Hyaluronic Acid for Treatment of Osteoarthritis of the Knee

Repeated Injections and Progression to Knee Replacement

Judith Walsh, MD, MPH

CTAF

Abstract and Introduction

Introduction

The California Technology Assessment Forum (CTAF) is requested to review the scientific evidence for the use of hyaluronic acid (HA) for the treatment of osteoarthritis. Several prior reviews and meta-analyses including two done by The Blue Cross Blue Shield Technology Evaluation Center have concluded that despite study flaws, there is a positive effect of hyaluronic acid on the symptoms of knee osteoarthritis.^[1,2] Although there is evidence that injections of hyaluronic acid can improve symptoms of knee osteoarthritis, other questions remain. In this review, CTAF will specifically focus on the efficacy of repeat injections of HA and whether or not repeated injections of intra-articular HA can slow the progression of OA or reduce the need for joint replacement. This is the first time that CTAF has addressed this topic.

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Table 1. Descriptions of studies of the efficacy of repeated intra articular injections of HA in knee osteoarthritis
Study, Author	Study type	N	Country	Inclusion Criteria	Intervention	Intervention Outcomes
Lussier, 1996²¹	Retrospective	336	Canada	OA of the knee	•All patients with knee OA treated with hylan by five Canadian clinicians	•Patients overall response to treatment and changes in patient activity level (both measured on a 5 point scale on a survey)
Waddell, 2007²²	Retrospective	863	USA	Received hylan G-F 20 intra-articular injection and were TKR candidates	•Intra-articular hylan G-F 20 injection: one or more courses	•Time to TKR
Puttick, 1995²³	Retrospective	22	Canada	Patients who received hylan G-F 20 injections to one or both knees from three rheumatologists	•Intra-articular hylan G-F 20: one or more courses	•Safety •Reactions after injections
Neustadt, 2003²⁴	Prospective cohort	76	USA		•Five weekly injections of intra-articular HA •Optional repeat course	•VAS for pain
Scali, 1995²⁵	Prospective Open Label, uncontrolled	75			•Intra-articular Hyalgan: 5 courses at 6 month intervals	•"Clinical benefit"
Kolarz, 1999²⁶	Prospective open label, uncontrolled	108	Austria	Knee OA	•Intra-articular hyalgan- 5 injections at one week intervals. Second injection could be requested at 4 months	•VAS pain scale
Listrat, 1997²⁷	Prospective controlled study	39	France	Painful knee arthritis	•Conventional therapy or three cycles (every three months) of three intra-articular injections of Hyalgan	•Visual pain analog score •Functional impairment •Lequesne's index •Arthritis impact measurement scale (AIMS2)
Pham, 2004²⁸	Multicenter randomized double blind RCT	301	France	Symptomatic knee osteoarthritis JSW > 2 mm	•Three courses of three HA injections •Diacerein 100 mg a day •Placebo	•Changes in pain VAS
Raynauld, 2005²⁹	Prospective randomized open label trial	255	Canada, Australia, US	Symptomatic knee osteoarthritis and prior treatment with NSAIDS or acetaminophen	•Appropriate care without hylan G-F 20 Appropriate care with hylan G-F 20. Those who got hylan G-F 20 were partitioned into two subgroups- those who got a single course of hylan G-F 20 and those who received two or more courses	•Change in Western Ontario and McMaster universities osteoarthritis index (WOMAC)
Navarro-Saraboa. 2011 AMELIA³⁰	RCT	306	Spain	American College of Rheumatology criteria for knee OA.;	•Four cycles of five Intra-articular injections of HA vs placebo	•OARSI 2004 responder criteria •Use of rescue medications •Adverse events

AIMS: Arthritis Impact Measurement Scale
HA: Hyaluronic Acid
JSW: Joint Space Width
OA: Osteoarthritis
OARSI: Osteoarthritis Research Society International
TKR: Total Knee Replacement
VAS: Visual Analog Scale
WOMAC: Western Ontario and McMaster Universities Arthritis Index

Table 2. Outcomes of studies of the efficacy of repeated intra articular injections of hyaluronic acid in knee osteoarthritis
Study, Author	N	Length of follow-up	Main outcomes	Comments
Lussier, 1996²¹	336	2 years	•77% of knees better or much better after one course of treatment •87% of knees were better or much better after two courses •Activity level: 76% better after one course and 84% better after two courses	Retrospective and no comparison group
Waddell, 2007²²	863		•19% had TKR •75% of knees did not have TKR by 3.8 years	No comparison group
Puttick, 1995²³	22	Not stated	88 injections to 28 knees •10/88 injections associated with reaction •6 out of 22 patients had an adverse reaction	Small retrospective study focusing on safety
Neustadt, 2003²⁴	78	1 year	•VAS pain score was 3.2 vs 5.9 at baseline •15/19 who were considering knee replacement did not get knee replaced	•Not randomized for 1 vs 2 injections •No comparison group
Scali, 1995²⁵	75	30 months	•60% with good to excellent results after first round of injections (six months) •88% had good to excellent results after five rounds of injections (30 months) •VAS level of pain improved from 6 up to 30 months	No comparison group
Kolarz, 2003³¹	1081	1 year	•14 received a second cycle of hylan and nine of these were lost to follow up	Hylan single or multiple injections were efficacious but few received multiple injections
Listrat, 1997²⁷	39	1 year	•AIMS 2 better in hyalgan group •Less deterioration in structural parameters in hyalgan group (overall assessment of chondropathy)	Small study
Pham, 2004²⁸	301	1 year	•Pain VAS score improved in all 3 groups; no difference between groups
Raynauld, 2005²⁹	255 n=128 usual care n=78 single course n=48 repeated course		•Change in WOMAC pain score from baseline 41% in single , 35% in repeat course groups vs 14% in usual care group (p<0.05 for either course vs usual care; NS for difference between single and repeat course	•Post hoc analysis •The subgroups among those who received hylan were not randomized
Navarro-Saraboa. 2011 AMELIA³⁰	306	40 months	At 40 months more patients responded to HA than to placebo Number of responders to HA increased during the study	Improvement noted during treatment and carry over for at least a year

AIMS: Arthritis Impact Measurement Scale
AMELIA: Osteoarthritis Modifying Effects of Long-Term Intra-articular Adant
HA: Hyaluronic Acid
VAS: Visual Analog Scale
TKR: Total Knee Replacement

Table 3. Description of studies of the efficacy of repeated courses of hyaluronic acid on progression of osteoarthritis
Study, Author	Study type	N	Country	Inclusion Criteria	Intervention	Intervention Outcomes
Listrat, 1997²⁷	Prospective controlled study	39	France	Painful knee arthritis	•Conventional therapy or 3 cycles (every 3 months) of three intra-articular injections of Hyalgan	•JSN SFA for measuring chondropathy Overall assessment of chondropathy using VAS
Pham, 2004²⁸	RCT double blind	301	France	Symptomatic knee OA	•Three courses of three HA injections •Diacerein 100 mg a day •Placebo	•JSW JSN Percentage of progressors (JSN >0.5 mm over course of study)

Diacerein: is a NSAID disease modifiying agent that affects interleukin 2 instead of cyclo-oxygenase
JSN: Joint space narrowing
JSW: Joint space width
SFA: Système Française D'Arthroscopie - Grading system for chondropathy measures severity of chondropathy as assessed during arthroscopy on a validated scale

Table 4. Outcome of studies of the efficacy of repeated courses of hyaluronic acid on progression of osteoarthritis
Study, Author	N	Length of follow-up	Main outcomes	Comments
Listrat, 1997²⁷	39	1 year	•Less deterioration in structural parameters in the HA group •Overall assessment of chondropathy: •5.1 vs 16.7 (p=0.016) improvement in SFA scoring for HA 3.7 vs 7.3 (p=0.05)	•Small study that suggests that repeated intra-articular injections of HA might delay the structural progression of the disease
Pham, 2004²⁸	301	1 year	•JSW deteriorated but with no difference between groups •Percentage of progressors similar between groups (17.7%, 18.9%, 20.3%: NS)	•No structural benefits of either HA or diacerein

HA: Hyaluronic Acid
JSW: Joint Space Width

Product Name	Manufacturer	Formulation	Typical recommended course of treatment
Eufflexa	Ferring Pharmaceuticals	1% Sodium Hyaluronate	One injection per week for three weeks
Nuflexxa	Savient Pharmaceuticals	1% Sodium Hyaluronate	One injection per week for three weeks
Synvisc	Genzyme Biosurgery/Sanofi	Hylan GF-20 (high molecular weight fluid containing derivatives of hyaluronan or sodium hyaluronate)	Synvisc: One injection per week for three weeks Synvisc-One: Single injection
Orthovisc	Registered trademark of Anika Therapeutics, Inc. Distributed by DePuy Mitek, Inc	High Molecular Weight Hyaluronan (Sodium Hyaluronate)	One injection per week for three or four weeks
Hyalgan	Fidia Farmaceutical	Sodium Hyaluronate	One injection per week for five weeks
Supartz	Smith & Nephew Seigakaku Corp.	Sodium Hyaluronate	One injection per week for five weeks

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