INTRODUCTION
With an estimated worldwide prevalence of 3%, osteoarthritis (OA) is among the most frequent problems in elderly clinical practice. For a long time, it was considered a disease that only involved wear and tear of the articular cartilage, but today, with the advances in the understanding of the disease, the understanding is that the pathophysiological changes involve the joints as a whole (cartilage, bone, synovial membrane, ligaments, adipose tissue, and meniscus), as well as pain processing nerve pathways. Changes may arise due to internal (obesity) and external mechanical loads, joint misalignment (genu varus and genu valgus), metabolic, and genetic factors. Excessive load on the bone can result in spinal cord injuries with microfractures, necrosis, fibrosis, and adipocytes, all suggestive of damage and remodeling in the injured area. Synovitis is commonly observed, and it plays an important role in joint destruction. Factors with pro-inflammatory cytokines (interleukin-6 [IL6]), monocyte chemoattractant protein, vascular endothelial growth factor, protein, and monokine induced by interferon γ are responsible for the progressive destruction due to the stimulation of degradation enzymes, and the growth factors stimulate the production of matrix for remodeling but end up promoting the formation of osteophytosis, thus contributing to subchondral sclerosis. Cytokines are not only the drivers of joint destruction but also potential targets for intervention to modify disease progression. Cartilage, as the only tissue without vascular, nervous, or lymphatic supply, has properties that condition its low intrinsic repair capacity, making repair difficult 1 .
The treatment of knee OA begins with clear and consistent information about the history of the disease to patients, clarifying the benefits of exercise, weight loss, and physiotherapy, which are behaviors that have well-established benefits to reduce pain, in addition to anti-inflammatory drugs, administered topically or orally, which are the backbone of pharmacological treatment. Intra-articular (IA) corticosteroid injections provide temporary relief. Hyaluronic acid (HA) injection is also frequently offered, although evidence of its benefit remains controversial 1 .
With the discovery of HA in bovine vitreous humor in 1934, it began to play an important role in the repair of wounds and skin damage. Thus, the use of HA in the form of IA injections in patients with OA of the knee, called viscosupplementation, was the first indication for clinical use in orthopedics and traumatology, with the aim of treating joint cartilage injuries by having a lubricating effect, mechanical and biochemical, with the expected result of partial relief of painful symptoms and improvement in function. The effect is not immediate but long-term. Currently, the use of HA is widespread and frequent, but without clear evidence of benefit and with the risk of potential harm 1 .
The objective of this study was to evaluate the clinical efficacy and adverse effects of treatment with HA for anterior knee pain caused by grade II and III OA, as it causes discomfort and an inability to perform daily activities. Assessments will be short- and medium-term, measuring different scores.
METHODOLOGY
In the methodology, we will express the clinical question, the structured question (PICO), eligibility criteria of the studies, consulted information sources, search strategies used, critical evaluation method (risk of bias), quality of evidence, data to be extracted, measures to be used to express results, and the method of analysis.
Clinical question
Is the use of HA in IA application for the treatment of knee OA efficacy and safe?
Structured question
P (population): Patients with osteoarthritis or osteoarthrosis of the knee
I (intervention): High or low molecular weight hyaluronic acid
C (comparison): Placebo or sham or steroid or usual care
O (outcome): Clinical improvement (overall - pain - stiffness - gait)
Sources of information consulted and search strategies
The searches they were performed in the Medline database (PubMed), with the next terms: (Osteoarthritis OR Osteoarthritides OR Osteoarthrosis OR Osteoarthroses) AND Knee AND (Viscosupplements OR Viscosupplement OR Visco Supplements OR Viscosupplementation OR Viscosupplementations OR Hyaluronic Acid OR Hyaluronate Sodium) AND Random*.
Eligibility criteria
PICO components; randomized clinical trials (RCTs); no period restriction; languages English, Spanish, and Portuguese; full text or abstract with the necessary data; outcomes expressed in absolute number of events or mean/median with variation.
Exclusion criteria
Observational and noncomparative studies, in vitro and/or animal studies, case series or case reports, narrative or systematic reviews, and guidelines.
Risk of bias and quality of evidence
For RCTs, the following risks of bias will be evaluated: focal question, randomization, blinded allocation, double blinding, losses, analysis by intention to treat (ITT), definition of outcomes, sample calculation, early interruption, and prognostic characteristics.
Extracted data
Author, year of publication, study design, characteristics and number of patients, intervention, comparison, and outcomes (clinical improvement and adverse effects). Each study was described individually in a qualitative analysis of the evidence. Evaluation of seven outcomes (adverse and clinical events) with priority for categorical outcomes and/or averages (SD). Subgroup analysis: HA versus CORTICOID and HA versus SALINE SOLUTION (SS). Outcomes - overall WOMAC - pain WOMAC - functional WOMAC - overall KSS - overall VAS. Measured with continuous variables (final mean or mean difference with standard deviation) and dichotomous variables.
Outcome measures
For categorical variables, we will use absolute numbers, percentages, absolute risk, reduction or increase in risk, number needed to treat or number of harm (NNH), and 95% confidence interval (95%CI). For continuous variables, we will use means or the difference of means with a standard deviation.
Expression of results
If it is possible to aggregate the results of one or more included studies regarding one or more common outcomes, a meta-analysis will be performed [RevMan 5.4 software (Cochrane)].
Evidence quality analysis
Comparisons were demonstrated in the risk difference and 95%CI. The inconsistency of effects across interventions was assessed using I2. The random effects model was used if I2>50% and the fixed effects model if I2≤50%. To access possible publication biases, Egger’s test (funnel plot) was analyzed for asymmetry. The certainty of the evidence was assessed using the GRADEpro guideline development tool and rated as high, moderate, low, or very low.
RESULTS
The results presented will be: study recovery and selection diagram (Figure 1), study characteristics (Tables 1A, B), risk of bias (Tables 2A, B), results (Tables 3A, B), analysis by outcomes (Figures 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), quality of evidence (Tables 4 and 5), and synthesis of evidence.
Figure 1. Flowchart of selected works.
Table 1A. Description of studies comparing hyaluronic acid with saline solution (n=17).
| Author/year | Patients number | Outcomes measured - Instrument | Adverse effects reported | Molecular weight | Injection number | Follow-up weeks | ||
|---|---|---|---|---|---|---|---|---|
| Hyaluronic Acid | Saline Solution | Pain | Function | |||||
| Altman RD 2004 | 173 | 174 | WOMAC | WOMAC | Yes | High | 1 | 24 |
| Altman RD 2009 | 293 | 295 | WOMAC | WOMAC | Yes | High | 3 | 26 |
| Arden N 2013 | 108 | 110 | WOMAC | WOMAC | Yes | Intermediate | 1 | 6 |
| Baltzer AWA 2008 | 135 | 107 | WOMAC | VAS | Yes | High | 3 | 26 |
| Brandt KD 2001 | 114 | 112 | WOMAC | Yes | Intermediate | 3 | 16 | |
| Chevalier X 2010 | 124 | 129 | WOMAC | WOMAC | Yes | High | 1 | 26 |
| Day R 2004 | 116 | 124 | WOMAC | Yes | High | 5 | 18 | |
| Dougados M 1993 | 55 | 55 | VAS | Lequesne index | Yes | High | 4 | 52 |
| Hangody L 2018 | 150 | 69 | WOMAC | WOMAC | Yes | Intermediate | 1 | 2 |
| Henderson EB 1994 | 45 | 46 | VAS | VAS | Yes | High | 4 | 5 |
| Huang TL 2011 | 98 | 100 | Pain on walking (VAS) | WOMAC | Yes | Low | 5 | 25 |
| Huskisson EC1999 | 50 | 50 | Pain on walking (VAS) | Lequesne index | Yes | High | 5 | 24 |
| Karlsson J 2002 | 88 | 66 | VAS | Lequesne index | Yes | High | 3 | 52 |
| Migliore A 2021 | 347 | 345 | VAS | Lequesne index | Yes | Low/high | 1 | 24 |
| Petterson SC 2019 | 184 | 185 | WOMAC | WOMAC | Yes | High | 1 | 26 |
| Pham T 2004 | 131 | 85 | Global pain (VAS) | Lequesne index | No | Intermediate | 3 | 52 |
| Strand V 2012 | 251 | 128 | WOMAC | Yes | Intermediate | 1 | 1 | |
Table 1B. Description of studies comparing hyaluronic acid with steroids (n=10).
| Author/year | Patients number | Outcomes measured - Instrument | Adverse effects reported | Molecular weight | Injection number | Follow-up weeks | ||
|---|---|---|---|---|---|---|---|---|
| Hyaluronic acid | Saline solution | Pain | Function | |||||
| Askari A 2016 | 71 | 69 | WOMAC | VAS | No | High | 1 | 12 |
| Bisicchia S 2016 | 75 | 75 | WOMAC | No | High | 2 | 26 and 52 | |
| Caborn D 2004 | 113 | 102 | WOMAC / VAS | WOMAC | No | High | 3 | 26 |
| Maia PAV 2019 | 16 | 12 | WOMAC | WOMAC | No | High | 1 | 24 |
| Shimizu M 2010 | 32 | 29 | VAS | No | High | 5 | 24 | |
| Skwara A 2009 | 30 | 30 | VAS | Lequesne index | No | Intermediate | 1 | 12 |
| Tammachote N 2016 | 50 | 49 | VAS | WOMAC | Yes | High | 1 | 24 |
| Tasciotaoglu F 2003 | 28 | 27 | VAS | Lequesne index | Yes | High | 3 | 26 |
| Housman L 2014 | 129 | 132 | WOMAC | Yes | High | 1 | 26 | |
| Leighton R 2014 | 221 | 221 | WOMAC | Yes | Intermediate | 1 | 26 | |
Table 2A. Overall risk of bias in studies comparing HA and saline AI.
| Author/year | Randomization | Allocation | Double blind | Evaluator blindness | Losses | Prognostic | Outcomes | Intention to treat | Sample | Interruption |
|---|---|---|---|---|---|---|---|---|---|---|
| Baltzer AWA 2008 | ||||||||||
| Chevalier X 2010 | ||||||||||
| Day R 2004 | ||||||||||
| Dougados M 1993 | ||||||||||
| Pham T 2004 | ||||||||||
| Huskisson EC 1999 | ||||||||||
| Karlsson J 2002 | ||||||||||
| Migliore A 2021 | ||||||||||
| Altman RD 2004 | ||||||||||
| Altman RD 2009 | ||||||||||
| Petterson SC 2019 | ||||||||||
| Brandt KD 2001 | ||||||||||
| Hangody L 2018 | ||||||||||
| Huang TL 2011 | ||||||||||
| Arden NK 2014 | ||||||||||
| Henderson EB 1994 | ||||||||||
| Strand V 2012 | ||||||||||
| Subtitle | Low bias risk | Without information | High bias risk | |||||||
Table 2B. Overall risk of bias in studies comparing HA and steroid AI.
| Author/Year | Randomization | Allocation | Double blind | Evaluator blindness | Losses | Prognostic | Outcomes | Intention to treat | Sample | Interruption |
|---|---|---|---|---|---|---|---|---|---|---|
| Askari A 2016 | ||||||||||
| Maia PAV 2019 | ||||||||||
| Caborn D 2004 | ||||||||||
| Tammachote N 2016 | ||||||||||
| Skwara A 2009 | ||||||||||
| Bisicchia S 2016 | ||||||||||
| Shimizu M 2010 | ||||||||||
| Tasciotaoglu F 2003 | ||||||||||
| Housman L 2014 | ||||||||||
| Leighton R 2014 | ||||||||||
| Subtitle | Low bias risk | Without information | High bias risk | |||||||
Table 3A. Description of results by outcomes (IA-HA versus IA-SS).
| Author/Year |
|
|
|
|
Adverse events n/N |
|
|
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | |
| Baltzer AWA 2008 | 3.74 (2.44) (135) | 3.94 (2.48) (107) | 49.3 (25.9) (135) | 48.2 (25.59) (107) | 51/135 | 30/107 | 3.75 (2.42) (135) | 3.93 (2.38) (107) | ||||||
| Chevalier X 2010 | 70/124 | 79/129 | 1.43 (0.06) (124) | 1.59 (0.058) (129) | ||||||||||
| Day R 2004 | 3.84 (3.27) (116) | 4.61 (3.14) (124) | ||||||||||||
| Dougados M 1993 | 38.9 (30.9) (55) | 32.71 (28.8) (55) | 4.4(5.1) (55) | 2.7 (4.1) (55) | 18/55 | 18/55 | 17.9 (30.0) (55) | 16.9 (23.4) (55) | ||||||
| Pham T 2004 | 20.0 (16.5) (131) | 18.9 (16.9) (85) | 33.5 (28.5) (131) | 34.5 (27.4) (85) | ||||||||||
| Huskisson EC 1999 | 39.4 (27.8) (50) | 53.7 (29.9) (50) | 11.2 (4.4) (50) | 12.6 (4.8) (50) | 17/50 | 14/50 | ||||||||
| Karlsson J 2002 | 4.4 (4.1) (88) | 4.7 (4.4) (66) | 51/88 | 50/66 | ||||||||||
| Migliore A 2021 | 29 (24) (347) | 33 (24) (345) | 7.4 (4.1) (347) | 8.2 (4.3) (345) | 187/347 | 180/345 | ||||||||
| Altman RD 2004 | 5.82 (12.16) (173) | 7.42 (13.52) (174) | 2.50 (4.00) (173) | 2.89 (4.17) (174) | 112/173 | 114/174 | ||||||||
| Altman RD 2009 | 19.6 (31.27) (293) | 15.4 (29.33) (295) | 19.2 (26.8) (293) | 16.3 (26.8) (295) | 30.0 (26.1) (293) | 36.1 (28.6) (295) | 158/293 | 168/295 | ||||||
| Petterson SC 2019 | 32.5 (24.8) (184) | 33.1 (25.2) (185) | 31.9 (22.0) (184) | 30.9 (22.9) (185) | 121/184 | 123/185 | ||||||||
| Brandt KD 2001 | 2.1 (0.7) (114) | 2.0 (0.7) (112) | 76/114 | 74/112 | ||||||||||
| Hangody L 2018 | 39.5 (22.8) (150) | 32.9 (23.6) (69) | ||||||||||||
| Huang TL 2011 | 29.28 (1.92) (100) | 21.52 (1.94) (98) | 17.00 (14.32) (100) | 21.53 (15.69) (100) | 39/100 | 48/100 | ||||||||
| Arden NK 2014 | 68/108 | 69/110 | ||||||||||||
| Henderson EB 1994 | 21/45 | 10 de 46 | ||||||||||||
| Strand V 2012 | 172/251 | 81/128 | ||||||||||||
Table 3B. Description of results by outcomes (IA-HA versus IA-SS).
| Author/Year |
|
|
|
|
|
|
Adverse events n/N | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | Hyaluronic acid | Saline solution | |
| Askari A 2016 | 13.22 (4.24) (71) | 12.60 (3.69) (69) | 6.7 (2.01) (71) | 6.56 (2.15) (69) | ||||||||||
| Maia PAV 2019 | 14.3 (3.6) (16) | 7.1 (3.9) (12) | ||||||||||||
| Caborn D 2004 | 0.7 (0.1) (113) | 0.4 (0.1) (102) | 28.0 (2.5) (113) | 12.4 (2.6) (102) | 18.4 (1.7) (113) | 10.4 (1.8) (102) | 87/113 | 71/102 | ||||||
| Tammachote N 2016 | 21 (15) (55) | 21 (19) (55) | 24 (22) (55) | 21 (22) (55) | ||||||||||
| Skwara A 2009 | 44.0 (22.3) (30) | 45.8 (27.8) (30) | ||||||||||||
| Bisicchia S 2016 | 4.0 (2.0) (75) | 5.0 (1.0) (75) | 27.3 (10.8) (75) | 36.0 (7.1) (75) | 39.6 (17.9) (75) | 42.3 (7.5) (75) | ||||||||
| Shimizu M 2010 | 21.5 (19.3) (32) | 22.6 (18.3) (29) | ||||||||||||
| Tasciotaoglu F 2003 | 23.56 (10.11) (30) | 26.46 (14.30) (30) | 16/30 | 13/30 | ||||||||||
| Housman L 2014 | 91/130 | 81/132 | ||||||||||||
| Leighton R 2014 | 50/221 | 9/221 | ||||||||||||
Figure 2. Western Ontario McMaster University Osteoarthritis (WOMAC global) - IA-HA versus IA-SS.
Figure 3. Decreased pain at rest (VAS) - IA-AH versus IA-SS.
Figure 4. Lequesne’s functional index from 26 to 52 weeks - IA-HA versus IA-SS.
Figure 5. WOMAC (functional subscale) - score decrease - IA-HA versus IA-SS.
Figure 6. WOMAC (pain subscale) - score decrease - IA-HA versus IA-SS.
Figure 7. Decreased walking pain (VAS) - IA-HA versus IA-SS.
Figure 8. Adverse events - IA-AH versus IA-SS.
Figure 9. WOMAC pain score (12 and 26 weeks) - IA-HA versus IA-SS.
Figure 10. Pain assessment - VAS (12 and 26 weeks) - IA-HA versus IA-SS.
Figure 11. Pain assessment - overall WOMAC (26 and 52 weeks) - IA-HA versus IA-SS.
Figure 12. Adverse events - IA-HA versus IA-SS.
Table 4. Question: knee infiltration with hyaluronic acid versus saline solution - GRADE.
| Certainty assessment | Patients number | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies number | Study design | Bias risk | Inconsistency | Indirect evidence | Imprecision | Other considerations | Hyaluronic acid | Saline solution | Relative (95%CI) | Absolute (95%CI) | ||
| WOMAC global - pain - 18-26 weeks | ||||||||||||
| 3 | Randomized clinical trials | Seriousa,b | Seriousc | Not serious | Seriousd | None | 375 | 360 | - |
|
|
|
| VAS - pain reduction (rest) - 52 weeks | ||||||||||||
| 2 | Randomized clinical trials | Seriousa, b | Seriousc | Not serious | Seriousd | None | 186 | 140 | - |
|
|
|
| Lequesne’s Functional Index - 26 and 52 weeks | ||||||||||||
| 5 | Randomized clinical trials | Seriousa,b | Seriousc | Not serious | Seriousd | None | 671 | 601 | - |
|
|
|
| WOMAC - Functional - Reduction from Base Line - 26 weeks | ||||||||||||
| 4 | Randomized clinical trials | Seriousa,b | Seriousc | Not serious | Seriousd | None | 785 | 761 | - |
|
|
|
| WOMAC - Pain - Reduction from Base Line - 26 weeks | ||||||||||||
| 5 | Randomized clinical trials | Seriousa,b | Seriousc | Not serious | Seriousd | None | 830 | 748 | - |
|
|
|
| VAS 0-100 Pain (walking) - 26-52 weeks | ||||||||||||
| 7 | Randomized clinical trials | Seriousa, b | Seriousc | Not serious | Seriousd | None | 1,164 | 1,137 | - |
|
|
|
| Adverse events | ||||||||||||
| 14 | Randomized clinical trials | Seriousa,b | Seriousc | Not serious | Seriousd | None | 1,161/2,067 (56.2%) | 1,058/1,902 (55.6%) | L |
|
|
|
Table 5. Question: knee infiltration with hyaluronic acid versus steroids - GRADE.
| Certainty assessment | Patients number | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Studies number | Study design | Bias risk | Inconsistency | Indirect evidence | Imprecision | Other considerations | Hyaluronic acid | Steroids | Relative (95%CI) | Absolute (95%CI) | ||
| WOMAC score evaluation - Pain | ||||||||||||
| 4 | Randomized clinical trials | Not serious | Not serious | Not serious | Not serious | None | 255 | 238 | - |
|
|
|
| VAS score evaluation - Pain | ||||||||||||
| 7 | Randomized clinical trials | Not serious | Seriousa | Not serious | Seriousb | None | 406 | 390 | - |
|
|
|
| WOMAC overall | ||||||||||||
| 2 | Randomized clinical trials | Not serious | Serious a | Not serious | Not serious | None | 150 | 150 | - |
|
|
|
| Adverse events | ||||||||||||
| 4 | Randomized clinical trials | Not serious | Seriousa | Not serious | Not serious | None | 244/494 (49.4%) | 174/485 (35.9%) |
|
|
||
A total of 680 studies were retrieved, of which, meeting the eligibility criteria, 27 studies were selected 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , of which 17 were comparisons against saline solution (Table 1A) 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 and 10 comparisons against steroids (Table 1B) 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 . The main reasons for exclusion were orphan studies and outcomes, technical comparisons, and lack of comparisons.
Characteristics of the included studies
A total of 5,917 patients with OA or knee osteoarthrosis who underwent IA injection of HA (n=3,101) compared to saline solution (n=2,816) were studied and followed for a period between 8 and 52 weeks. Molecular weight ranged from high to intermediate, and the outcomes measured were pain and functional (WOMAC, Lequesne index, KSS, and VAS) (Table 1A).
A total of 1,677 patients with OA or osteoarthrosis of the knee who underwent IA injection of HA (n=847) compared to steroids (n=830) were studied and followed for a period between 12 and 52 weeks. Molecular weight ranged from high to intermediate, and the outcomes measured were pain and functional (WOMAC, Fansne index, KSS, and VAS) (Table 1B).
Risk of bias
The overall risk of bias in studies comparing HA and saline solution AI is high, with most of this risk concentrated in the lack of blinding, losses, and analysis by ITT (Table 2A).
The overall risk of bias in studies comparing HA and steroid AI is high, with most of this risk concentrated in the lack of blinding, losses, and analysis by ITT (Table 2B).
Results of the quantitative analysis by comparison and by outcomes (meta-analysis)
Comparison between HA IA (IA-HA) and saline solution IA (IA-SS) ( Figures 2 - 8 )
In this comparison and analysis, it was possible to aggregate the results of 17 studies in relation to seven outcomes: overall WOMAC for pain, pain at rest (VAS), functional index (Lequesne), WOMAC (functional), WOMAC (pain), pain (VAS) walking, and adverse events (Table 3A).
Overall WOMAC for pain at 18 to 26 weeks - IA-HA versus IA-SS ( Figure 2 )
In pain assessment using the global WOMAC score (Figure 2), comparing IA-HA (n=375) and IA-SS (n=360), three studies were included 2 , 3 , 4 . The analysis identified a benefit of HA with a mean score reduction of -0.16 [95%CI -0.23, -0.10] 2 , 3 , 4 . The quality of evidence is very low (Table 4).
Pain at rest (VAS) - IA-HA versus IA-SS ( Figure 3 )
In the assessment of pain at rest using the VAS score (Figure 3), comparing IA-HA (n=186) and IA-SS (n=140), two studies were included 5 , 6 . In the analysis, no difference in pain was identified between the -0.27 [-6.34, +5.79] comparisons. The quality of evidence is very low (Table 4).
Lequesne’s functional assessment (Figure 4), comparing IA-AH (n=671) and IA-SS (n=601), five studies were included 5 , 6 , 7 , 8 , 9 . In the analysis, no difference in function was identified between comparisons -0.24 [95%CI -1.24, +0.76]. The quality of evidence is very low (Table 4).
WOMAC - functional subscale (baseline up to 26 weeks) - IA-HA versus IA-SS ( Figure 5 )
In the functional assessment (WOMAC), comparing IA-HA (n=785) and IA-SS (n=761), four studies were included 2 , 10 , 11 , 12 . In the analysis, no difference in function (WOMAC) was identified between comparisons -0.18 [95%CI -1.61, +1.26] 2 , 10 , 11 , 12 . The quality of evidence is very low (Table 4).
WOMAC - pain subscale (baseline up to 26 weeks) - IA-HA versus IA-SS ( Figure 6 )
In the pain assessment (WOMAC), comparing IA-HA (n=830) and IA-SS (n=748), five studies were included 10 - 11 , 13 , 14 , 15 . In the analysis, no difference in function (WOMAC) was identified between comparisons +3.16 [95%CI -1.12, +7.44] 10 - 11 , 13 , 14 , 15 . Very low quality of evidence (Table 4).
Walking pain at 26-52 weeks (VAS) - IA-HA versus IA-SS ( Figure 7 )
In the assessment of pain on walking using the VAS score (Figure 7), comparing IA-HA (n=1,164) and IA-SS (n=1,137), seven studies were included 2 , 5 , 7 , 9 , 11 , 12 , 15 . In the analysis, no difference in pain was identified between the -2.95 [-6.07, +0.18] comparisons. The quality of evidence is very low (Table 4).
Adverse events - IA-HA versus IA-SS ( Figure 8 )
In the evaluation of adverse events between IA-HA and IA-SS, 14 studies were included with 2,067 patients in the HA group (intervention) and 1,902 in the SS group (control). There was no difference in the risk of adverse events 0.00 [95%CI -0.04, +0.04] 2 , 3 , 5 , 6 , 7 , 9 , 10 , 11 , 12 , 13 , 15 , 16 , 17 , 18 . The quality of evidence is very low (Table 4).
Comparison between HA IA (IA-HA) and Steroid IA (IA-SS) (Figures 9-12)
In this comparison and analysis, it was possible to aggregate the results of 10 studies, in relation to four outcomes: WOMAC (pain) (12 and 26 weeks), pain at rest (VAS) (12 and 26 weeks), WOMAC overall for pain, and adverse events (Table 3B).
WOMAC pain score (12 and 26 weeks) - IA-HA versus IA-SS ( Figure 9 )
In assessing pain using the WOMAC score and comparing IA-HA and IA-SS, two studies were included in the 12-week evaluation (87 patients in the IA-HA group and 81 in the IA-SS group), and two studies were included in the 26-week evaluation (168 patients in the IA-HA group and 157 in the IA-SS group). The result of the analysis of subgroups by follow-up time does not identify a difference between the comparisons at 12 weeks: 3.79 [95%CI -2.66, +10.23] and results in an increase in the pain score with HA of 0.30 [95%CI +0.27, +0.33] at 26 weeks. In the global analysis (regardless of the follow-up time), no difference was identified between the comparisons: 1.95 [-0.28, +4.19] (Figure 9) 19 , 20 , 21 , 22 . High quality of evidence (Table 5).
PAIN assessment (VAS) at 12 and 26 weeks - IA-HA versus IA-SS ( Figure 10 )
In the assessment of pain using the VAS score comparing IA-HA and IA-SS, two studies were included in the 12-week assessment (101 patients in the IA-HA group and 99 in the IA-SS group), and at 26 weeks, five studies were included (305 patients in the IA-HA group and 291 in the IA-SS group). No differences were identified in the score at the 12-week follow-up [0.13 (95%CI -0.55, +0.82)], the 26-week [2.92 (95%CI -7.60, +13.44)], or in the global analysis regardless of follow-up time [2.05 (95%CI -5.00, +9.11)] (Figure 10) 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 . Low quality of evidence (Table 5).
Overall WOMAC for pain at 26 and 52 weeks - IA-HA versus IA-SS ( Figure 11 )
In pain assessment (global WOMAC score), comparing IA-HA and IA-SS, two studies were included in the 26-week follow-up (188 patients in the IA-HA group and 177 in the IA-SS group), and one study in 52 weeks of follow-up (75 patients in groups IA-HA and IA-SS). There was no difference between the two groups at the follow-up of 26 [-0.29 (95%CI -16.65, +16.08)], or 52 weeks [-2.70 (95%CI -7.09, +1.69)], or at global assessment [- 1.06 (95%CI -13.16, +11.03)] (Figure 11) 21 , 24 . Moderate quality of evidence (Table 5).
Adverse events - IA-HA versus IA-SS ( Figure 12 )
In the evaluation of adverse events, in the comparison between IA-HA and IA-SS, four studies were included (494 patients in the IA-HA group and 485 in the IA-SS group). The analysis demonstrates that there is an increase in the risk of adverse events with the 13% HA [95%CI 6-20%] 21 , 26 , 27 , 28 . Moderate quality of evidence (Table 5).
Quality of evidence by comparison and outcome (Tables 4 and 5)
Knee infiltration comparing hyaluronic acid to saline solution (placebo) in osteoarthritis
Outcomes: Overall WOMAC for pain, pain at rest (VAS), functional index (Lequesne), WOMAC (functional), WOMAC (pain), pain (VAS) while walking, and adverse events.
Knee infiltration comparing hyaluronic acid to steroids in osteoarthritis
Outcomes: WOMAC (pain) (12 and 26 weeks), pain at rest (VAS) (12 and 26 weeks), overall WOMAC for pain, and adverse events.
SUMMARY OF EVIDENCE
There were seven analyses (seven outcomes) comparing IA injection with HA and saline solution and four analyses (four outcomes) comparing steroids, with follow-up at different times (8 weeks to 52 weeks). In only two outcomes, there was a difference in effect between the comparisons: (1) In the comparison between HA and saline solution: reduction in the Western Ontario McMaster University Osteoarthritis (global WOMAC) score of 0.16 points favorable to HA on a scale ranging from 0 to 96 points; (2) Increase in adverse events by 13% (NNH: 8) with the use of HA compared to steroids.
RECOMMENDATION
Despite the frequent and disseminate use of IA-HA in the treatment of knee OA, there is no high-quality evidence sustaining this form of treatment.
Funding: none.
The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field to standardize how to conduct research and to assist in the reasoning and decision-making of doctors. The information provided by this project must be critically evaluated by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical condition of each patient.
Guideline submission: 6 may 2023
Guideline conclusion: 19 July 2023.
Societies: Brazilian Medical Association.
REFERENCES
- 1.Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis: a review. JAMA. 2021;325(6):568–578. doi: 10.1001/jama.2020.22171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009;17(2):152–160. doi: 10.1016/j.joca.2008.06.014. [DOI] [PubMed] [Google Scholar]
- 3.Chevalier X, Jerosch J, Goupille P, Dijk N, Luyten FP, Scott DL, et al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Ann Rheum Dis. 2010;69(1):113–119. doi: 10.1136/ard.2008.094623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Day R, Brooks P, Conaghan PG, Petersen M, Multicenter Trial Crane A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee. J Rheumatol. 2004;31(4):775–782. [PubMed] [Google Scholar]
- 5.Dougados M, Nguyen M, Listrat V, Amor B. High molecular weight sodium hyaluronate (hyalectin) in osteoarthritis of the knee: a 1 year placebo-controlled trial. Osteoarthritis Cartilage. 1993;1(2):97–103. doi: 10.1016/s1063-4584(05)80024-x. [DOI] [PubMed] [Google Scholar]
- 6.Pham T, Henanff A, Ravaud P, Dieppe P, Paolozzi L, Dougados M. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Ann Rheum Dis. 2004;63(12):1611–1617. doi: 10.1136/ard.2003.019703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Huskisson EC, Donnelly S. Hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology (Oxford) 1999;38(7):602–607. doi: 10.1093/rheumatology/38.7.602. [DOI] [PubMed] [Google Scholar]
- 8.Karlsson J, Sjögren LS, Lohmander LS. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study. Rheumatology (Oxford) 2002;41(11):1240–1248. doi: 10.1093/rheumatology/41.11.1240. [DOI] [PubMed] [Google Scholar]
- 9.Migliore A, Blicharski T, Plebanski R, Zegota Z, Gyula G, Rannou F, et al. Knee osteoarthritis pain management with an innovative high and low molecular weight hyaluronic acid formulation (HA-HL): a randomized clinical trial. Rheumatol Ther. 2021;8(4):1617–1636. doi: 10.1007/s40744-021-00363-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Altman RD, Akermark C, Beaulieu AD, Schnitzer T, Durolane International Study Group Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthritis Cartilage. 2004;12(8):642–649. doi: 10.1016/j.joca.2004.04.010. [DOI] [PubMed] [Google Scholar]
- 11.Altman RD, Rosen JE, Bloch DA, Hatoum HT, Korner P. A double-blind, randomized, saline-controlled study of the efficacy and safety of EUFLEXXA for treatment of painful osteoarthritis of the knee, with an open-label safety extension (the FLEXX trial) Semin Arthritis Rheum. 2009;39(1):1–9. doi: 10.1016/j.semarthrit.2009.04.001. [DOI] [PubMed] [Google Scholar]
- 12.Petterson SC, Plancher KD. Single intra-articular injection of lightly cross-linked hyaluronic acid reduces knee pain in symptomatic knee osteoarthritis: a multicenter, double-blind, randomized, placebo-controlled trial. Knee Surg Sports Traumatol Arthrosc. 2019;27(6):1992–2002. doi: 10.1007/s00167-018-5114-0. [DOI] [PubMed] [Google Scholar]
- 13.Brandt KD, Block JA, Michalski JP, Moreland LW, Caldwell JR, Lavin PT. Efficacy and safety of intraarticular sodium hyaluronate in knee osteoarthritis. ORTHOVISC Study Group. Clin Orthop Relat Res. 2001;(385):130–143. doi: 10.1097/00003086-200104000-00021. [DOI] [PubMed] [Google Scholar]
- 14.Hangody L, Szody R, Lukasik P, Zgadzaj W, Lénárt E, Dokoupilova E, et al. Intraarticular injection of a cross-linked sodium hyaluronate combined with triamcinolone hexacetonide (cingal) to provide symptomatic relief of osteoarthritis of the knee: a randomized, double-blind, placebo-controlled multicenter clinical trial. Cartilage. 2018;9(3):276–283. doi: 10.1177/1947603517703732. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Huang TL, Chang CC, Lee CH, Chen SC, Lai CH, Tsai CL. Intra-articular injections of sodium hyaluronate (Hyalgan®) in osteoarthritis of the knee. a randomized, controlled, double-blind, multicenter trial in the Asian population. BMC Musculoskelet Disord. 2011;12:221–221. doi: 10.1186/1471-2474-12-221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Arden NK, Åkermark C, Andersson M, Todman MG, Altman RD. A randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. Curr Med Res Opin. 2014;30(2):279–286. doi: 10.1185/03007995.2013.855631. [DOI] [PubMed] [Google Scholar]
- 17.Henderson EB, Smith EC, Pegley F, Blake DR. Intra-articular injections of 750 kD hyaluronan in the treatment of osteoarthritis: a randomised single centre double-blind placebo-controlled trial of 91 patients demonstrating lack of efficacy. Ann Rheum Dis. 1994;53(8):529–534. doi: 10.1136/ard.53.8.529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Strand V, Baraf HSB, Lavin PT, Lim S, Hosokawa H. A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. 2012;20(5):350–356. doi: 10.1016/j.joca.2012.01.013. [DOI] [PubMed] [Google Scholar]
- 19.Askari A, Gholami T, NaghiZadeh MM, Farjam M, Kouhpayeh SA, Shahabfard Z. Hyaluronic acid compared with corticosteroid injections for the treatment of osteoarthritis of the knee: a randomized control trail. Springerplus. 2016;5:442–442. doi: 10.1186/s40064-016-2020-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Maia PAV, Cossich VRA, Salles-Neto JI, Aguiar DP, Sousa EB. Viscosupplementation improves pain, function and muscle strength, but not proprioception, in patients with knee osteoarthritis: a prospective randomized trial. Clinics (Sao Paulo) 2019;74:e1207. doi: 10.6061/clinics/2019/e1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Caborn D, Rush J, Lanzer W, Parenti D, Murray C, Synvisc 901 Study Group A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee. J Rheumatol. 2004;31(2):333–343. [PubMed] [Google Scholar]
- 22.Tammachote N, Kanitnate S, Yakumpor T, Panichkul P. Intra-articular, single-shot hylan G-F 20 hyaluronic acid injection compared with corticosteroid in knee osteoarthritis: a double-blind, randomized controlled trial. J Bone Joint Surg Am. 2016;98(11):885–892. doi: 10.2106/JBJS.15.00544. [DOI] [PubMed] [Google Scholar]
- 23.Skwara A, Ponelis R, Tibesku CO, Rosenbaum D, Fuchs-Winkelmann S. Gait patterns after intraarticular treatment of patients with osteoarthritis of the knee--hyaluronan versus triamcinolone: a prospective, randomized, doubleblind, monocentric study. Eur J Med Res. 2009;14(4):157–164. doi: 10.1186/2047-783x-14-4-157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Bisicchia S, Bernardi G, Tudisco C. HYADD 4 versus methylprednisolone acetate in symptomatic knee osteoarthritis: a single-centre single blind prospective randomised controlled clinical study with 1-year follow-up. Clin Exp Rheumatol. 2016;34(5):857–863. [PubMed] [Google Scholar]
- 25.Shimizu M, Higuchi H, Takagishi K, Shinozaki T, Kobayashi T. Clinical and biochemical characteristics after intra-articular injection for the treatment of osteoarthritis of the knee: prospective randomized study of sodium hyaluronate and corticosteroid. J Orthop Sci. 2010;15(1):51–56. doi: 10.1007/s00776-009-1421-0. [DOI] [PubMed] [Google Scholar]
- 26.Tasciotaoglu F, Oner C. Efficacy of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis. Clin Rheumatol. 2003;22(2):112–117. doi: 10.1007/s10067-002-0690-1. [DOI] [PubMed] [Google Scholar]
- 27.Housman L, Arden N, Schnitzer TJ, Birbara C, Conrozier T, Skrepnik N, et al. Intra-articular hylastan versus steroid for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2014;22(7):1684–1692. doi: 10.1007/s00167-013-2438-7. [DOI] [PubMed] [Google Scholar]
- 28.Leighton R, Akermark C, Therrien R, Richardson JB, Andersson M, Todman MG, et al. NASHA hyaluronic acid vs. methylprednisolone for knee osteoarthritis: a prospective, multi-centre, randomized, non-inferiority trial. Osteoarthritis Cartilage. 2014;22(1):17–25. doi: 10.1016/j.joca.2013.10.009. [DOI] [PubMed] [Google Scholar]