. 2021 Dec 2;13:255–273. doi: 10.2147/ORR.S336185

Table 3.

Results of Systematic Literature Research for HA in the Treatment of Knee OA

First Author Year Design	Inclusion Criteria	Exclusion Criteria	Patients Treatment Procedure	Control	Assessment	Results
Castellacci¹⁶ 2004, Observational, retrospective.	18–82 years with primary or secondary symptomatic Knee OA (confirmed by X rays < 1 year before enrolment).	Acute synovitis, joint effusion, knee prosthesis, RA or other inflammatory diseases, severe osteoporosis, skin disease near the inj. site.	Patients: 40 Treatment: HA 0.8% Procedure: Weekly IA inj. for a total of 5 inj.	None.	Tolerability, LI (baseline, 3, 5 weeks and final visit), pain level, analgesic consumption with follow up at seven weeks.	Tolerability excellent/good)- LI from 7.9 to 3.2 at the final visit, similar decrease for pain.
Depont⁴⁶ 2004, Observational, retrospective.	>20 years knee OA treated with HA 0.8% between Jan. 1, 2003 and Mar. 31, 2003 never treated previously with VS.	Not reported.	Patients: 408 Treatment: HA 0.8% Procedure: IA inj.	None.	Pain at Likert scale, tolerability, consumption of NSAIDs, analgesics and gastro protectors. Total of 12 months.	64.5% of the patients reported improvement of function—better improvement in patients with low BMI and < 5 years Knee OA. The lack of treatment with NSAIDs before injections was also associated with a better response.
Theiler¹⁷ 2005, Prospective, open-label.	18−85 years, symptomatic knee OA (KL II–I), pain on walking > 30 mm at 100 mm VAS.	Chondrocalcinosis, crystal arthropathies, synovitis or effusion, axis deviations, arthritides, metabolic diseases of the bone, symptomatic hip OA, knee surgery or IA injection of steroids in the last three months, steroid therapy.	Patients: 63 Treatment: HA 0.8% Procedure: weekly IA inj. of HA 0.8% for five consecutive weeks.		Primary endpoint: AE; secondary endpoint WOMAC score, additional follow up at 19 weeks.	WOMAC score was significantly reduced within the first two weeks of treatment, further decreased by the end of the inj. series (week 6) and maintained during the follow-up (week 24). WOMAC subscores significantly decreased from week 4 for “pain” and from week 6 for “stiffness” and “physical function”. Most frequent AE was pain at the inj. site (5.8% of the inj.).
Pavelka²² 2011 RCT.	40−81 years with symptomatic knee OA (KL grades II–III), non-responder or intolerant to analgesics and/or NSAIDs. Mean WOMAC pain sub-score >40mm and <80mm, and <30mm in the contralateral knee.	BMI > 32, secondary OA, femoral patellar OA, KL -IV, hip OA, varus/ valgus deformity, arthritides, rheumatic disease, previous knee injury or surgery, allergy to HA. Venous or lymphatic stasis, systemic or IA steroids, concomitant SySADOA, anticoagulant or pain killers.	Patients: 192 Treatment: HA 0.8% Procedure: 1 IA inj. weekly for three weeks.	Patients: 189 Treatment: HA 16mg/2mL Procedure: 1 IA inj. weekly for three weeks	Follow up at 4, 12 and 26 weeks. Primary endpoint: WOMAC Index pain subscore at 26 weeks. Secondary endpoints: Stiffness and function LI, PGA.	HA 0.8% and HA 16mg/2mL treatments were equivalent, both in terms of efficacy and safety.
Polacco¹⁸ 2013, Open-label, double-blind.	Symptomatic knee OA, classified into moderate, severe and very severe according to WOMAC Index and the KL scales.	Use of systemic steroids or SySADOA within the previous three months; IA inj. of steroids or HA within three months. Sepsis or arthritides.	Patients: 21 (24 knees) Treatment: HA 2% Procedure: 1 IA inj.	None	Primary endpoint: WOMAC score. Secondary outcomes: I) Pain at rest; 2) Walking distance increase; 3) joint range increase; 4) walking upstairs 5) walking downstairs. At 30, 60, 90, and 120 days.	At four months, there was an improvement in clinical parameters in 77.6% of the 24 treated knees, particularly in patients with moderate and severe OA (improvement in 100% and 66.7%, respectively).
Bottegoni²⁰ 2014, Observational.	>65 years; moderate or severe knee OA.	Not reported.	Patients: 60 Treatment: HA 1.6% Procedure: 3 inj.	Patients: 60 Treatment: PRP Procedure: 3 inj.	Knee Injury, KOOS score, EQ-VAS baseline, 2 and 6 months.	Significant improvement in both groups Better results of PRP than HA 1.6% at two months; better results of HA 1.6% at six months. Worst results in aged > 80 and higher grade of OA (in this class better results of HA 0.8%).
Papalia¹⁹ 2016, RCT.	Professional soccer players with unilateral pain not responsive to conservative treatment.	Haematological diseases, previous knee surgery, NSAIDs or steroids within two weeks, recent fever, infections, cancer.	Patients: 24 Treatment: HA 3.2% (1400–2100 kDa/65–110 kDa) Procedure: 3 IA inj.	Patients: 24 Treatment: PRP 5.5 mL Procedure: 3 IA inj.	IKDC score, KOOS score, pain assessment by VAS at baseline, 3-6-12 months.	Good response in both groups at three and six months, better response in HA 3.2% (1400–2100 kDa/65–110 kDa) group but a non-significant difference at 12 months.
Abate and Salini²⁵ 2017, Observational.	Symptomatic Knee OA (KL I-II–III) for more than three months.	Knee surgery, recent trauma, lower limb length discrepancy, rheumatic pathologies, endocrinopathies, systemic diseases. IA injection or treatments with steroids or NSAIDs within the previous three months.	Patients: 15 Treatment: HA 1.6%; HA 2% Procedure: Weekly IA inj. of HA 1.6% for three weeks. Then, at 4, 8 and 12 months, one inj. of HA 2%.	None.	Pain at rest and during activities, LI, KOOS score, and monthly NSAIDs consumption. Follow up at 1, 4, 6, 8, 12 and 14 months, and patient satisfaction (five-points Likert scale).	Persistent positive results in terms of reduced pain and improved function.
Papalia²¹ 2017, RCT.	Knee 0A Patients with BMI > 30, KL> III, not responsive to conservative treatments. No-inj. treatment.	Previous knee surgery or IA inj., knee instability, axial deformity, osteochondral lesion, general or haematological disorders.	Patients: 24 Treatment: HA 3.2% (1400–2100 kDa/65–110 kDa) Procedure: 2 IA inj.	Patients: 24 Treatment: HA 1.6% Procedure: 2 IA inj.	IKDC score, pain assessment by VAS at baseline, 3 and 6 months.	HA 3.2% (1400–2100 kDa/ 65–110 kDa) improved function and pain of the knee, the treatment with a hybrid HA showed better outcomes than high molecular weight HA in obese patients.
Galluccio⁴⁶ 2017, Prospective comparative.	Patients with KL grades I/II Knee OA.	Not reported.	Patients: 30 Treatment: HA 2% Procedure: 1 IA inj.	Patients: 30 Treatment: HA 20mg/2mL; Procedure 5 IA inj. Patients: 30 Treatment: HA 1.6% Procedure 3 IA inj.	WOMAC score, NHS and social costs.	The three treatments resulted equally effective without statistically significant differences. HA 2% is as clinically effective as the other two regimens but with a very efficient efficacy/cost profile.
Manciameli³⁵ 2018, Observational.	Symptomatic Knee OA confirmed by X rays.	Systemic or local infections, local inflammation or skin diseases near the inj. site.	Patients: 35 Treatment: HA 3.2% (1400–2100 kDa/65–110 kDa) Procedure: 2 IA inj. 2 weeks apart.	None.	Pain measured by VAS, WOMAC score, ROM, NSAIDs or analgesics consumption at baseline and 1-3-6 months	The results are long-lasting with good outcomes also over six months, with reduction of VAS pain, WOMAC total score, consumption of NSAIDs and improvement of ROM.
Migliore⁴⁸ 2018, Observational, retrospective.	≥18 years active football players; symptomatic Knee OA confirmed by X rays (KL grades I–II)	Arthritis <18 years. Allergy to HA.	Patients: 17 Treatment: HA 0.8% Procedure: 1 inj. at time T0, one after two weeks.	None.	Pain measured by VAS at time 0, 1 and 2 days after the 1st injection; at two weeks; 1 and 2 days after the 2nd inj., and at 4, 12, and 24 weeks. LI and PGA assessed at baseline, at 1, 4, 12, and 24 weeks.	The use of HA 0.8% in football players affected by knee OA seems efficacious and safe and resulted in a stable improvement of the symptoms.
Papalia²³ 2019, RCT.	40–70 years with Knee OA (KL II and III), not responsive to pharmacologic treatment, rehabilitation, or physical therapy.	<45 >70 years KL >III, diabetes, RA, previous IA injections, cardiovascular diseases, coagulopathies, immunodepression, varus > 20° or valgus >20° morphotype.	Patients: 30 Treatment: HA 3.2% (1400–2100 kDa/65–110 kDa) Procedure: 3 inj.	Patients: 30 Treatment: HA 3.2% (1400–2100 kDa/65–110 kDa) plus PRP Procedure: 3 inj.	KOOS score, pain assessment by VAS at baseline, 3-6-12 months.	PRP and HA 3.2% (1400–2100 kDa/65–110 kDa) are safe and resulted in being more effective than HA 3.2% (1400–2100 kDa/65–110 kDa) injective therapy alone.

Abbreviations: Inj, injection(s); KL, Kellgren-Lawrence; IKDC, International Knee Documentation Committee; KOOS, Knee injury and Osteoarthritis Outcome Score; HA, Hyaluronic Acid; IA, Intra Articular; LI, Lequesne Index; NHS, National Healthcare Service; NSAID, Nonsteroidal anti-inflammatory drug; OA, Osteoarthritis; PGA, Patient’s Global Assessment; PRP, Platelet Rich Plasma; RA, Rheumatoid Arthritis; ROM, Range of Motion; WOMAC, Western Ontario and Mac Master University score.