Hyaluronic Acid for Treatment of Osteoarthritis of the Knee

Repeated Injections and Progression to Knee Replacement

Judith Walsh, MD, MPH

Disclosures

CTAF 

In This Article

Technology Assessment (TA)

TA Criterion 1:The Technology Must have Final Approval from the Appropriate Government Regulatory Bodies

The FDA classifies HA for intra-articular use as Class 3 devices. There are six HA products that have FDA PMA approval for osteoarthritis of the knee. Intra—articular HA is not currently FDA approved for use in other joints. The recommended course of a single treatment varies from one injection only to one injection per week up to five weeks.

TA Criterion #1 is met

TA Criterion #2: The Scientific Evidence Must Permit Conclusions Concerning the Effectiveness of the Technology Regarding Health Outcomes

The Medline database, Cochrane clinical trials database, Cochrane reviews database and Database of Abstracts of Reviews of Effects (DARE) were searched using the search terms osteoarthritis, hyaluronic acid, and hyaluron. The search was performed for the period from 1966 to November, 2011. The bibliographies of systematic reviews and key articles were manually searched for additional references and references were requested form the device manufacturer.

The abstracts of citations were reviewed for relevance and all potentially relevant articles were reviewed in full.

Inclusion criteria:

  • Study had to evaluate intra-articular hyaluronic acid in patients with osteoarthritis of the knee

  • Comparative studies had to intra-articular hyaluronic acid to another treatment

  • Study had to measure clinically relevant outcomes

  • Included only humans

  • Published in English as a peer reviewed article

Studies were excluded if they only focused on non-clinical outcomes.

A total of 424 potentially relevant articles were identified. All 424 titles were reviewed. Three hundred ninety articles were excluded for not addressing the research question. A total of 34 abstracts were evaluated. Twenty three abstracts were excluded. Reasons for exclusion included not evaluating multiple courses of HA, not focusing on the knee, or not reporting clinical or structural outcomes. Of these, three published prospective studies, three published retrospective studies and five clinical trials are included in this evaluation.

Ten studies addressed the question of whether or not there is efficacy of repeated injections of HA into an affected joint. Two studies addressed the question of whether repeated injections of intra-articular HA can reduce the progression of OA or reduce the need for joint replacement

Details of the studies assessing the impact of HA on clinical outcomes are described in Table 1 and Table 2. Details of studies assessing the impact of HA on progression of osteoarthritis are described in Table 3 and Table 4.

Although the outcomes varied among the studies, typical outcomes included visual analog pain scales, patient activity level, Osteoarthritis Research Society International (OARSI) 2004 responder criteria and the Western Ontario and McMaster University Osteoarthritis indices (WOMAC).

Two standardized outcome variables have been developed for measuring the impact of osteoarthritis on an individual's life. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale is a commonly used pain scale for assessing the impact of arthritis. The WOMAC is a self—administered disease specific quality of life instrument that asks the patients questions about the study knee. There are three subscales - pain, stiffness and aggregate functioning - as well as an aggregate total score.[19]

The second outcome variable is the OARSI 2004 responder criteria. The OARSI developed two sets of responder criteria to be used as a uniform set of outcome measures for osteoarthritis trials. The goal was to develop a set of criteria based on multiple domains that could be used as a single variable in clinical trials. The included symptomatic variables were pain, functional impairment and patient's global assessment. These criteria have been proposed to be used across clinical trials that evaluate the impact of osteoarthritis treatments.[20]

Level of Evidence: 1,3

TA Criterion # 2 is met

TA Criterion #3: The Technology Must Improve the Net Health Outcomes

Intra-articular HA is a well established treatment option for OA. However, fewer studies have assessed the impact of repeated courses of intra-articular HA on treatment efficacy, and on disease progression, including the need for total knee replacement.

Potential Benefits Ten studies have assessed the impact of repeated intra-articular injections of HA on treatment efficacy. Three were retrospective, three were prospective and uncontrolled and four were trials. Study size ranged from 22 to 863. Outcomes included visual analog pain scales, changes in the WOMAC and OARSI standardized scales. Two studies assessed the impact of a single course of HA with several courses of HA.[21,25] Both studies found that there was more clinical improvement after two or more courses of HA than after one course of HA, although neither had a comparison group that did not receive HA. In other prospective studies, patients could receive an additional treatment course after a defined period (often four months), but the impact of repeated courses vs a single course were not always analyzed separately.[24,31] In the trials that evaluated the impact of repeated courses of HA, all showed improvements in outcomes, including pain VAS scores, change in WOMAC pain scores, and OARSI responder criteria.[20,27,29,30]

Two studies have assessed the impact of repeated courses of intra-articular HA for knee OA on disease progression, measured either radiographically or arthroscopically.[20,27] In the first, a small prospective study of 39 patients, those who received repeated courses of HA had improvement in arthroscopically measured chondropathy.[27] In the second, a larger RCT, outcomes were measured radiographically and there was no clear impact on radiographic disease progression.[20]

Potential Harms The main potential harms of intra-articular HA are local reactions (pain or bleeding at the injection site), allergic reactions (including rash and swelling) and arthralgias. Post-injection flare is characterized by increased pain, swelling and the presence of an inflammatory joint effusion and has been estimated to occur in 1.5–5% of injected knees. Post-injection flare may be more common in injections given via the medial approach than by the lateral approach.[21,32]

Few studies have assessed the potential adverse effects of repeated courses of HA on safety outcomes. However, in the one large randomized controlled trial that compared repetitive intra-articular HA injections with placebo, safety outcomes were also assessed.[30] The number of adverse events were similar in the treatment and the control groups (9.8% in the HA group vs 9.1% in the placebo group). All side effects were mild to moderate. Common side effects included allergic reaction (rash and swelling), pain or bleeding at the injection site or arthralgias. There were no serious side effects in either group.

In summary, overall repeated injections of HA for knee OA has shown efficacy in symptomatic relief of OA. The side effects have generally been relatively minor in contrast to the potential benefits. Thus repeated injections of intra-articular HA are associated with a net benefit in health outcomes.

TA Criterion #3 is met

TA Criterion #4: The Technology Must Be as Beneficial as Any Established Alternatives

An important question is how repeated injections of intra-articular HA compare with the established alternatives for the treatment of osteoarthritis. Established treatments would include non-pharmacologic measures such as physical therapy, weight loss, education and counseling, devoices as well as medications including nonsteroidals and acetaminophen, and surgical treatments such as arthroscopy or total knee replacement.

Impact of HA on Clinical Outcomes Three studies have compared the impact of repeated injections of intra-articular HA with another treatment on clinical outcomes. The first was a multi-center open label study conducted in multiple sites in Canada. Patients with knee osteoarthritis, who had received prior treatment with acetaminophen or NSAIDS were randomized to receive "appropriate care with hylan G-F 20 or "appropriate care without hylan G-F 20." Appropriate care was defined as the preferred management strategy of the referring physician, who was encouraged to follow the guidelines of the American College of Rheumatology. A course of intra-articular hylan G-F 20 was a series of three injections at one week intervals. Individuals could receive subsequent injections to the knee during the study. The main goal of the study was to compare intra-articular hylan G-F 20 plus appropriate care to appropriate care alone. The main outcome was a change in the WOMAC pain score in the study knee from baseline to the end of the study. The main study results showed that adding hylan G-F 20 to appropriate care led to significant improvement in the main outcome - reduction in the WOMAC pain scale.[33]

A secondary publication from this study evaluated the safety and efficacy of repeated courses of hylan G-F 20 plus appropriate care on the same primary outcome (reduction in the WOMAC pain score).[29] For this analysis, the investigators divided the hylan G-F 20 group into two subgroups - 1) those who received one injection of hylan G-F 20 and 2) those who received more than one injection of hylan G-F-20. Importantly, participants were not randomized to receive one or more than one dose. For the main outcome - improvement in the WOMAC pain scale, the single course group improved by 41% and the repeat course group improved by 35%, compared with an improvement of 14% in the appropriate care subgroup. Both groups improved more than the appropriate care subgroup (p<0.05), and were not statistically different from each other. The repeat course group did not have more adverse events than the other groups, nor was there a difference in arthrocentesis rates between the first and repeated courses of treatment. This post- hoc analysis suggests that multiple courses of hylan G-F 20 may be efficacious and safe, but the study was not designed to specifically answer this question.[29]

A French study randomized patients to receive one of three treatments: 1) three courses (3 injections each) of intra-articular HA, 2) diacerein 100 mg a day (an anti-inflammatory drug that affects the interleukin pathway) or 3) placebo. Participants and investigators were blinded to the treatments. Participants were followed for a year. The main outcome was pain score as rated by a visual analog scale. The VAS pain score improved in all three groups, but there was no significant difference between groups.

The AMELIA project (OsteoArthritis Modifying Effects of Long-term Intra-articular Adant) was designed to assess the efficacy and the carry-over effect of repeated intra-articular injections of HA in knee osteoarthritis. This was a randomized controlled multicenter trial conducted over 40 months.[30] Patients with knee osteoarthritis (as defined by ACR criteria with Grade II got III radiographic stage OA) were randomized to receive intra-articular Adant (1% HA) or placebo. There were four treatment cycles - each treatment cycle consisted of 5 weekly injections. Study participants could receive periodic courses of acetaminophen or nonsteroidals, but were not allowed to receive intra-articular corticosteroids over the course of the study. Follow up was for six months after the first and second cycles and one year after the third and fourth cycles. The repeated injection cycles were administered regardless of whether or not the patient had symptoms. The main outcome was the percentage of individuals with a clinical response as defined by the Osteoarthritis Research Society International (OARSI) 2004 criteria. Patients were classified as responders if the pain or physical function score decreased at least 50% and at least 20 mm on the VAS, or if two of the following three findings were present:

  1. a decrease in pain of at least 20% and at least 10 mm on the VAS,

  2. a decrease in physical function of at least 20% and at least 10 mm on the VAS, or

  3. an increase in the score of the patient's global assessment by at least 20% and at least 10 mm on the VAS.

  4. Safety and tolerability were evaluated based on the incidence and type of adverse events.

A total of 306 patients were included in the study. At study termination (40 months; one year after the final series of injections), significantly more patients responded to HA than to placebo (OARSI 2004 criteria; p=0.004). The number of responders to HA increased throughout the study (from 71.1% to 80.5%), whereas the number of placebo responders did not change (67.8% to 65.8%). Rescue medications were taken by 71.1% of the HA patients and 71.7% of the placebo patients over the course of the study. A total of 22 patients (11 in each group) had an adverse reaction. Since all were receiving injections, the majority of the adverse reactions were related to the study intervention, such as bleeding, pain at the site or allergic reaction. There were no serious adverse events.

The results of this well done trial show that among patients with knee OA, receipt of four courses of injections over a 36 month period had evidence of lasting benefit. In addition, the benefit appeared to last at least one year after the final series of injection. Questions that remain unanswered include whether different treatment schedules will achieve the same effect, and the extent to which the may persist after one year. In addition, a group that only received one series of injections was not included and so the incremental benefit (four series of injections vs one series of injections) cannot be determined.

In summary, although several studies have evaluated whether or not repeat injections of HA can be beneficial with respect to clinical outcomes, only one study has randomized patients to receive a series of repeated injections vs placebo. No randomized study has compared a single injection of HA with multiple injections of HA. Among patients who received four courses of HA treatment over a two and a half year period, significantly more responded to treatment than did those who received placebo and the effect appeared to last for at least a year.

Impact of HA on Progression of RA or on Need for Knee Replacement No studies have evaluated whether or not repeated course of treatment of knee osteoarthritis with HA can delay the need for knee replacement, but several studies have assessed the impact of repeated treatments of HA on intermediate outcomes related to the progression of arthritis. These outcomes include joint space width (JSW), joint space narrowing (JSN) and the Systeme Francaise D'Arthroscopie (SFA) grading system for chondropathy as measured during arthroscopy on a validated scale.

Two studies have assessed the impact of repeated courses of HA on the progression of OA. The first was a small prospective study of 39 patients. Participants received conventional therapy or three cycles (every four months) of intra-articular injections of Hyalgan. All participants underwent arthroscopy where chondropathy was assessed by the SFA. Chondropathy was also assessed using a VAS. At one year follow-up, there was less deterioration in the overall assessment of chondropathy in the HA group (5.1 vs 16.7: p=0.016). There was also an improvement in the SFA chondropathy scoring for the HA group (3.7 vs 7.3: p=0.05). This was a small study of one year duration. The results suggest that repeated courses of intra-articular HA may delay the structural progression of OA.

A second study was a double blind placebo controlled trial conducted in France. A total of 301 participants with symptomatic knee OA were randomized to three courses (3 injections each) of intra-articular HA, 2) diacerein 100 mg a day (an anti-inflammatory drug that affects the interleukin pathway) of 3) placebo. Participants and investigators were blinded to the treatments. Participants were followed for a year. The main structural outcomes were joint space width (JSW), joint space narrowing (JSN) between baseline and final visits, and percentage of progressors (defined as JSN >0.5 mm during the study) . They found that JSW deteriorated by an average of 0.09 mm over the course of the study, but there was no difference between groups. The percentage of progressors (those who had JSN of >5 mm over the course of the study) was 17.7% in the HA group, 18,9% in the diacerein group and 20.3% in the placebo group with no difference between groups. Thus the results of this study showed no significant effect of either repeated courses of HA or diacerein on outcomes related to OA progression.

In summary, no studies have assessed the impact of HA on need for knee replacement. Only two studies have assessed the impact of repeated injections of HA on disease progression as measured radiographically or arthroscopically, and these studies have reached different conclusions about efficacy. The larger double blind placebo controlled study did not show an impact of HA on disease progression. Additional studies will be needed to answer this question but at this time, there is no evidence that intra-articular HA slows disease progression when compared with other treatments.

TA Criterion 4 is met for whether repeated injections of HA can improve symptoms of knee arthritis

TA Criterion 4 is not met for whether repeated injections of HA can slow disease progression.

TA Criterion #5: The Improvement Must Be Attainable Outside the Investigational Settings

A well done clinical trial showed that patients who received four courses of intra-articular HA over a two and a half year period had an improvement in OA related symptoms. However, this study did not compare multiple courses of HA with a single course of HA. In addition, the impact of other treatment schedules on clinical outcomes has not been evaluated. One study evaluated long term outcomes of repeated injections of hyaluronic acid for the treatment of knee OA. In this study, among 897 patients referred to a large center for OA management. Among them, 537 met criteria and received a series of HA injections for knee OA. Patients were told that they could return for consideration of repeat injection series depending on their perception of symptom severity. Among the 537 patients, only 21 did not return for a second injection series. Outcomes included change in rest and walking pain visual analog scores. Participants were followed for 6.7 years. Participants experienced a significant reduction in VAS walking pain score from baseline after both the first and second injection series81.3% and 86.7%; both p<0.001). There was also an improvement in resting pain. Patient satisfaction was also improved after each injection series and there were few adverse events.[34] The results of this observational study of repeated injections performed in routine clinical practice suggest that repeated injections can lead to improved symptom relief in a real world setting.

For the impact of HA on knee replacement or disease progression, since the improvement has not yet been shown in the investigational setting, it cannot be shown to be attainable outside the investigational setting.

TA Criterion 5 is met for repeated injections of HA improving symptoms of knee arthritis TA Criterion 5 is not met for whether repeated injections of HA can slow disease progression or delay knee replacement. .

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....