Systematic Literature Review and Expert Opinion for the Use of Viscosupplementation with Hyaluronic Acid in Different Localizations of Osteoarthritis

Figures & data

Table 1 Formulation of Clinical Questions in PICO Format

P	Human Patients, Adults, Osteoarthritis
I	Hyaluronic acid, infiltrations, viscosupplementation or hyaluronic acid 0.8%, 1.6%, 2%, 800–1200 kDa, 3.2% (1400–2100 kDa/65–110 kDa), infiltrations, viscosupplementation
C	–
O	All

Figure 1 Selection of papers during the SLR.

Table 2 Calculated MMAT Scores for Studies Included in This Systematic Review

Study	MMAT Score
Castellacci 2004^Citation16	4
Depont 2004^Citation46	3
Theiler 2005^Citation17	5
Pavelka 2011^Citation22	5
Polacco 2013^Citation18	5
Bottegoni 2014^Citation20	5
Papalia 2016^Citation19	4
Abate 2017^Citation25	5
Papalia 2017^Citation21	4
Galluccio 2021^Citation47	5
Manciameli 2018^Citation35	4
Migliore 2018^Citation48	5
Papalia 2019^Citation23	5
Migliore 2012^Citation24	5
Lùrati 2015^Citation32	3
Abate and Salini 2017^Citation25	5
Abate 2014^Citation26	5
La Paglia 2017^Citation27	5
Busilacchi 2011^Citation29	3
Gigante 2013^Citation28	5
D’Avola 2013^Citation34	3
Bartoloni 2019^Citation33	4
Tenti 2017^Citation31	5
Callegari 2011^Citation36	5
Roux 2007^Citation30	5

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
Castellacci^Citation16 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.
Depont^Citation46 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.
Theiler^Citation17 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.).
Pavelka^Citation22 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.
Polacco^Citation18 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).
Bottegoni^Citation20 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%).
Papalia^Citation19 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 Salini^Citation25 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.
Papalia^Citation21 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.
Galluccio^Citation46 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.
Manciameli^Citation35 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.
Migliore^Citation48 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.
Papalia^Citation23 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.

Table 4 Results of Systematic Literature Research for HA in the Treatment of OA in Other Joints

First Author Year Design	Joint (Condition)	Inclusion Criteria	Exclusion Criteria	Patients Treatment Procedure	Control	Assessment	Results
Migliore^Citation24 2012, Observational Prospective.	HIP (OA).	>40 years; symptomatic hip OA (ACR criteria); KL grade II or III.	Oral anticoagulant; no articular space; previous IA CS or HA; significant co-morbidities; allergy to HA and systemic CS.	Patients: 114 Treatment: HA 1.6% Procedure: 4 mL (2 vials) IA inj.	None.	Follow-up every three months, for a total of 6 months (pain VAS), LI score, NSAID use AEs.	Statistically significant reduction in LI score, VAS pain score and NSAID intake were observed at all time-points (p < 0.05). No systemic, severe, or even moderate side effects were observed.
Lùrati^Citation32 2015, Observational.	KNEE AND HIP (OA).	Bilateral knee or hip OA (ACR Criteria), with a 2 and 3 KL and Pain VAS ≥ 50.	RA or other arthritides, pregnancy, allergic to HA, knee, or skin infections. Polyarticular OA.	Patients: 24 knee; 13 hip Treatment: HA 1.6% Procedure: 3 inj. at weekly intervals.	Patients: 35 knee and 14 hip OA; 24 healthy subjects Treatment: None Procedure: None.	Flow cytometry was performed from blood samples to assess T cells subpopulations at baseline and 3-months visit.	The presence of activated T cells confirms that OA is a disease with an immunological- inflammatory involvement. These preliminary results seem to show that HA 1.6% could lower the levels of activated T cells, and thus regulate the articular milieu.
Abate and Salini^Citation25 2017, Observational retrospective.	HIP (OA).	Patients with moderate-severe hip OA (K-L grades II–IV), symptomatic for more than three months.	Recent hip trauma; IA CS, HA, or PRP and/or oral CS or NSAIDs within the previous three months (paracetamol allowed); rheumatic pathologies, and severe systemic diseases (renal, hepatic, cardiac, etc.).	Patients: 20 Treatment: HA H-L 3.2% (HMW 1400–2100 kDa-LMW 65–110 kDa) Procedure: US-guided IA inj. 2 mL HA H-L 3.2% (HMW 1400–2100 kDa-LMW 65–110 kDa) at baseline and after 40 days.	Patients: 20 Treatment: HMW HA Procedure: US-guided IA inj of 2 mL HA at baseline and after 40 days.	Demographic and anthropometric data, pain at rest and during activities in the previous week VAS, Lequesne Index (LI), HHS, and monthly consumption of NSAIDs baseline, 3 and 6 months.	Combination of LMW and HMW HA provides better therapeutic results in comparison with HMW HA. In both groups at 3 and 6 months, VAS scores at rest and during activities decreased significantly, as well as disability (LI) with an improvement of HHS; better results were observed in patients treated with the new hybrid compound, both in terms of pain and improved function.
Abate^Citation26 2014, Open prospective.	HIP (IMPINGEMENT).	Pain for at least three months, as determined by the hip impingement test; in patients with cam FAI (angle ≥55).	A-angle ≤55; age >55 years, history of hip disease (slipped capital femoral epiphysis, Perthes disease, osteotomy, dysplasia), hip surgery, evidence of radiographic hip OA and previous IA injection with CS.	Patients: 20 Treatment: HA 1.6% Procedure: 1 inj. at baseline and after 40 days; same dosing schedule repeated after six months.	None.	Demographic, anthropometric, and clinical data, pain VAS during the previous week, LI, HHS and monthly consumption of NSAIDs (baseline, 6 and 12 months).	HA 1.6% is safe and effective in the treatment of mild femoral-acetabular impingement, with significant pain reduction and function improvement.
La Paglia^Citation27 2017, Retrospective.	HIP (IMPINGEMENT).	Femoro-acetabular impingement (FAI).	Group I: rheumatic diseases, allergy to HA, recurrent infections, pregnant or lactating patients; besides, for control Group: platelet function disorder, thrombocytopenia, hypofibrinogenemia, septicaemia, history of cancer, HGB < 10 g/dl, platelet count < 105.	Patients: 16 Treatment: HA 2% Procedure: 1 US-guided injection.	Patients: 16 Treatment: HA 3.2% (1400–2100 kDa/ 65–110 kDa) and PRP Procedure: 1 US-guided inj.	HOOS questionnaire with pain score and function assessed before treatment (T0), at 2 (T1) and 6 (T2) months after treatment. All patients were evaluated by MRI and/or MRA before treatment (T0) and at 2 (T1) and 6 (T2) months after treatment.	Combined hf-HA 3.2% (HMW 1400–2100 kDa-LMW 65–110 kDa) + PRP IA shows early and lasting improvement in younger patients with a low-grade chondropathy. The combined treatment proved to be more effective vs the HMW HA treatment at T1 and T2 (P < 0.05). Follow-up in the mild grade arthropathy group and 75% of the high-grade arthropathy group revealed a significant clinical improvement and MRI. In the very high-grade arthropathy group, the combined treatment produced a clinical improvement in only 15% of patients, with MRI stability and similar results in both hf-HA + PRP IA therapy and HMW HA IA therapy.
Busilacchi^Citation29 2011, Prospective non controlled.	SHOULDER (CUFF, PATHOLOGY).	Cuff pathology four groups (Neer classification) with an added fourth group (cuff tear arthropathy).	Not reported.	Patients: 100 Treatment: HA 0.8% Procedure: 3 US-guided inj, one every 15 days.	None.	Follow up every 15 days (T0, T15, T30, T45 e T90), using VAS, OSS and Constant-Murley score.	In grades I and II, at day 30 of FU, a significant reduction of VAS and an increase in Constant-Murley and OSS were recorded. In grade IV, benefits were recorded for the first 45 days, while OSS and Constant Murley scores did not show any improvement.
Gigante^Citation28 2013 Prospective, open-label, non-controlled.	SHOULDER (PAIN).	Shoulder pain and reduction of ROM, allocated to 4 groups (Neer’s classification). X-ray and MRI performed.	<30 or >80 years, shoulder instability, SLAP lesions, arthritides, shoulder trauma, adhesive capsulitis/calcific tendonitis, previous subacromial injection therapies, diabetes, major depressive syndrome.	Patients: 100 Treatment: HA 0.8% Procedure: 1 US-guided inj. through the anterolateral way, one inj. every two weeks.	None.	Follow-up at 0, 15, 30, 45 and 90 days. VAS, OSS and Constant-Murley score.	In grades I and II, at day 45, a significant reduction of VAS and an increase in Constant-Murley and OSS scores were observed. In grade IV, VAS slowly decreased in the first 45 days, while OSS and Constant Murley scores did not improve significantly. Grade III patients had no clinical and subjective benefits. In grades I, II, and IV, the beneficial effect was still maintained at 90 days.
D’Avola^Citation34 2013, Retrospective.	HAND (CMC OA).	49–70 years, diagnosis of rhizarthrosis.	Not reported.	Patients: 52 Treatment: HA 0.8% (800–1200 kDa) Procedure: 1 US-guided inj./month for six months received only the IA HA.	Patients: 29 Treatment: HA 0.8% (800–1200 kDa), and oral CS 800 mg/day Procedure: 1 US guided inj. /month for 6 months CS 800 mg/day for 90 days.	Pain VAS at baseline and 1, 3 and 6 months after the first injection. One month after the end of treatment 6-point Likert scale as a secondary endpoint. Compliance and AE.	The IA injections of HA 0.8% (MW 800–1200 kDa) produced significant relief from pain by restoring the joint function during the whole follow-up. A more marked reduction of symptoms was observed in patients concomitantly treated with US-guided injection of HA and oral CS.
Bartoloni^Citation33 2019, Prospective pilot study.	HAND (CMC OA).	Symptomatic CMC OA; pain ≥40 VAS; KL evaluation.	Arthritides, major trauma, NSAIDs or HA and corticosteroid IA inj. within the previous month.	Patients: 12 Treatment: HA 3.2% (1400–2100 kDa/65–110 kDa) Procedure: 2 US-guided inj.	None.	Pain on the VAS scale and DASH questionnaire were recorded at T0 and 1, 3 and 6 months.	Reduction of pain and improvement of hand function. Efficacy on articular function was evident as early as the first month and persistent at six months of follow-up.
Tenti^Citation31 2017, Retrospective comparative.	HAND (CMC).	45–75 years, CMC OA, pain score >30 mm on VAS and a FIHOA score >6. Hand OA KL grades II and III.	Arthritides, septic arthritis, trauma or prior surgery of the hand, wrist, and elbow, coagulation disorders, severe co-morbidity. Patients taking SySADOAs, steroids and IA injection of any joint with HA during the previous six months.	Patients: 55 Treatment: HA 3.2% (1400–2100 kDa/65–110 kDa) Procedure: 2 inj. TO and after 15 days.	Patients: 45 Treatment: 0.5 mL of triamcinolone acetonide intraarticular. Procedure: 2 inj.: baseline and after 15 days.	The primary outcome criteria were the change of global hand pain VAS and FIHOA from baseline to month 6. Secondary outcomes were the change of the duration of morning stiffness, HAQ and SF 36 from T0 to month 6.	The hybrid formulation of HA may be more effective than triamcinolone in pain relief and joint function improvement with a rapid and persistent effect, resulting as a valid alternative to steroids in the management of CMC OA.
Callegari^Citation36 2011, Open-label, randomised study.	HAND (TRIGGER FINGER).	35 and 70 years with US-confirmed diagnosis of trigger finger.	Patients with grade IV TF or diabetes mellitus; RA; hypercholesterolaemia; hypotension; and hypertension.	Patients: 15 Treatment: HA 0.8% Procedure: MPA 40 mg/mL with 0.8mL lidocaine into the flexor sheath plus inj. of 1mL HA 0.8% ten days later.	Patients: 15 Treatment: Surgery Procedure: Surgical release of the first annular pulley.	DASH questionnaire, satisfaction VAS, pain VAS, before treatment and after six weeks, and 3, 6, and 12 months.	Fourteen patients (93.3%) in the treatment group showed a complete symptom resolution at six months, which persisted for 12 months in 11 patients (73.3%); 3 patients experienced recurrences and 1 reported no improvement. The 15 patients in the control group achieved complete resolution by three weeks after surgery; of these, ten patients needed physiotherapy or analgesics for a complete resolution of the symptoms.
Roux^Citation30 2007, Prospective randomised.	HAND (CMC OA).	VAS < 40 and refractory to other treatment. CMC OA KL grades II to IV, and met ACR criteria for hand OA.	Symptomatic OA in any other digit, use of steroid injection in the previous six months and previous use of HA injection. Subjects with blood coagulation abnormalities, infection, and hand trauma.	Patients: 42 Treatment: HA 0.8% Procedure: allocated to 4 groups: Group 1 (1 inj.); group 2 (2 inj.); and group 3 (3 inj.) at weekly intervals.	None.	Pain on a 100-point VAS. DFA Index for hand OA. Prospective follow-up parameters were pain, tolerability, and function at T0, 1 and 3 months.	No significant differences were found between each group for pain relief and function. However, the intra groups analysis results showed that IA injections into the thumb in OA could be efficacious on pain and function.

Abbreviations: ACR, American College Rheumatology; CMC, Carpometacarpal joint; CS, Chondroitin sulfate; DASH, Disabilities of the Arm, Shoulder and Hand questionnaire; CS, Chondroitin Sulfate; DFA, Dreiser Functional Index; FAI, Femoral-Acetabular Impingement; FIHOA, Functional Index for Hand Osteo Arthritis score; HA, Hyaluronic Acid; hf-HA, hybrid form Hyaluronic Acid; HHS, Harris Hip Score; IA, Intra articular; HAQ, Health Assessment Questionnaire; KL, Kellgren-Lawrence; MRI, Magnetic Resonance Imaging; MPA, Methylprednisolone acetate; OA, Osteoarthritis; OSS, Oxford-Shoulder-Score; RA, Rheumatoid Arthritis; TF, Trigger Finger; CMC, Carpometacarpal Joint; US, Ultrasound.

Table 5 Domains and Items Approved After Discussion

Domain	Item	Aggregation (%)
		7–9	4–6	1–3
1	Patients features. Characteristics of the patient to be considered before starting the VS.
1.1	Patients affected by primary OA can be a candidate to VS with HA	100	0	0
1.2	Patients affected by secondary OA can be a candidate to VS with HA	100	0	0
1.3	Patients with X-ray KL grades I-II–III are the better categories of patients affected by OA of the knee to treat with HA	92.9	7.1	0
1.4	In patients with X-ray KL grade IV affected by knee OA HA can be used in selected cases.	85.7	14.3	0
1.5	Patients with X-ray KL grades I-II–III hip OA are the most suitable patients for VS with HA	85.7	14.3	0
1.6	Patients affected by OA of the CMC with X-ray KL grades I-II-III-IV can be treated with HA	71.4	28.6	0
2	Risk of failure (Conditions and contraindications that are linked to increased risk of failure)
2.1	An isolated femoral patellar syndrome at the target knee is a condition linked to increased risk of failure.	64.3	28.6	7.1
2.2	Severe varus/valgus deformity in the target knee is a condition linked to increased risk of failure.	71.4	21.4	7.1
2.3	Viscosupplementation with HA is not indicated in active arthritides with acute synovitis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, etc.).	85.7	14.3	0
2.4	Viscosupplementation with HA is not indicated in crystal arthropathies with acute synovitis (eg chondrocalcinosis, gout, etc.).	100	0	0
2.5	Viscosupplementation with HA is not indicated in patients with active systemic sepsis.	100	0	0
2.6	Viscosupplementation with HA is contraindicated in patients with septic knee arthritis within the previous 3–6 months.	92.9	7.1	0
2.7	Viscosupplementation with HA is contraindicated in patients with hypersensitivity to HA.	92.9	7.1	0
2.8	Viscosupplementation with HA is contraindicated in the presence of an infected or seriously inflamed joint.	100	0	0
2.9	Viscosupplementation with HA is contraindicated in patients with cutaneous disease or infection in the area of the injection site.	92.9	7.1	0
2.10	Viscosupplementation with HA is not indicated in patients assuming double antiaggregant and NOACs. With NOACs, the injection in the knee is possible if performed by a skilled, senior doctor.	57.1	28.6	14.3
3	Clinical situations in which the VS with HA is considered appropriate
3.1	The use of HA in patients taking systemic NSAIDs is recommended to reduce the assumption of these drugs.	92.9	7.1	0
3.2	The concomitant use of HA in patients taking SySADOAs (chondroitin sulfate, glucosamine, etc.) may improve clinical efficacy.	92.9	0	7.1
3.3	A treatment model associating intra-articular HA to exercise and rehabilitative interventions can be useful to improve joint function.	92.9	0	7.1
3.4	In the case of multiple joint involvement, HA can be considered in different joints (at best step by step starting from the most painful joint).	85.7	7.1	7.1
3.5	The injection of HA after a failure of other viscosupplements, having significantly different characteristics from HA (MW, concentration, and volume), can be given to verify if the change of product is associated to a better clinical response.	85.7	14.3	0

Abbreviations: HA, hyaluronic acid; KL, Kellgren-Lawrence; MW, Molecular Weight; NOAC, Novel Anti Coagulant; NSAID, Nonsteroidal Anti-inflammatory drug; OA, Osteoarthritis; CMC, Carpometacarpal Joint; SySADOA, Symptomatic Slow Acting Drugs for Osteoarthritis; VS, Viscosupplementation.

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