REVIEW

Hyaluronic Acid Injections in the Treatmentof Osteoarthritis Secondary to Primary InflammatoryRheumatic Diseases: A Systematic Reviewand Qualitative Synthesis

Orazio De Lucia . Antonella Murgo . Francesca Pregnolato .

Irene Pontikaki . Mirian De Souza . Alessandro Sinelli .

Rolando Cimaz . Roberto Caporali

Received: December 24, 2019 / Published online: March 5, 2020� The Author(s) 2020

ABSTRACT

The purpose of this study is to review the cur-rent literature on the use of hyaluronic acid(HA) specifically applied to the treatment ofosteoarthritis (OA) secondary to primaryinflammatory rheumatic diseases. Osteoarthritisshould be carefully considered because it haspotentially devastating effects on health-relatedquality of life. Locally injected HA seems to bean effective treatment for OA but it is not clearhow to place this treatment in the context of

inflammatory rheumatic disorders. To retrieverelevant articles, we conducted the searchthrough MEDLINE, EMBASE and CochraneDatabases performing the PICO strategy. Wefinally selected four randomized clinical trialsand six observational studies and grouped themin accordance with its main objective withinthree focuses: the clinical effect of HA therapyin joints without any signs of inflammation, theclinical effects of HA therapy in joints withactive synovitis, and the involvement andchanges of synovial fluid in the treatment ofsecondary OA. Our qualitative analysis clearlyshowed that the current literature is marked byhigh levels of heterogeneity and therefore dif-ficult to interpret. Therefore, our hypothesisthat viscosupplementation should be consid-ered as a treatment for chronic moderatesymptomatic OA secondary to inflammatoryrheumatic diseases, and not for flares with jointswelling, cannot be definitely supported. Well-designed studies are necessary to definitivelyclarify the range of application of intra-articularHA injections in the treatment of inflammatoryrheumatic disorders.

Keywords: Hyaluronic acid; Osteoarthritis;Qualitative synthesis; Rheumatic diseases;Rheumatology; Systematic review; Viscosupple-mentation

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11808723.

O. De Lucia (&) � A. Murgo � M. De Souza �A. Sinelli � R. CaporaliUnit of Clinical Rheumatology, Department ofRheumatology and Medical Sciences, ASST CentroTraumatologico Ortopedico G. Pini-CTO, Milan,Italye-mail: orazio.delucia@asst-pini-cto.it

F. PregnolatoImmunorheumatology Research Laboratory, IstitutoAuxologico Italiano, Milan, Italy

I. Pontikaki � R. CimazUnit of Rheumatology of the Growing Age,Department of Rheumatology and Medical Sciences,ASST Centro Traumatologico OrtopedicoG. Pini-CTO, Milan, Italy

M. De Souza � A. Sinelli � R. Cimaz � R. CaporaliDepartment of Clinical Sciences and CommunityHealth, University of Milan, Milan, Italy

Adv Ther (2020) 37:1347–1359

https://doi.org/10.1007/s12325-020-01256-7

Key Summary Points

Why carry out this study?

Osteoarthritis (OA) is the most frequentcomorbidity with self-reporteddetrimental outcome in patients withsystemic rheumatic disorders.

Locally injected hyaluronic acid (HA)seems to be an effective treatment for OAcomorbidity and despite its increasing usein various conditions, doubts still existwith regard to the most successful field ofapplication.

We conducted a systematic review aimedat investigating the role of HA as localtreatment in OA secondary to chronicinflammatory arthritis.

What was learned from the study?

Our review clearly showed that the currentliterature on HA is affected by highheterogeneity.

Well-designed studies are necessary todefinitively clarify the range ofapplication of viscosupplementationtherapy.

INTRODUCTION

Osteoarthritis (OA) is the most frequentcomorbidity with self-reported detrimentaloutcome in patients with systemic rheumaticdisorders such as rheumatoid arthritis and otherinflammatory arthritides that progressivelyaffect joints. Osteoarthritis presence should becarefully considered because it may alters painperception and functional status especially inlong-standing patients [1]. Inflammation playsa central role in the development and progres-sion of OA involving multiple mediators such asinterleukin-1 (IL-1), interleukin-6 (IL-6),tumour necrosis factor alpha (TNFa) and met-alloproteases that are responsible for

degradation of proteoglycans in the extracellu-lar matrix and reduction in the molecularweight and concentration of endogenous hya-luronic acid (HA) [2]. HA is the major compo-nent of synovial fluid and is responsible for itsviscoelastic properties. As a natural componentof cartilage, HA plays a crucial role in thetrophic status of the cartilage and in the regu-lation of intra-articular environment.

Over the last decades, the introduction ofdisease-modifying antirheumatic drugs(DMARDs) and the acknowledgement of theimportance of early diagnosis, prompt treat-ment and treat-to-target approach have radi-cally changed the prognosis of these patients,preventing cartilage damage and leading to anotable decrease in total joint replacement[3, 4]. Furthermore, locally injected HA seems tobe an effective treatment for OA comorbidity.Indeed, results from several in vitro and in vivostudies have indicated that exogenous HA candecrease the production of pro-inflammatorycytokines and stimulate the endogenous syn-thesis of HA and extracellular matrix compo-nents by synovial fibroblasts [5–9]. In allinflammatory conditions of the joint, themolecular weight of HA is reduced. Also, severalclinical studies have shown that intra-articularHA relieves pain and improves function insymptomatic OA joints [9–12] and that thetreatment has a positive global effect and is welltolerated. Some studies, mainly focused on theknee joint, have shown that repeated courses ofHA treatment are safe and associated with totaljoint replacement delay for up to 3 years[13, 14].

In a meta-analysis published in 2009 [15],the authors summarised results from five trials[16–20] aimed at evaluating the efficacy of intra-articular HA injection in rheumatoid knees(Table 1). The main extracted outcomes wereglobal pain and inflammation, global thera-peutic efficacy and adverse effects. Risk ratiowas used as a measure of effect size. The therapywas considered effective if it brought a moder-ate to remarkable benefit according to a Likertscale. The authors concluded that viscosupple-mentation therapy is an effective and safealternative local treatment for the rheumatoidknee when compared to placebo as they

1348 Adv Ther (2020) 37:1347–1359

estimated a pooled overall efficacy of 1.64 infavour of HA. The most common side effectsencountered were arthralgia and joint swelling.

Despite this body of evidence and theincreasing use of HA injections in primaryosteoarthritis, doubts still existwith regard to themost successful field of application [21]. First ofall, viscosupplementation should be consideredas a treatment for chronic moderate symp-tomaticOA, andnot forflareswith joint swelling,and therefore some poor results may be due toinappropriate use of HA injections. To betterunderstand theplace ofHA local treatment inOAsecondary to chronic inflammatory arthritis weconducted a systematic review of the studies thatuntil now have accumulated evidence of safetyand efficacy/effectiveness of HA in relieving painand recovering joint functionality. As a result ofthe high heterogeneity of the retrieved studies(study design, treated joints, scheduling andduration of the treatment, etc.), a qualitativesynthesis was performed.

METHODS

Search Strategy and Eligibility Criteria

The systematic review was conducted accordingto the recommendations of PRISMA (PreferredReporting Items for Systematic Review andMeta-Analysis) as conveyed in Moher’s

guidelines [22]. We performed an accuratesearch of studies that evaluated patients suffer-ing from OA secondary to primary inflamma-tory arthritis undergoing intra-articularinjections of HA with the aim of assessingtreatment efficacy/effectiveness. To retrieve rel-evant articles, we conducted the search throughMEDLINE (Pubmed), EMBASE and CochraneDatabase of Systematic Reviews. The searchterms entered were psoriatic arthritis, rheuma-toid arthritis, ankylosing spondylitis, juvenileidiopathic arthritis, spondyloarthropathies,systemic lupus erythematosus, systemic sclero-sis and Sjogren’s syndrome as ‘‘population’’,hyaluronic acid, hyaluronate, sodium hyalur-onate, hyaluronate injection(s), viscosupple-mentation as ‘‘intervention’’ and Lequesneindex, VAS, WOMAC, pain, SF-36, HAQ, effec-tiveness, efficacy, satisfactory as ‘‘outcome’’. Allrelevant index and natural language terms weretailored for all databases searched. In addition,further relevant references were manually sear-ched if needed. In particular, the latest meta-analysis and systematic reviews were addition-ally screened for any other relevant articles thatcould have been missed using the literaturesearch strategy. Duplicate results were removedand the first screening process was done con-sidering the title and abstract only. The inclu-sion/exclusion criteria used to determine whichresearch should be retrieved are included inTable 2. A second selection was performed by

Table 1 Results of the meta-analysis by Saito and Kotake [15]

References Patients, n RRa of pain [95% CI] RRa of inflammation[95% CI]

RRa of efficacy[95% CI]

Tanaka et al. [16] 175 1.19 [0.96–1.47] 1.40 [1.07–1.83] 1.29 [1.07–1.55]

Tanaka et al. [17] 203 1.83 [1.44–2.32] 1.78 [1.37–2.32] 1.76 [1.40–2.21]

Goto [18] 20 2.00 [0.68–5.85] 1.60 [0.80–3.20] 2.12 [1.06–4.26]

Matuno [19] 26 2.75 [1.18–6.42] 3.50 [0.89–13.78] 4.00 [1.46–10.93]

Komatubara et al. [20]b 286 – – 1.10 [0.95–1.27]

Pooled RR 1.64 [1.14–2.35] 1.61 [1.34–1.92] 1.64 [1.14–2.35]

a A value of risk ratio (RR) greater than 1 indicates that the observed results favours HA injections as compared to placebob The study by Komatubara et al. was excluded from the estimation of RR of pain and inflammation because the authorsused a different outcome measure with respect to the other included studies

Adv Ther (2020) 37:1347–1359 1349

fully reading the manuscript of the previouslyselected references. The review selection wasindependently performed by two reviewers(ODL and FP) whereas the discrepancies weresolved by discussion with a third reviewer (AM)involved in case of no consensus could beachieved. The information about the numbersof articles generated by using search terms, thenumbers of articles ruled out after the firstscreening and the reason for any excluded arti-cle were inserted in a PRISMA flow chart.

The last part of this work focused on a criticalreview of the selected literature. This article isbased on previously conducted studies and doesnot contain any studies with humanparticipantsor animals performed by any of the authors.

Quality Assessment

The articles that met all inclusion criteria wereevaluated in relation to methodological quality.The Quality Assessment Tool for before–after

(pre–post) studies with no control group andcross-sectional studies (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools)was used as appraisal tool for evaluating thequality of observational studies, whereas eachrandomized controlled trial (RCT) was scored bythe Jadad scale [23].

RESULTS

Systematic Review Process

Articles were retrieved from the databases onSeptember 24, 2019. Our search yielded 122records, 73 from EMBASE, 18 from MEDLINEand 31 from Cochrane Library. After removal ofduplicates (n = 15), 107 titles and abstracts wereassessed according to inclusion/exclusion crite-ria. From this first screening, 11 potentially eli-gible articles underwent a full reading and onlyone text was removed as the included infor-mation was not relevant for answering ourresearch question. It was not possible to includethe five articles from the meta-analysis per-formed by Saito and Kotake [15] as they were allpublished in Japanese. Therefore, the qualita-tive synthesis was based on ten original articles(Fig. 1).

Overall Characteristics of Selected Studies

The main characteristics of the articles areshown in Table 3. They included four RCT[24–27] and six observational studies [28–34](five pre–post study with no control group andone cross-sectional design). In all studies,patients were affected by RA. In general, thesestudies differed in the primary endpoint, HApreparation and scheduling, injection site andoutcome measures. Therefore, we grouped eachstudy in accordance with its main objectivewithin three main focuses: the clinical effect ofHA therapy in joints without any signs ofinflammation, the clinical effects of HA therapyin joints with active synovitis, and theinvolvement and changes of synovial fluid inthe treatment of secondary OA (impact of thearthrocentesis and biochemical effects of

Table 2 Inclusion/exclusion criteria for screening titlesand abstracts

Inclusion criteria Exclusion criteria

Full-text original articles

English language

Articles concerning OA

secondary to the following

diseases: psoriatic arthritis,

rheumatoid arthritis,

ankylosing spondylitis,

juvenile idiopathic

arthritis,

spondyloarthropathies,

systemic lupus

erythematosus, systemic

sclerosis and Sjogren’s

syndrome

Providing relevant

information (e.g. response

rate or other measures of

effectiveness)

Study design: any

Abstract-only, letters to

editor, reviews, case

reports

Papers that do not deal

with intra-articular

injection in patients with

osteoarthritis secondary

to inflammatory

rheumatic diseases

When multiple articles

were based on the same

study population, we

included only the most

complete (or recent) one

1350 Adv Ther (2020) 37:1347–1359

exogenous HA in synovial fluid). As the inclu-ded studies themselves have not clearly definedor clinically described joints with or withoutinflammation, we included the manuscripts inthe group of joints with active synovitis whenthe authors did not specifically exclude patientswith active disease. Indeed, in these cases theaveraged values of the disease activity score-28(DAS28) indicated a moderate to severe activerheumatic disease. On the other hand, weincluded the manuscript by Chou et al. [30] intothe group of secondary osteoarthritis withoutany sign of inflammation as the authors statedthat patients with RA were excluded in case ofsignificantly inflamed osteoarthritic knees.

Overall, among the retrieved RCTs, onlyTanaka [27] and Kopp [25] achieved a poorerrating score (Jadad score = 3) because the

randomization method was not declared,whereas the observational studies fell withinfair and good categories.

Qualitative Synthesis

Clinical Effects of Intra-Articular HAAdministration in Joints Affected by SecondaryOsteoarthritis Without Any Signof InflammationOnly one study [30] specifically covered thistopic. However, it was not possible to com-pletely rule out the inflammatory condition aspatients with RA were excluded in case of sig-nificantly but only radiologically verifiedinflamed osteoarthritis of the knee. Briefly, HAintra-articular injections allowed an overallsignificant and quick improvement (after

Fig. 1 Flow chart showing the number of records identified and removed at each stage of the review, according to thePRISMA statement

Adv Ther (2020) 37:1347–1359 1351

Table3

Characteristics

ofthefin

alselected

studies

Stud

yDesign

NJoint(s)

HA

HA

schedu

ling

Com

parison

Outcome

Clin

icaleffectsin

non-swollenjoints

Chou

etal.

[30]

Pre–post

treatm

ent

20Kneein

RA

Artz

Five

injections

(once

aweekfor

5weeks)

Any

WOMAC

atbaselin

e,week5,

andweek9

(1month

afterthelastinjection)

Clin

icaleffectsin

jointswithactive

synovitis

Wang

etal.

[24]

PilotRCT

48Ankle,footin

RA

Artz

Twoinjections

(onceaweekfor

2weeks)

Intra-articularHA(n

=24)

vsintra-articularlidocaine

(2%

xylocaine,n=20)

VASpain

daily;FF

Iat

baselin

e,4and

12weeks

afterinjection;

CDUSscore

Saito

etal.

[31]

Cross-

sectional

4725

Knee,

shoulder,

elbow,w

rist,

ankle,

fingers,toes

inRA

Intra-articularHA

(n=291)

vsintra-

articularcorticosteroid

(n=371)

vsnon-

injection(n

=4057)

VASpain

daily;FF

I.at

baselin

e,4and

12weeks

afterinjection

Cheng

andTan

[32]

Pre–post

treatm

ent

31Knee,shoulder

inRA

Five

injections

(once

aweekfor

5weeks)

Any

Pain,infl

ammation,

pain

onwalking,

morning

stiffness

Kopp

etal.

[25]

RCT

41TMJin

RA

Hylartil

Three

injections

(biweeklyfor

4weeks)

Intra-articularHA

vsintra-

articularglucortocoids

(N=14),salin

e

(N=13)

VASpain,globalevaluation,routine

clinical

exam

inationaccordingto

Krough-Po

ulsen,

CDSaccordingto

Helkimo

Isdale

etal.

[33]

Pre–post

treatm

ent,

dose-

ranging

10Kneein

RA

Healon

Three

injections

(onceaweekfor

3weeks)of

20,40

and60

mg

Any

Kneecircum

ferenceandrangeof

movem

ent

atbaselin

eandweekly;daily

diaryof

day/

nightpain

andstiffness

1352 Adv Ther (2020) 37:1347–1359

Table3

continued

Stud

yDesign

NJoint(s)

HA

HA

schedu

ling

Com

parison

Outcome

Exogeneoushyaluronan

andsynovialfluid

Goto

etal.

[29]

Pre–post

treatm

ent

25Kneein

RA

SI- 6601D

Five

injections

(once

aweekfor

5weeks)after

aspiration

of

synovialfluid

Any

Localclinicalsymptom

s(joint

pain

and

inflammation,pain

onwalking)atbaselin

e

and1weekaftertheendof

thestudy;

biochemicalparameters(PGE2and

cytokines);glycosam

inoglycans);system

ic

clinicalassessment(PCR,E

SR,E

MS);

safety

assessment;pain

motionand

swellin

gandradiographicalchangesof

the

knee

atarbitrarypoints(approximately

1–2years)aftertheendof

thestudy

Matsuno

etal.

[26]

RCT

26Kneein

RA

NRD101

Five

injections

(once

aweekfor

5weeks)

0.1%

vs0.01%

HA

inPB

SPain,signs

ofinflammationandactivities

of

daily

living,characteristics(volum

e,

viscosity,stringency,H

Aconcentration,

MW

ofHA,p

rotein

concentration,

chondroitin4,6-sulfate)of

synovialfluid

(beforeand1weekaftertheendof

the

trial)

Goto

etal.

[34]

Pre–post

treatm

ent

8Kneein

RA

Artz

Sixinjections

(biweeklyfor

12weeks)after

aspiration

of

synovialfluid

Any

Spontaneouspain,p

ainat

motion,

clinical

labdeterm

inations,volumeof

synovial

fluid,totalproteinandHAconcentration,

intrinsicandspecificviscosity,MW

of

HA,stringency,radiograph

ical

exam

ination

Adv Ther (2020) 37:1347–1359 1353

5 weeks) of patients’ conditions in terms ofpain, stiffness and physical function. Notewor-thy, the authors observed a score reductionfrom baseline of about 50% and the effects ofthe local therapy were still present 1 monthafter the last HA injection. Nevertheless, theseresults are affected by a fair risk of bias becauseof the small sample size (n = 20) and the lack ofa control group.

Clinical Effects of Intra-ArticularAdministration of HA in Joints with ActiveSynovitisFive studies were included in this topic, twoRCTs [24, 25], two uncontrolled longitudinalstudies [32, 33] and one cross-sectional study[31]. Overall, 370 HA injections within eightdifferent joints (shoulder, knee, ankle, foot,elbow, wrist, fingers and toes) were evaluated.The evaluated outcomes varied from genericscales of pain assessment such as VAS to morespecific measures of joint function such as footfunction index. Overall, each study resulted inimprovements in joint function and pain whencompared with baseline conditions, whereas thedifferences between HA and corticosteroidinjections were not always evident. In themedical survey approach by Saito et al. [31], theauthors concluded that, irrespective of joint,both HA and corticosteroids were almostequally effective in treating RA, where effec-tiveness was measured in terms of satisfactoryrate. Similar conclusions were reached also inthe RCT including patients with dysfunction ofthe temporomandibular joint (TMJ) [25], whereHA and glucocorticoids had similar beneficialeffects on both subjective and clinical signs ofTMJ arthritis with a better performance of thelatter in reducing lateral and posterior tender-ness to palpation.

When compared to lidocaine [24], HA vis-cosupplementation appeared more effective inquickly reducing pain and disability with regardto ankles and feet affected by RA. No anti-in-flammatory effect was seen because of the lackof reduction in synovial hypervascularization.

On the other hand, Isdale and colleagues[33] observed only a very little benefit of HA inthe treatment of the knee joint of ten patientswith RA compared to the group affected byT

able3

continued

Stud

yDesign

NJoint(s)

HA

HA

schedu

ling

Com

parison

Outcome

Tanaka

etal.

[27]

RCT

118

Kneein

RA

NRD101

Five

injections

(once

aweekfor

5weeks)after

aspiration

of

synovialfluid

Intra-articularHA

after

arthrocentesisvs

intra-

articularHA

without

arthrocentesis

Relapse

ofknee

arthritis(norelief,recurring

ofsymptom

sandsignsof

arthritis,

presence

ofjointfluid

confi

rmed

by

ultrasound

)

TMJtemporomandibularjoint,PB

Sphosphatebuffered

salin

e,WOMCACWestern

OntarioandMcM

asterUniversitiesOsteoarthritisIndex,VASvisualanalogue

scale,FF

Ifoot

function

index,CDUScolour

Doppler

ultrasound

,CDSclinicaldysfun

ctionscore.MW

molecular

weight

1354 Adv Ther (2020) 37:1347–1359

primary OA, but the conclusions referred onlyto short-term effects.

Lastly, the study by Cheng and Tan [32]differed from the others as HA effectiveness wastested on patients with elderly-onset RA. Briefly,the authors observed longer-lasting effects,from 2 months to 3 years, confirming the posi-tive trend of HA injections in reducing pain anddisability.

Exogeneous Hyaluronan and Synovial FluidBiodynamic Performance Regarding thistopic, we included three studies [26, 29, 34]. Inall studies except that by Matsuno et al. [26] thetreatment was preceded by synovial fluid aspi-ration. A total of 46 patients and 47 knees wereassessed before and after HA injection. Changesin some or all biochemical properties ofrheumatoid synovial fluid (i.e. endogenous HAconcentration, viscosity, stringency and syn-ovial fluid volume) after intra-articular injectionof HA were observed, whereas systemic inflam-matory parameters (erythrocyte sedimentationrate and C-reactive protein) did not show anystatistically significant improvement. A localsignificant reduction of the levels ofprostaglandin E2 and chondroitin sulfate maybe partly attributed to the improvement ofsynovitis parameters in the studies by Matsuno[26] and Goto [29]. The pain scores significantlydecreased in all cases. Radiographical examina-tion did not show any statistically significantimprovement. Of note, only one study [26] wasdesigned to have a control group (1% versus0.01% HA) randomly assigned to treatment.

Impact of Arthrocentesis The study by Tanaka[27] specifically focused on the effect of com-plete aspiration of the synovial fluid from theknee joint before the injection of high molec-ular weight hyaluronan. Patients suffering fromRA and with symptoms of knee arthritisincluding effusion were enrolled. The studyprotocol envisaged a second group of patientsin which the synovial fluid aspiration was notperformed. The strengths of this study are therandom allocation of patients to arthrocentesisor no arthrocentesis, the long-term evaluation(6 months of follow-up) and the quite large sizeof the sample (118 patients, 161 knees). The

authors observed a higher prevalence of norelapses in the arthrocentesis group (66% versus40% at 180 days). Predicting responders areduration of the knee arthritis (OR [95% CI] 1.07[1.02–1.12]), C-reactive protein (OR [95% CI]2.58 [1.11–5.95]) and radiological grade (OR[95% CI] 3.59 [1.53–8.39]) as assessed by theLarsen method.

Adverse Events

There were no adverse effects during the treat-ment. The only adverse event occurred afterfour intra-articular injections of HA and was dueto the aggravation of systemic rheumatoidinflammation. Therefore, it was probably notrelated to the local treatment.

DISCUSSION

In this study we performed a systematic reviewof the literature concerning the application ofviscosupplementation in the treatment of OA ininflammatory autoimmune rheumatic disorderswith the aim of investigating the current evi-dence of its efficacy/effectiveness.

The randomized and non-randomized stud-ies carried out in this field are very heteroge-neous and affected by some important biases(inadequate sample size; observational studiesmissing control groups; studies were conductedalmost exclusively in Asia; subjects with differ-ent radiological degrees were not always inde-pendently analysed; outcomes were not alwaysadequate, etc.). Furthermore, all the includedmanuscripts are exclusively restricted to RA andpublished many years ago, implicating thatinclusion criteria and drug formulations couldbe changed over time. Therefore, the mainconsideration that arises from our review is theneed to better clarify the correct scope of vis-cosupplementation in the treatment of rheu-matic inflammatory disorders in a modern andwell-designed setting.

The rationale of HA therapy in patients suf-fering from inflammatory rheumatic diseasessuch as RA derives from the results of severalin vitro and in vivo models experiments [35]. Ina hypothetical biochemical pathway,

Adv Ther (2020) 37:1347–1359 1355

inflammatory conditions lead to the depoly-merization of native HA into small fragmentsthat may produce a range of proinflammatoryresponses. It is speculated that these small pie-ces of different sizes directly bind Toll-likereceptor 4 (TLR-4) and CD44 inducing activa-tion of several pathways that finally trigger NF-jB activation and its translocation to thenucleus, then perpetuating the tissue injurythrough the transcription of several detrimentalintermediates. The injected HA would increasethe local concentration of the synovialpolysaccharide and displace the degraded HAfrom these receptors with consequent inhibi-tion of TLR4 and CD44 activity and blocking ofinflammation, finally allowing tissue repair. Inthis regard, several experimental animal modelsof OA in RA have elucidated the molecular andpathophysiological mechanisms of cartilageinflammation/degeneration and have demon-strated the positive effect of exogenous HA onthe preservation of joint cartilage. In spite ofthis, in our systematic review we observed thatthe current literature on clinical application ofviscosupplementation did not offer the sameunivocal message. In part, this heterogeneitycan be explained because, in the majority of thecases, the therapy has been applied in patientswith active synovitis. This is a critical pointbecause intra-articular injections of both HAand corticosteroids are symptom-modifyingagents and do not prevent or slow the diseaseprogression [36]. On the other hand, only onestudy investigated the mechanical properties ofHA but it did not offer enough evidence, miss-ing a control group and including a very smallsample size.

Furthermore, another doubtful conclusionraised from this systematic review was the lackof a substantial difference between corticos-teroid and hyaluronan injection. Only twostudies compared the value of these treatments,the survey by Saito et al. [31] and the manu-script by Kopp et al. [25] that concernedpatients with RA involving the TMJ. However,both studies displayed crucial limitations: theformer measured the effectiveness using sub-jective patient-reported experience, whereas thelatter was affected by confounding factorsinfluencing the outcome of treatments.

Noteworthy, although the exact mechanism ofaction of both agents remains unknown, it iswidely recognized that the viscosupplementa-tion has a more favourable long-term profilethan repeated steroids [36].

In summary, as many unresolved issuesencompass the use of HA in musculoskeletaldisorders, well-design studies are required todetermine its most appropriate position in theframework for clinical practice.

CONCLUSION

This review clearly shows that the results of thecurrent literature on HA utility in the treatmentof secondary OA are based on old and hetero-geneous studies, and therefore difficult tointerpret. Well-designed studies are necessary todefinitively clarify the range of application ofviscosupplementation therapy.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for this study or publication of thisarticle.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Authorship Contributions. Substantial con-tributions to study conception and design:ODL, AM, IP. Substantial contributions toacquisition of data: FP, ODL, AM, AS, MDS.Substantial contributions to analysis and inter-pretation of data: FP, ODL. Drafting the articleor revising it critically for important intellectualcontent: all the authors. Final approval of theversion of the article to be published: all theauthors.

Disclosures. Orazio De Lucia, AntonellaMurgo, Francesca Pregnolato, Irene Pontikaki,

1356 Adv Ther (2020) 37:1347–1359

Mirian De Souza, Alessandro Sinelli, RolandoCimaz and Roberto Caporali have nothing todisclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analysed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

REFERENCES

1. Luque Ramos A, Redeker I, Hoffmann F, Callhoff J,Zink A, Albrecht K. Comorbidities in patients withrheumatoid arthritis and their association withpatient-reported outcomes: results of claims datalinked to questionnaire survey. J Rheumatol.2019;46:564–571. http://www.jrheum.org/lookup/doi/10.3899/jrheum.180668.

2. Mehana E-SE, Khafaga AF, El-Blehi SS. The role ofmatrix metalloproteinases in osteoarthritis patho-genesis: an updated review. Life Sci. 2019;234:116786. https://linkinghub.elsevier.com/retrieve/pii/S0024320519307131. Accessed 20 Nov 2019.

3. Compagnoni R, Gualtierotti R, Randelli P. Totaljoint arthroplasty in patients with inflammatoryrheumatic diseases. Adv Ther. 2018;35:1133–9.http://link.springer.com/10.1007/s12325-018-0750-9.

4. Jamsen E, Virta LJ, Hakala M, Kauppi MJ, Malmi-vaara A, Lehto MUK. The decline in joint replace-ment surgery in rheumatoid arthritis is associatedwith a concomitant increase in the intensity ofanti-rheumatic therapy. Acta Orthop. 2013;84:331–7. http://www.tandfonline.com/doi/full/10.3109/17453674.2013.810519.

5. Shimazu A, Jikko A, Iwamoto M, et al. Effects ofhyaluronic acid on the release of proteoglycan fromthe cell matrix in rabbit chondrocyte cultures in thepresence and absence of cytokines. ArthritisRheumatol. 1993;36:247–53.

6. Moreland L. Intra-articular hyaluronan (hyaluronicacid) and hylans for the treatment of osteoarthritis:mechanisms of action. Arthritis Res Ther. 2003;5:54–67.

7. Hakansson L, Hallgren R, Venge P. Regulation ofgranulocyte function by hyaluronic acid. In vitroand in vivo effects on phagocytosis, locomotion,and metabolism. J Clin Investig. 1980;66:298–305.

8. Nicholls MA, Fierlinger A, Niazi F, Bhandari M. Thedisease-modifying effects of hyaluronan in theosteoarthritic disease state. Clin Med InsightsArthritis Musculoskelet Disord. 2017;10:117954411772361. http://journals.sagepub.com/doi/10.1177/1179544117723611.

9. Maheu E, Bannuru RR, Herrero-Beaumont G, AllaliF, Bard H, Migliore A. Why we should definitelyinclude intra-articular hyaluronic acid as a thera-peutic option in the management of kneeosteoarthritis: results of an extensive critical litera-ture review. Semin Arthritis Rheum. 2019;48:563–72. https://linkinghub.elsevier.com/retrieve/pii/S004901721830235X.

10. Bellamy N, Campbell J, Welch V, Gee TL, Bourne R,Wells GA. Viscosupplementation for the treatmentof osteoarthritis of the knee. Cochrane DatabaseSyst Rev. 2006. http://doi.wiley.com/10.1002/14651858.CD005321.pub2.

11. Wang C-T, Lin J, Chang C-J, Lin Y-T, Hou S-M.Therapeutic effects of hyaluronic acid onosteoarthritis of the knee. J Bone Jt Surg. 2004;86:538–45. http://insights.ovid.com/crossref?an=00004623-200403000-00012.

12. Quilliot J, Couderc M, Giraud C, Soubrier M,Mathieu S. Efficacy of intra-articular hyaluronicacid injection in knee osteoarthritis in everydaylife. Semin Arthritis Rheum. 2019;49:e10–1. https://

Adv Ther (2020) 37:1347–1359 1357

linkinghub.elsevier.com/retrieve/pii/S0049017219300046.

13. Dasa V, Lim S, Heeckt P. Real-world evidence forsafety and effectiveness of repeated courses of hya-luronic acid injections on the time to kneereplacement surgery. Am J Orthop. 2018;47.https://www.amjorthopedics.com/article/real-world-evidence-safety-and-effectiveness-repeated-courses-hyaluronic-acid-injections.

14. Delbarre A, Amor B, Bardoulat I, Tetafort A, Pel-letier-Fleury N. Do intra-articular hyaluronic acidinjections delay total knee replacement in patientswith osteoarthritis—a Cox model analysis. PLoSOne. 2017;12:e0187227. https://dx.plos.org/10.1371/journal.pone.0187227.

15. Saito S, Kotake S. Is there evidence in support of theuse of intra-articular hyaluronate in treatingrheumatoid arthritis of the knee? A meta-analysis ofthe published literature. Mod Rheumatol. 2009;19:493–501.

16. Tanaka S, Souen S, Yamamoto M, Komatubara Y,Sugawara S, Matubara T. Clinical study of highmolecular hyaluronic acid (NRD101) on rheuma-toid arthritis. A multi-center, joint phase III com-parative clinical study. Rinsho-Ryumachi. 1994;5:304–32.

17. Tanaka S, Souen S, Yamamoto M, Komatubara Y,Sugawara S, Matubara T. Clinical study of highmolecular hyaluronic acid (NRD101) on rheuma-toid arthritis. A multi-center, joint phase II clinicalstudy. Rinsho-Ryumachi. 1994;5:279–303.

18. Goto M. Clinical effect of intra-articular injection ofhigh molecular weight hyaluronic acid (NRD101)on rheumatoid arthritis and analysis of its synovialfluid. Rinsho-Ryumachi. 1994;6:33–49.

19. Matuno H. Effects of intra-articular therapy ofhyaluronate and changes in characteristics of syn-ovial fluid in RA patients. Rheumatology. 1996;16:154–63.

20. Komatubara Y, Inoue K, Souen S, Goto M, Tanaka S,Nakajima M. Dose-response study of high molecu-lar weight hyaluronic acid (NRD101) on knee painin rheumatoid arthritis. A multi-center comparativeclinical study. Rinsho-Ryumachi. 2004;12:179–204.

21. Jevsevar D, Donnelly P, Brown GA, Cummins DS.Viscosupplementation for osteoarthritis of theknee. J Bone Jt Surg Am Vol. 2015;97:2047–60.https://insights.ovid.com/crossref?an=00004623-201512160-00009.

22. Moher D, Liberati A, Tetzlaff J, Altman D. Preferredreporting items for systematic reviews and meta-

analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.

23. Jadad AR, Moore RA, Carroll D, et al. Assessing thequality of reports of randomized clinical trials: isblinding necessary? Control Clin Trials. 1996;17:1–12.

24. Wang CC, Lee SH, Lin HY, et al. Short-term effect ofultrasound-guided low-molecular-weight hya-luronic acid injection on clinical outcomes andimaging changes in patients with rheumatoidarthritis of the ankle and foot joints. A randomizedcontrolled pilot trial. Mod Rheumatol. 2017;27:973–80. https://doi.org/10.1080/14397595.2016.1270496.

25. Kopp S, Akerman S, Nilner M. Short-term effects ofintra-articular sodium hyaluronate, glucocorticoid,and saline injections on rheumatoid arthritis of thetemporomandibular joint. J Craniomandib DisordFacial Oral Pain. 1991;5:231–8.

26. Matsuno H, Yudoh K, Kondo M, Goto M, Kimura T.Biochemical effect of intra-articular injections ofhigh molecular weight hyaluronate in rheumatoidarthritis patients. Inflamm Res. 1999;48:154–9.

27. Tanaka N, Sakahashi H, Sato E, Hirose K, Ishima T,Ishii S. Intra-articular injection of high molecularweight hyaluronan after arthrocentesis as treatmentfor rheumatoid knees with joint effusion.Rheumatol Int. 2002;22:151–4.

28. Goto M, Hosako Y, Katayama M, Yamada T. Bio-chemical analysis of rheumatoid synovial fluid afterserial intra-articular injection of high molecularweight sodium hyaluronate. Int J Clin Pharm Res.1993;XIII:161–6.

29. Goto M, Hanyu T, Yoshio T, et al. Intra-articularinjection of hyaluronate (SI-6601D) improves jointpain and synovial fluid prostaglandin E2 levels inrheumatoid arthritis: a multicenter clinical trial.Clin Exp Rheumatol. 2001;19:377–83.

30. Chou CL, Li HW, Lee SH, Tsai KL, Ling HY. Effect ofintra-articular injection of hyaluronic acid inrheumatoid arthritis patients with kneeosteoarthritis. J Chin Med Assoc. 2008;71:411–5.

31. Saito S, Momohara S, Taniguchi A, Yamanaka H.The intra-articular efficacy of hyaluronate injec-tions in the treatment of rheumatoid arthritis. ModRheumatol. 2009;19:643–51.

32. Cheng XF, Tan K. Intra-articular injections ofsodium hyaluronate in treatment of eledrly-onsetrheumatoid arthritis. Chin J Clin Rehabil. 2003;7:2476–7.

1358 Adv Ther (2020) 37:1347–1359

33. Isdale AH, Hordon LD, Bird HA, Wright V. Intra-articulra hyaluronate (Healon): a dose-rangingstudy in rheumatoid arthritis and osteoarthritis.J Drug Dev. 1991;4:93–9.

34. Goto M, Hosako Y, Katayama M, Yamada T. Bio-chemical analysis of rheumatoid synovial fluid afterserial intra-articular injection of high molecularweight sodium hyaluronate. Int J Clin PharmacolRes. 1993;13:161–6. http://www.ncbi.nlm.nih.gov/pubmed/8225699. Accessed 29 Oct 2019.

35. Avenoso A, D’Ascola A, Scuruchi M, et al.Hyaluronan in experimental injured/inflamed car-tilage: in vivo studies. Life Sci. 2018;193:132–40.https://linkinghub.elsevier.com/retrieve/pii/S0024320517305830.

36. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSIguidelines for the non-surgical management ofknee, hip, and polyarticular osteoarthritis.Osteoarthr Cartil. 2019;27:1578–89. https://doi.org/10.1016/j.joca.2019.06.011.

Adv Ther (2020) 37:1347–1359 1359