LI groups. There was no significant
506
difference in the intergroup or intragroup comparison.
507
508
Table 1. Demographic data and clinical characteristics of all patients in the two groups*
509
characteristics
HA Group (n=24)
LI Group (n=20)
P value
Age, mean± SD
53.4±2.34
62.7±2.9
0.04
Female/ Male,%
15/3, 83%
11/5
0.46
DAS28 , mean± SD
4.2±0.1
4.8±0.2
0.08
CRP , median(range)
15 (0–12)
19 (0–71)
0.67
ESR , median(range)
27(5–98)
34(2–118)
0.32
Disease activity level ,%
Remission
8
5
Low
25
20
moderate
50
60
high
17
15
Disease duration (years), mean± SD
4.1±0.9
3.3±0.8
0.72
One foot involved , n(%)
33%
25%
0.06
Both feet involved , n(%)
67%
75%
0.24
Global pain (VAS) , mean± SD
53.3±13.9
60.4±17.56
0.96

Foot function index ,mean± SD
Subscales of pain
65.7±20.2
62.7±22.2
0.69
Subscales of Disability,
64.1±16.2
56.3±11.9
0.23
Subscales of limitation
52.8±29.4
50±25.3
0.68
Total score
60.5±14.7
56.3±9.6
0.39
*DAS28 = Disease activity score 28; FFI = Foot function index; VAS= Visual analog scale ;n = numbers
510
of patients
511
512
Table 2.Ultrasound characteristics of all patients in the two groups at baseline*
513
Joint
Talocrual
(ankle)
Talocalcaneal
(subtalar)
Talo-
navicular
Cuneo-
narvicular
MTP
Calcaneao-
navicular
Calcaneo-
cuboid
HA Group
(N=40)
CDUS
1.8±0.8
1.5±0.7
1.2±0.4
1.3±0.4
0
1
1
N
13
12
10
3
0
1
1
LI Group
(N=35)
CDUS
1.3±0.6
1.2±0.6
1.1±0.8
1.7±0.7
1
1
1
N
10
11
6
4
1
1
2
P value
0.43
0.89
0.45
0.50
-
-
-
*N = numbers of joints , values are given as mean±SD; P value = comparison of CDUS between two
514
groups
515
516
Table 3. Changes in outcome measures, by HA injection and LI injection, from baseline to 4 weeks and
517
12 weeks*
518
HA Group
LI Group
Comparison of the
change
between two groups
(P value)
Baseline to
4 weeks
Baseline to
12 weeks
Baseline to
4 weeks
Baseline to
12 weeks
Baseline to
4 weeks
Baseline to
12 weeks
FFI total
14.1±8.7
22.8±10.4
9.2±5.9
16.8±8.9
0.105
0.032†∗
FFI (Pain)
14.4±9.7
23.4±13.4
7.3±6.3
13.7±9.9
0.033†
0.041†
FFI (Dis)
12.6±12.5
22.1±14.6
5.9±6.9
10.3±8.9
0.109
0.02†
FFI (Lim)
14.9±12.9
23.0±14.5
14.4±12.6
26.5±21.1
0.899
0.568
Global
pain( VAS)
14.6±9.5
28.3±11.1
9.6±5.8
17.3±10.2
0.12
0.009†
*Values are expressed as the mean ±SD;†Statistically significant difference in intergroup comparisons.
519

FFI =foot function index; Dis= subscales of Disability ; Lim= subscales of limitation.
520
521
522
523
524