Rheumatol Int (2011) 31:427–444DOI 10.1007/s00296-010-1660-6 REVIEWThe role of intra-articular hyaluronan (SinovialÒ)in th...
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Rheumatol Int (2011) 31:427–444                                                                                           ...
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Rheumatol Int (2011) 31:427–444                                                                                           ...
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Table 2 Clinical trials of intra-articular (IA) injections of hyaluronic acid (HA) in patients with osteoarthritis (OA) of...
Table 2 continued                                                                                                         ...
Rheumatol Int (2011) 31:427–444                                                                                           ...
436123      Table 3 Clinical trials of intra-articular (IA) injections of hylan in patients with osteoarthritis (OA) of th...
Table 4 Clinical trials of intra-articular (IA) injections of hyaluronic acid (HA) vs. hylan in patients with osteoarthrit...
(2011)the role of intra articular hyaluronan (sinovial)
(2011)the role of intra articular hyaluronan (sinovial)
(2011)the role of intra articular hyaluronan (sinovial)
(2011)the role of intra articular hyaluronan (sinovial)
(2011)the role of intra articular hyaluronan (sinovial)
(2011)the role of intra articular hyaluronan (sinovial)
(2011)the role of intra articular hyaluronan (sinovial)
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(2011)the role of intra articular hyaluronan (sinovial)

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(2011)the role of intra articular hyaluronan (sinovial)

  1. 1. Rheumatol Int (2011) 31:427–444DOI 10.1007/s00296-010-1660-6 REVIEWThe role of intra-articular hyaluronan (SinovialÒ)in the treatment of osteoarthritisAntonio Gigante • Leonardo CallegariReceived: 21 May 2010 / Accepted: 14 November 2010 / Published online: 28 November 2010Ó Springer-Verlag 2010Abstract Osteoarthritis (OA) leads to significant pain 3 months with no serious adverse events. Efficacy in otherand disability. For pain relief, a tailored approach using joints is being evaluated. Viscosupplementation with intra-non-pharmacological and pharmacological therapies is articular SinovialÒ (other trade names: YaralÒ, IntragelÒ)recommended. If adequate symptom relief is not achieved injections (an HA of low-medium MW) relieves pain andwith acetaminophen, other pharmacological options improves function in OA of the knee, and other jointsinclude non-steroidal anti-inflammatory drugs (NSAIDs), including the carpometacarpal joint of the thumb and thetopical analgesics, intra-articular corticosteroids and intra- shoulder. HA viscosupplementation, including use ofarticular hyaluronic acid (HA) viscosupplementation. Most SinovialÒ, is a valuable treatment approach for OAof these therapies generally do not improve functional patients, if other therapies are contraindicated or haveability or quality of life or are associated with tolerability failed.concerns. In OA patients, concentration and molecularweight (MW) of HA are reduced, diminishing elastovis- Keywords Osteoarthritis Á Hyaluronic acid Ácosity of the synovial fluid, joint lubrication and shock Viscosupplementation Á Viscoinductionabsorbancy, and possibly anti-inflammatory, analgesic andchondroprotective effects. In knee OA, viscosupplementa-tion with 3–5 weekly intra-articular HA injections dimin- Introductionishes pain and improves disability, generally within 1 weekand for up to 3–6 months and is well tolerated. HAs have Osteoarthritis (OA) is the most common form of arthritiscomparable efficacy as NSAIDs, with less gastrointestinal [1] and is responsible for considerable clinical and eco-adverse events, and compared with intra-articular cortico- nomic burden as a result of reduced quality of life (due tosteroids, benefits last generally longer. High MW hylans pain, disability, loss of mobility and independence),provide comparable benefits versus HA, albeit with an increased use of health care resources and lost of produc-increased risk of immunogenic adverse events. In mild-to- tivity. Although OA is essentially a broad clinical syn-moderate hip OA, intra-articular injection of HA moder- drome, it is characterised by the progressive loss ofately improved pain and function, generally for up to articular cartilage and chondrocytes within the synovial joints that manifests as chronic joint pain and functional limitation as a result of joint stiffness and progressive lossA. Gigante (&) in the range of joint motion.Dipartimento di Patologia Molecolare e Terapie Innovative, ` It is reported to be the most common cause of long-termSezione Clinica Ortopedica, Universita Politecnica delleMarche, Via Tronto 10, 60020 Ancona, Italy disability after chronic heart disease, with an estimatede-mail: a.gigante@univpm.it; Michele.fasola@ibsa.ch prevalence in adults of up to 16% in women and 25% in men [2]. Moreover, it is one of the most common causes ofL. Callegari ` disability worldwide [1]; 80% of patients with OA haveCattedra di Radiologia dell’Universita dell’Insubria, Ospedaledi Circolo e Fondazione Macchi, Viale Borri 57, some degree of movement limitation, and 25% cannot21100 Varese, Italy perform activities of daily life [3]. 123
  2. 2. 428 Rheumatol Int (2011) 31:427–444 The prevalence of OA increases with age; for those aged OA-related pain, the earliest and most consistentbetween 55 and 74 years, the estimated prevalence of OA symptom of the disease is generally caused by the strainof the hand is 70%, foot 40%, knee 10% and hip 3% [2]. that irregular cartilage and the loss of joint-structure putsInterestingly, below the age of 45, more men are affected on the adjacent ligaments, muscles and connective tissuesthan women, while over the age of 45, more women are [6]. The demonstration of pain receptors in tissues aroundaffected than men [2]. It is not surprising then that demo- joints (but not in cartilage, menisci and the synovial cavity)graphic changes including longer life expectancy, higher suggests an involvement in triggering pain and the releaselevels of obesity and lower levels of physical fitness are of inflammatory mediators (e.g., substance P) [6].increasing the burden and demand for OA-related healthresources [2]. Any synovial joint may be affected by OA, but it is Management strategiesmainly seen in the weight-bearing joints found in theknees, hands and hips [1]. Treatment options are primarily To date, there is no a definitive cure for OA, hence theaimed at relieving the pain stemming from OA, yet many goals of treatment are focused on the relief of pain,patients do not respond to management strategies involving maintenance and/or improvement in joint mobility, and innon-pharmacological interventions or are not able to tol- limiting functional impairment that impacts on an indi-erate analgesic/anti-inflammatory therapy due to tolerabil- vidual’s ability to perform activities of daily living (ADL).ity concerns, especially in the elderly [4, 5]. Both expert consensus and research evidence contribute to Among the different treatment modalities available for the EULAR recommendations for the management of kneethe management of OA, viscosupplementation with [7] and hip [8] OA. The optimal management of OA of thehyaluronic acid (HA) is widely accepted in the clinical knee requires a combination of non-pharmacological andpractice. pharmacological treatment modalities. Treatment should be The objectives of this paper are to examine the rationale tailored according to: knee risk factors (obesity, adverseand the efficacy of intra-articular HA products (in general) mechanical factors, physical activity); general risk factorsand of SinovialÒ (also known as YaralÒ/IntragelÒ), in (age, comorbidity, polypharmacy); level of pain, intensityparticular, in the management of OA. References included and disability; signs of inflammation (e.g., effusion); andin this review were selected by non-systematic literature the location and degree of any structural damage [7].searches of PubMed and treatment guidelines. Non-pharmacologic management strategies such as regular patient education, weight reduction, use of orthot- ics, exercise and mechanical supports are advocated forPathology of OA patients with mild symptoms [7]. Among the available pharmacologic options for the treatment of pain associatedOA is recognised as a metabolically active, dynamic pro- with OA of the knee, oral acetaminophen (paracetamol) iscess of degradation and synthesis involving all tissues of the first line therapy, and if favourable, is the preferredthe affected joint including cartilage, bone, synovium, long-term oral analgesic. For patients in whom theseligaments and muscle [1]. The pathological changes result measures do not provide adequate symptom relief, sub-from failure of the repair process of the synovial joints that sequent treatment options include topical application of ais activated by joint damage and includes loss of chon- non-steroidal anti-inflammatory drug (NSAID) or capsai-drocytes and cartilage matrix, and bone remodelling, cin, and systemic NSAIDs. In patients with an increasedleading to biomechanical joint failure. gastrointestinal risk (e.g., the elderly, those with ulcers), While the aetiology of OA is not completely understood, non-selective NSAIDs and gastroprotective agents ora number of risk factors are known to contribute including selective COX-2 inhibitors should be considered. Admin-genetic, constitutional (obesity, age, gender, high bone istration of chondroitin sulphate, glucosamine sulphate,density) and biomechanical (injury, occupational or recre- avocado-soybean unsaponifiables (ASU), diacerin andational joint trauma, muscle weakness) [1]. Some of these hyaluronic acid, which mimic natural hyaluronan, haverisk factors are modifiable or avoidable, such as environ- symptomatic effect and may also modify structure. Intra-mental or lifestyle factors including obesity, muscle articular administration of corticosteroids may also beweakness and occupational or recreational joint trauma. considered, especially for flare of knee pain, accompaniedImportantly, some may contribute to OA development by effusion. Failing conservative pharmacological options,(high bone density) while others are considered to be risk surgical treatment may be considered, while alternative/factors for disease progression and poor clinical outcome complementary therapies—e.g., acupuncture, have also(low bone density). been associated with benefits in OA.123
  3. 3. Rheumatol Int (2011) 31:427–444 429Rationale for the use of hyaluronan derivatives anabolic and chondroprotective effects that reduce pain and disability and improve joint function [12–14].Function of natural hyaluronan The term viscoinduction has been coined to describe the phenomenon of the clinical benefits of HA exceeding thatHyaluronan (also referred to as hyaluronic acid [HA] or of a physical lubricant/cushioning effect alone. Viscoin-sodium hyaluronate) is a highly viscous polysaccharide duction ensures that clinical efficacy is maintained forfound in the extracellular matrix, particularly in soft several months despite the half-life of intra-articular HAconnective tissues and is a major component of the being only a few days.synovial fluid and of cartilage [9]. Following synthesis in It has been suggested that exogenous HA inducesthe joints by chondrocytes and synoviocytes, HA is endogenous HA synthesis, possibly stimulating the regen-released into the synovial space and accumulates on erative process within the joint [15]. Indeed, in vitro, incartilage and ligament surfaces. Belonging to the family studies of synoviocytes from joints of subjects with OA,of glycosaminoglycans, the HA molecule is composed of exogenous HA was associated with de novo synthesis of1,000 s of repeating disaccharide units (N-acetylgluco- HA [15].samine and glucuronic acid) to form a long polysac- HAs may also have structure-modifying actions andcharide chain of varying length with a high molecular may, therefore, have benefits on the disease process;weight (3–4 9 106 Da) that when fully hydrated, occu- however, this effect is still a matter of debate, as currentlypies a large spherical domain. In addition to its elastic there is minimal evidence to support a role of HA in OAand viscous properties, this physical presence of HA disease modification [7].supports its significant role in maintaining the rheological HA agents are generally administered as a weeklyhomoeostasis of the synovial fluid in the joint and also injection over a course of 3–5 weeks, and although theycontributes to lubrication, shock absorption, elasticity, have a slower onset of action relative to steroid treatment,hydration and nutrition for the joint tissue. the pain relief obtained generally lasts longer—for up to The normal concentration of HA in the synovial fluid of several months [7].the human knee is about 2.5–4.0 mg/mL (with an estimatedtotal concentration of 4–8 mg/knee); however, in patho- Commercially available HA derivativeslogical conditions, both the concentration (estimated to behalved, 1–2 mg/ml) [9] and molecular weight of HA are A number of different preparations of HA are currentlyreduced resulting in synovial fluid of lower elasticity and available in Europe and USA (Table 1) [5, 14, 16–19].viscosity, with a consequent impact on the joint [10]. Each is produced from either rooster combs (avian type) or by recombinant technology (biofermentation) and differsInjection of exogenous hyaluronan derivatives by molecular weight and hence residence time in the joint, and rheological properties [5, 14, 16–19].Intra-articular injections of HA (i.e., viscosupplementation)are approved worldwide for the treatment of pain associ- Treatment guidelinesated with OA of the knee. The aim of HA treatment is toreduce pain and improve physical function by supple- HA therapy is recommended in the American College ofmenting the viscosity and elasticity of synovial fluid which Rheumatology (ACR) and European League of Arthritis &are reduced in OA [7, 11]. Most commercial preparations Rheumatism (EULAR) guidelines for the management ofof HA have the same structure as endogenous HA, patients with hip or knee OA and is advocated for use inalthough high molecular weight products containing cross- those patients who have not responded to other therapieslinked HA molecules (hylans) have also been engineered (as discussed above) [7, 8, 20, 21].(e.g., hylan G-F 20 has a MW of 6,000 kDa) to achieve However, in an effort to minimise cardiovascular, gas-greater elastoviscosity and intra-articular dwell-time [1]. trointestinal (ulcers, bleeding) and renal safety concerns The exact mechanism of action of injected HA is not with COX-2 selective and other non-selective NSAIDs,well understood; however, it is believed that several and to maximise HA efficacy, other authors propose usingmechanisms contribute to the clinical effects achieved with an HA earlier in the treatment paradigm for knee OA, andHA in the treatment of OA [12–14]. In addition to a purely in general as part of a comprehensive treatment strategymechanical effect due to the viscosity of the products [18].(restoration of visco-elastic properties of the synovial fluid: A Cochrane meta-analysis of 76 trials (including 40cushioning, lubrication, elasticity), intra-articular HA placebo-controlled trials of HA or hylan) showed thatviscosupplementation is thought to provide a range of viscosupplementation is effective in OA of the knee withbiological actions including anti-inflammatory, analgesic, beneficial effects on pain, function and patient global 123
  4. 4. 430 Rheumatol Int (2011) 31:427–444Table 1 Preparations of intra-articular hyaluronic acid (HA) and hylan available in Europe and/or the USATradename Concentration Generic name Source (type) Molecular (mg/ml) weight (kDa)AdantÒ 25 mg/2.5 ml Sodium hyaluronate Biofermentation 900 ÒArthrum 40 mg/2 ml Sodium hyaluronate Biofermentation 2,400ArtzÒ/SupartzÒ 25 mg/2.5 ml Sodium hyaluronate Rooster combs (avian) 600–1,200CoxarthrumÒ 75 mg/3 ml Sodium hyaluronate Biofermentation 2,400DurolaneÒ 20 mg/3 ml Sodium hyaluronate Biofermentation NAErectusÒ NA NA NA 1,100EuflexxaÒ 20 mg/2 ml Sodium hyaluronate Biofermentation 2,400–3,600FermathronÒ 20 mg/2 ml Sodium hyaluronate Biofermentation 1,000Go-OnÒ 25 mg/2.5 ml Sodium hyaluronate Biofermentation 800–1,200Go-OnÒ Mini 10 mg/1 mlHyalartÒ 20 mg/2 ml Sodium hyaluronate Rooster combs (avian) 500–730 ÒHyalgan 20 mg/2 ml Sodium hyaluronate Rooster combs (avian) 500–730HyalubrixÒ 30 mg/2 ml Sodium hyaluronate Biofermentation [1,500IntragelÒ 0.8% 16 mg/2 ml Sodium hyaluronate Biofermentation 800–1,200IntragelÒ 1.6% 32 mg/2 mlJointexÒ 16 mg/2 ml Sodium hyaluronate Biofermentation 800–1,200JointexÒ Starter 32 mg/2 mlMonoViscÒ 20 mg/ml Sodium hyaluronate Biofermentation, lightly cross-linked NANeoViscÒ 20 mg/2 ml Sodium hyaluronate Biofermentation 1,000OrthoviscÒ 30 mg/2 ml High molecular weight hyaluronan Biofermentation/chemical modification 1,100–2,900OrthoviscÒ mini 15 mg/1 ml 1,450OstenilÒ 20 mg/2 ml Sodium hyaluronate Biofermentation 1,200OstenilÒ mini 10 mg/mlRenehaVisÒ 7 mg/0.7 ml ? Sodium hyaluronate Biofermentation 1,000 15.4 mg/0.7 ml 2,000SinovialÒ 16 mg/2 ml Sodium hyaluronate Biofermentation 800–1,200SinovialÒ Mini 8 mg/1 mlSinovialÒ Forte 32 mg/2 mlSportVisÒ 12 mg/1.2 ml ? Sodium hyaluronate Biofermentation NASuplasynÒ 20 mg/2 ml Sodium hyaluronate Biofermentation 500–730SuplasynÒ m.d. 7 mg/0.7 mlSynocromÒ 20 mg/2 ml Sodium hyaluronate Biofermentation 1,600SynocromÒ mini 10 mg/1 ml 2,100SynocromÒ forte 40 mg/2 mlSynviscÒ 16 mg/2 ml Hylan G-F 20 Rooster combs (avian), cross-linked 6,000SynviscÒ One 48 mg/6 mlViscorneal-orthoÒ 20 mg/2 ml Sodium hyaluronate Rooster combs (avian) 6,000YaralÒ 16 mg/2 ml Sodium hyaluronate Biofermentation 800–1,200YaralÒ Mini 8 mg/1 mlYaralÒ Forte 32 mg/2 mlassessment, especially at the 5- to 13-week post-injection drawn regarding the relative value of each HA productperiod when pain and function were improved from base- [22]. Although, in general, the efficacy of HAs was com-line by 28–54 and 9–32%, respectively. However, the parable with NSAIDs, benefits were of longer durationanalysts reported that as there was marked variability with HAs compared with intra-articular corticosteroids.between different HAs on different outcome parameters, Few adverse events were reported with the use of HAs, andespecially at different time points, conclusions could not be overall it was surmised that within the constraints of the123
  5. 5. Rheumatol Int (2011) 31:427–444 431trial designs (some used small sample size), there were no shown this (as discussed below), and although results of amajor safety concerns. meta-analysis of 22 studies by Lo et al. [28] suggested greater effects with HA of higher molecular weight, the heterogeneity of the included trials limited the validity ofOverview of SinovialÒ such a definitive conclusion. In addition, other evidence including results from largeSinovialÒ (sodium hyaluronate) is a non-modified HA, a lin- animal models of OA shows that HAs with molecularear polymer composed of the disaccharide units N-acetyl-D- weight between 500 and 1,000 KDa are more effective thanglucosamine and Na-D-glucuronate, linked by glycosidic high molecular weight HAs in reducing synovial inflam-bonds. It is classified as a medical device; it is a 0.8% physi- mation and for restoring the rheological properties ofological solution of HA (16 mg/2 ml) in sodium chloride in a synovial fluid [30]. Also, several preclinical studies eval-ready-to-use sterile syringe for intra-articular injection [23]. uating joint-structure modification in animal models of OAHA is obtained by biofermentation and undergoes a stringent have reported advantages of using HAs of molecularpurification process (in the absence of chemical modification) weight in the low- to mid-range, as they can access dis-to produce a highly purified, non-pyrogenic polymer of a eased tissue more easily, suggesting potential for diseasedefined molecular weight (800–1,200 kDa) that is completely modification [14].free from animal proteins [23]. Furthermore, some studies show no difference in effi- SinovialÒ is indicated in patients undergoing joint cacy but an overall risk: benefit profile favouring lowerreplacement and/or supplementation of synovial fluid molecular weight HAs [31–33]. In a post-hoc analysis of adamaged following degenerative joint disease or trauma; randomised head-to-head study of hylan G-F 20 versuscurrently, it is used mainly in the knee [24]. bioengineered high weight hyaluronic acid (Bio-HA), there In clinical studies, administration of SinovialÒ resulted was no significant difference in response with eitherin a marked reduction in pain, improvement of joint treatment (63% vs. 71%; P = 0.10), and both were gen-mobility and decreased use of rescue medication (see later erally well tolerated; however, the incidence of effusionssection) [12, 24, 25]. Importantly, the effects of SinovialÒ was greater with hylan G-F 20 [32]. Similarly, the meta-are evident from the first injection (out of a cycle of 3–5) analysis of Reichenbach et al. [31] evaluated 13 random-and last up to 6 months, suggesting a long-lasting carry- ised trials in 2,085 patients comparing hylan with HA inover effect of the treatment [12, 24, 25]. the treatment of OA of the knee. When all the trials were SinovialÒ is also available in other ready-to-use for- considered, the pooled effect size favoured hylan (-0.27);mulations [23]; a higher concentration formulation, Sino- however, the heterogeneity of these trials was considerable,vialÒ Forte 1.6% (32 mg/2 ml) for major joint lubrication and a further analysis of the more robust studies showed aand during an acute attack in active OA, and a lower negligible effect size. Moreover, a safety analysis demon-volume formulation, SinovialÒ Mini 0.8% (8 mg/1 ml) for strated a twofold increased risk of local adverse eventsultrasound-guided infiltration of small joints, e.g. for (pain, swelling or warming to severe inflammation) andtreatment of rhizarthrosis (OA in the base of the thumb), flares with hylan.tenosynovitis (wrist tendonitis), or trigger finger. Thus, a likely explanation for the lack of definitive corre- lation between HA molecular weight and therapeutic effectMain differentiating points from other HA derivatives may be that the mechanism of action of HA for relief of OA symptoms is an interplay between mechanical and biologicalMolecular weight effects. In vitro studies have shown that HA has chondro- protective [34], and anti-inflammatory and structure-modi-HAs of various molecular weights are available (Table 1). fying effects in synoviocytes through down-regulation of geneLow molecular weight HAs consist of long unbranched expression for various cytokines, aggrecanase-2 and otherchains of natural HA, not chemically modified, e.g. Sino- enzymes [35]; effects thought to occur via CD44-mediatedvialÒ (800–1,200 kDa) and HyalganÒ (500–730 kDa). High metabolic modulation [34–36]. In addition, the enduringmolecular weight HAs consist of chemically modified cross- clinical efficacy (months) of intra-articular HA compared withlinked HA chains (hylans), e.g., SynviscÒ (6,000 kDa). its relatively short half-life may also be accounted for by The efficacy of intra-articular HA injections may be CD44-mediated metabolic modulation.dependent, in part, on the viscoelastic properties of the HAinjected, this being a function of its molecular weight [9, Source of hyaluronan13]. It was initially suggested that an HA with a highermolecular weight may provide improved clinical benefits SinovialÒ is obtained by biofermentation, which ensures[26–29]. However, clinical studies have generally not that the product is pure and free of potentially allergenic 123
  6. 6. 432 Rheumatol Int (2011) 31:427–444animal proteins [23]. Other HAs/hylans, e.g. HyalganÒand and dosing schedules (3–5 consecutive once-weeklySynviscÒ are obtained by extraction from rooster combs injections) were used in these trials, and concomitant(containing avian proteins) and, therefore, may have an analgesic therapy was permitted in some studies. Carr-increased risk of immunogenicity [17]. abba et al. [40] showed that 3 or 5 once-weekly intra- In contrast with HAs, cross-linked hylan G-F 20 use has articular HA injections were superior to a single injec-been associated with infrequent but dramatic pseudoseptic tion, providing relief of symptoms for up to 2 monthsacute local reactions [37–39]. The incidence (8–27%) and (Table 2). Longer-term (up to 52 weeks) functionalcharacteristics of pseudosepsis (i.e., severe acute inflam- improvement was seen with a course of 4 weeklymatory reactions that are clinically distinct from local injections [41], and Listrat et al. [42] showed that withinflammatory reactions) with the use of Hylan from reports an increased HA dosing schedule (9 injections overpublished up to 2003 (4 clinical and 5 case studies) were 9 months), there was less structural deterioration atcollated by Goldberg and Coutts [39]. Characteristics 1 year compared with control, providing evidence of aincluded severe inflammation of the joint, often associated delay in progression of structural deterioration in thewith significant cellular effusion and pain generally knee with HA.occurring within 24- to 72-h post-intra-articular hylan In non-comparative trials, both a rapid onset of actioninjection; first occurrence after exposure to second or third (1 week after injection) [43] and subsequent symptominjection of first course, or post first injection of a repeat relief with a second cycle of treatment (6 months after thecourse; and generally not self-limiting but requiring clini- first) that was comparable to that obtained with the firstcal intervention. Despite a lack of understanding of both cycle were shown [44].the aetiology of pseudosepsis and the long-term effects of In trials of HA versus active treatment, efficacy wasthese local immunological reactions in the knee, such comparable with NSAID therapy [45], and of longerevents would be expected to incur addition socioeconomic duration than that of corticosteroid treatment [46], find-costs. ings that are in agreement with those of the Cochrane Further evidence for the potential increased immuno- review discussed above [22]. In one large study [45], notgenicity with hylan comes from a meta-analysis (discussed only HA was superior to placebo for reduction in painabove) that showed no superior effectiveness of hylan over (from 4 to 26 weeks), it was also as effective as twiceHA in the treatment of OA of the knee, but rather an daily naproxen (from 4 to 26 weeks) with significantlyincreased risk of local adverse events [31]. It is established fewer gastrointestinal adverse events. The investigatorsthat cross-linked proteins are relatively more immuno- concluded that HA is an effective therapeutic alternativegenic. In addition, it has been proposed that contaminating to NSAIDs for patients not responding to non-pharma-chicken proteins and other components of rooster combs cologic therapy and non-opiate analgesics, especially forpotentially present during the cross-linking process of hy- those with a history of NSAID intolerance, e.g. thelans could result in the production of novel epitopes that elderly or patients with active ulcer disease [45]. In amay induce pseudosepsis in sensitised subjects [39]. study in patients with inflammatory OA of the knee, although there was a high dropout rate, it was shown that HA provided similar efficacy as corticosteroidClinical evidence for hyaluronan derivatives treatment for relief of pain over the first 4 weeks, while during the 6-month follow-up period, patients remainingKnee OA in the study had greater pain relief with HA [46]. Trials of hylan preparations for OA of the knee are fewThe efficacy of intra-articular HA or hylan in the relief of and have been mostly limited to 12-week durationpain and improvement in joint function in patients with OA (Table 3). In one study, hylan was superior to saline con-of the knee (of varying severity, Larsen grade I–V) has trol for pain relief and for increasing mobility [47], while inbeen shown in numerous controlled and observational another study, both hylan alone, and as adjunct to NSAIDclinical studies (Tables 2, 3, 4). therapy was as effective as continuous NSAID therapy, In placebo-controlled trials (some used a negligible although the incidence of adverse events was greater withconcentration of HA in the vehicle solution to maintain a hylan [48]. One small study showed intra-articular hylanviscous appearance) of intra-articular HA, superior and was superior to NSAID therapy [49], while in another,sustained relief of pain and functional ability were gen- hylan was as effective as corticosteroid treatment, but waserally shown in the absence of safety and tolerability associated with an acute local reaction causing the affectedconcerns, with effects seen from as early as 1 week after patient to withdraw [50].the first injection, and generally at week 3, then lasting Head-to-head trials of intra-articular HA versus hylanup to 6 months (Table 2). Various preparations of HA are also few (Table 4). In the first trial, a small 12-week123
  7. 7. Table 2 Clinical trials of intra-articular (IA) injections of hyaluronic acid (HA) in patients with osteoarthritis (OA) of the knee Study (design, duration) Patients (gender, Intervention, number of Primary efficacy assessments Safety analysis mean age, weight) once-weekly injections (n) HA vs. PL Carrabba et al. [40] 37 M/63 F HAa 20 mg/2 ml 19 (n = 20) Painb on movement/at rest, Lequesne One transient local AE (pain post- a index of severity for OA of the knee, injection) in each group except PL; (db, r, pc, sc, 6 mo) 60 years, 72 kg HA 20 mg/2 ml 39 (n = 20) joint mobility, and overall judgement of no relevant changes in laboratory HAa 20 mg/2 ml 59 (n = 20) efficacy up to 60 days were significantly parameters Knee athrocentesis (n = 20) better in the 39 and 59 injection PL (n = 20) groups vs. PL and athrocentesis Rheumatol Int (2011) 31:427–444 (P 0.005) Dixon et al. [15] 29 M/34 F HAa 20 mg/2 ml up to 11 injections/ Significant reductions in joint painb at rest Well tolerated, 1 case of haemarthrosis in 23 weeks (n = 33) vs. PL from week 5–23 and for painb on HA group; no clinically significant movement at wk 5 (P 0.05 for both); changes in laboratory parameters no marked improvements in ADLs as only one joint treated in pts with polyarticular disease (db, r, pc, 23 wks) 69 (43–85) years, 75 PL (HA 0.25 mg/2.5 ml) up to 11 (42–105) kg injections/23 weeks (n = 33) Dougados et al. [41] 32 M/78 F HAa 20 mg/2 ml 49 (n = 55) At wk 7, improvements from baseline in Minor and transient AEs, not considered painb after exercise (but not at rest) and treatment-related; no clinically functional impairment (Lequesne’s significant changes in laboratory index) were significantly greater with parameters HA vs. PL (P = 0.03 for both); at 52 weeks, significant improvements in functional index were maintained (P 0.05) (db, r, pc, mc, 1 yr) 68 years, 70 kg PL 49 (n = 55) Listrat et al. [42] 13 M/26 F HAa 20 mg/2 ml 3 cycles of 39/3 Painb and functional impairment Not done mo = 9 in total (n = 20) improved in both groups (NS); athroscopic parameters showed significantly less structural deterioration with HA vs. control; QoL assessment significantly better with HA vs. control at 1 yr (P B 0.05) (r, c, 1 yr) 62 years Control (n = 19) Lohmander et al. [91] 106 M/134 F HAc 25 mg/2.5 ml (1%) 59 (n = 96) Lequesne algofunctional index, painb, No serious AEs; severity of injection site range of motionb, activity levelb and swelling greater with HA than PL total knee functionb were improved (P = 0.041); AEs led to 5 PL and 2 HA from baseline with both HA and PL; recipients withdrawing prior to 5th stratification by age ([60 years) and injection baseline algofunctional index ([10) showed significantly greater improvements with HA vs. PL (P 0.05) 433123
  8. 8. Table 2 continued 434 Study (design, duration) Patients (gender, Intervention, number of Primary efficacy assessments Safety analysis mean age, weight) once-weekly injections (n)123 (r, db, pc, mc, 5 wks) 58 yrs, 79 kg PL (n = 93) Puhl et al. [92] 71 M/124 F HAd 25 mg/2.5 ml 59 (n = 95) Compared with control, progressive and Tolerability was good/very good in both significant reduction in mean Lequesne groups (96% for both); 4 HA and 5 Index of the severity of the knee joint control pts had a transient local AE from wk 3–14 (P 0.025) (pain post-injection); no between-group difference in laboratory parameters (r, db, pg, mc, 14 weeks) 61 years, 75 kg Control (HA 0.25 mg/2.5 ml) 59 (n = 100) Wu et al. [93] 83 M/33 F HAd 2.5 ml (1%) 59 (n = 62) Mean values for clinical symptoms and No side effects reported over 6 mo ADL were markedly improved with HA follow-up (r, db, pc, mc, 6 mo) 69 years, PL (n = 54) vs. PL from wk 5; significant improvements with HA vs. PL (P 0.05), especially for relief of motion pain and knee movement, with a peak at 6 wks, improvements sustained up to 3 mo Non-comparative trials with HA Novaes et al. [43] 69 M/296 F HAe 25 mg/2.5 ml 59 (n = 296) Pain, stiffness and functional capacity AEs in 3% of administrations included (ol, mc, 5 wks) 65 years were all progressively and significantly synovitis (n = 5), pruritus (1), eczema improved from baseline from wk 2–5 (1), pain at injection site (3) and (P 0.05) tendonitis (1) Petrella [44] 188 M/349 F HAf (10 mg/ml/2 ml) 39 (n = 537) Improvement (%) from baseline in self- Few minor local AEs (pain and swelling) (prospective, naturalistic, 6.7 yrs) 68 years, paced 40 m walking painb was BMI = 27 kg/m2 significant at visit 2, 3 and 4 (81%; P 0.001) of the 1st series of injections, and at visit 6, 7 and 8 (87%; P 0.001) of second series 6 mo after the 1st HA vs. active treatment Altman et al. [45] 143 M/190 F; HAa 5 9 20 mg/2 ml (n = 105) Painb during a 50 foot walk was less with Incidence of injection site pain greater PL (n = 115) HA vs. PL from week 1 through 26 with HA vs. PL or naproxen (23% vs. (P 0.05 at wks 4, 5, 12, 21) and 13% and 9%; P 0.001) that lead to maximally less at wk 26 (P = 0.004) study withdrawal from each group (6, 1, and 1); more GI AEs with naproxen vs. HA and PL (41% vs. 29% and 36%; P = 0.087) leading to 14, 4 and 4 withdrawals (r, pc, 26 wks) 64 (40–90) years, Naproxen 500 mg bid PO (n = 113) 89 kg Pain was also less with HA vs. naproxen from wk 4–26 Rheumatol Int (2011) 31:427–444
  9. 9. Rheumatol Int (2011) 31:427–444 435 High dropout rate,19 in the HA and 23 in ADL activities of daily living, db double-blind, NSAID non-steroidal anti-inflammatory drug, mc multi-centre, mo months, ol open-label, pts patients, pc placebo-controlled, pg parallel-group, study, significantly greater pain relief with hylan than a lower molecular weight hyaluronan was shown (P 0.05) [29]. Notably, one uncontrolled study in patients with advanced OA of the knee (candidates for total knee replacement) showed similar improvements at 1 year of follow-up with both HA and hylan [51]; however, a 1-year placebo-controlled trial failed to show any significant dif- ference in treatment effect between intra-articular placebo, the TH group Safety analysis HA or hylan [52]. Hip OA OA of the hip is the second most common form of arthritis Trend for less painb on activity, rest and at night in the HA than the TH group from after OA of the knee and is also a source of chronic pain, functional impairment and disability, especially in the elderly. Viscosupplementation with intra-articular HA has Primary efficacy assessments also been studied in OA of the hip, although to a lesser extent. There is some difficulty and potential danger associated with intra-articular injection of the hip (guided by fluoroscopy or ultrasound) due to the anatomical fea- tures of the hip joint and its locality in relation to the wk 4–29 femoral neurovascular structure. Of note, the ease and safety of sonographically guided intra-articular HA injec- tions for OA of the hip has been shown [53]. A number of recent reviews [5, 19, 54] and a meta- Triamcinolone hexacetonide (TH) 20 mg analysis [55] have provided an overview of studies to date of viscosupplementation with HA in hip OA. There is some evidence that efficacy may be greater in cases of less radiographic changes of hip OA [56] and may last up to once-weekly injections (n) HAa 20 mg 59 (n = 32) IA ? 4 9 PL (n = 31) 3 months post first injection with sustained benefits with Intervention, number of further injections [57]. Among eight trials evaluated in a systematic review, only 2 were controlled leading to the conclusion that lack PL placebo, PO per os, r randomised, sc single-centre, wk week, yr year of control groups, small sample size, variable dosing, short follow-up (3–6 months) and variability in outcome mea- sures limited valid recommendations, although symptom- atic relief for pain and function was evident in some studies Assessed using 100 mm visual analogue scales (VAS) [58], with efficacy generally seen at 1-month post-injection mean age, weight) Patients (gender, [55]. These studies used 1–5 injections of either low [59] or SuplasynÒ, Bioniche Life Sciences, Switzerland high [58] molecular weight HA, and no marked between- 24 M/39 F treatment differences in clinical efficacy were apparent. 71 years Results of available controlled trials have also been ARTZÒ, Seikagaku Co., Tokyo, Japan inconclusive. One study showed no significant difference ArtzalÒ, Astra Lakemedel, Sweden AdantÒ, Meiji Seika Kaisha, Japan between HA (3 injections), saline and corticosteroid use at HyalganÒ, Fidia S.p.A., Italy 3-month follow-up, despite some level of clinical benefit with corticosteroid and HA use [59]. Findings from an Study (design, duration) uncontrolled study by Conrozier et al. [60] suggested that a ¨ single injection of HA was efficacious in hip OA; however,Table 2 continued Jones et al. [46] a recent, randomised, placebo-controlled trial in 85 patients (db, r, 6 mo) showed no significant difference between placebo and a single intra-articular injection of HA for reduction in pain at 3-month follow-up [61]. Clearly, large well-controlled trials of HA in hip OA are warranted. b d a c e f 123
  10. 10. 436123 Table 3 Clinical trials of intra-articular (IA) injections of hylan in patients with osteoarthritis (OA) of the knee Study (design, duration) Patients (gender, Intervention, number Primary efficacy assessments Safety analysis mean age, weight) of once-weekly injections (n) Hylan vs. PL Wobig et al. [47] 38 M/72 F Hylan G-F 20a 2.0 ml (0.8%) Painb scores during weight bearing (wk 3–26), at 3 hylan recipients reported 39 (n = 52) night rest, and during the most painful movement systemic reactions - itching, (r, db, mc, 12 wks) 62 years, 76 kg Saline (n = 54) of knee, in addition to treatment success at 12 wks, cramps, and haemorrhoids were all better with hylan vs. control (P 0.01 for Hylan G-F 20a ? Saline (n = 4) all) Hylan vs. Comparator Adams et al. [48] 36 M/66 F Hylan G-F 20a 2.0 ml Painb on motion with weight-bearing, at rest, at 3 pts reported transient local 39 (n = 31) night, restriction of activity and overall assessment reactions (2 were pain with (r, mc, pg, 26 wks) 61 (35–76) years, 72 kg NSAID (n = 34) of arthritic pain were all significantly improved vs. warmth and effusion within baseline at wk 12 in all groups (P 0.01); at 26 24-h of injection) in the hylan NSAID ? Hylan G-F 20a 2.0 ml wks, improvements in the the hylan and the group resulting in one study 39 (n = 37) hylan ? NSAID group were significantly better in withdrawal some, and every evaluation, respectively, vs. NSAID Dickson et al. [49] 73 M/92 F Hylan G-F 20a (20 mg/2 ml) Improvements from baseline in the WOMAC A Significantly more systemic 39 (n = 53) score were significant with Hylan G-F 20 vs. (48% vs. 22% and 11%) and (db, r, pc, pg, 12 weeks) 64 (35–81) years Diclofenac 100 mg/ control (33 vs. 24; P = 0.04) and diclofenac (33 GI adverse events (38% vs. day ? 3 9 athrocentesIs vs. 23; P = 0.03), but not for diclofenac vs. 12% and 9%) with diclofenac (n = 55) control (P = 0.84) vs. Hylan G-F 20 and control (P 0.01 for both) Control: (n = 57) Leopold et al. [50] 37 M/43 F Hylan G-F 20a 2.0 ml (0.8%) WOMAC scores improved from baseline in both One pt in the Hylan G-F 20 39 (n = 38) groups (P 0.01); VAS scores improved from group withdrew due to an (r, 6 mo) 65 years, 86 kg Betamethasone sodium phosphate- baseline with Hylan G-F 20-but not with acute local reaction within betamethasone acetate 2 ml corticosteroid (P 0.01); no significant between- 24-h of an injection (n = 42) group difference on any scale db double-blind, mo month, NSAID non-steroidal anti-inflammatory drug, mc multi-centre, pc placebo-controlled, pg parallel-group, PL placebo, pt patient, r randomised, wk week, yr year a SynviscÒ, Genzyme Biosurgery, US b Assessed using 100-mm visual analogue scales (VAS) Rheumatol Int (2011) 31:427–444
  11. 11. Table 4 Clinical trials of intra-articular (IA) injections of hyaluronic acid (HA) vs. hylan in patients with osteoarthritis (OA) of the knee Study (design, duration) Patients (gender, mean age, weight) Intervention, number of once-weekly Primary efficacy assessments Safety analysis injections (n) HA vs. Hylan Rheumatol Int (2011) 31:427–444 Karatosun et al. [51] 17 M/75 F HAa 39 (n = 46) At 1 yr, mean improvement in No reported injection-related AEs total Hospital for Special Surgery knee score was significantly greater than baseline with HA and hylan, both P 0.01 (r, db, 1 year) 61 years, BMI 30 kg/m2 Hylan G-F 20b 2.0 ml (0.8%) 39 (n = 46) Karlsson et al. [52] 97 M/143 F HAc 2.5 ml (1%) 39 (n = 72) Weight-bearing paind during the No treatment-related AEs (r, db, pc, 1 year) 71 years, 80 kg Hylan G-F 20b 2.0 ml (0.8%) 39 (n = 71) first 26 wks was similar with each treatment and PL; neither PL 39 (n = 71) treatment alone showed a significantly longer duration of clinical benefit vs. PL over 0–52 wks but when data from these groups was pooled, significance vs. PL was shown (P = 0.047) Wobig et al. [29] 34 M/36 F Hylan G-F 20b 2.0 ml (0.8%) 39 (n = 38) Significant improvements in paind No systemic AEs, more (NS) local (db, r, mc, 12 weeks) 60 (22–88) years LMW HAe (1%) 2.0 ml 39 (n = 32) on weight-bearing, most painful AEs (pain/swelling) with Hylan knee movement, and overall G-F 20 vs. LMW HA (1.8% vs. treatment response with Hylan 0.9%) G-F 20 vs. LMW HA at wk 12 (P 0.05) AE adverse event, db double-blind, LMW HA Lower -molecular-weight hyaluronan, mc multi-centre, pc placebo-controlled, PL placebo, r randomised, wk week, yr year a OrthoviscÒ, Anika, Biomeks, Turkey b SynviscÒ, Genzyme Biosurgery, USA c ¨ ArtzalÒ, Astra Lakemedel, Sweden d Assessed using 100-mm visual analogue scales (VAS) e ArtzalÒ, Seikagaku, Kogyo Co. Ltd, Tokyo, Japan 437123

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