All procedures were performed in an outpatient setting with the patients receiving local anesthesia. The joint punctures were performed by three orthopaedic surgeons (GCC, AFP, RF) who had experience in viscosupplementation. If present, knee effusion was extracted before the injection. Patients were blinded (blocked from watching the procedures by the use of a windscreen sunshade and did not know to which group they were assigned). Patients with bilateral disease had both knees treated with the same drug, but only one knee (reported by the patient as the worst) was included in the study. All patients were discharged immediately after the procedures without any restrictions and with a prescription of 500 mg paracetamol that was to be administered every 6 hours for 3 days. All patients continued to receive usual care. The use of NSAIDs was forbidden.
The VAS, WOMAC™, and Lequesne questionnaires were given again at the scheduled visits at Weeks 1, 4, 12, and 24. The primary outcomes were improvements in knee pain and function, as expressed by the results of the questionnaires. Secondary outcomes were the presence of adverse effects (knee pain, effusion, or erythema at Week 1), and any correlation between the anthropometric data and the clinical outcomes.
The pain and functionality scales were described according to groups and times of assessments using summary measures. We compared the values between groups at each followup using ANOVA, followed by Tukey’s multiple comparison, to compare groups and followups, two by two.
Baseline scores were similar (p = 0.062 to p = 0.969) between the groups. At Week 1, Group VS + T showed improvement in all the scores (Table 3), with a difference from baseline. Group VS showed mild improvement at Week 1 (Table 3), with a difference from baseline (p = 0.009) only in VAS. Comparing the two groups, Group VS + T showed lower levels in WOMAC™ (p = 0.038) and VAS (p = 0.014) at Week 1.
Seventeen percent of all patients reported knee pain or discomfort and 4.8% had joint effusions after the injections. There were no differences between the groups (Table 4). One patient in Group VS presented with severe effusion and pain at Week 1 and was treated with arthrocentesis and an intraarticular corticosteroid injection. This patient was excluded from the study. All other cases of adverse events were mild, and the symptoms were relieved with ice, rest, and analgesics.
During the followup, the difference between the groups decreased and at Weeks 4, 12, and 24 there were no differences between the groups in any score. At 6 months followup, both groups showed similar values in WOMAC™ (p > 0.999), VAS (p > 0.999), and Lequesne index (p = 0.942).
Viscosupplementation remains a controversial OA treatment option, especially because of the delayed onset of pain and functional improvement. Adding corticosteroids to the procedure could speed the relief of symptoms owing to its fast mechanism of action. We therefore addressed three questions: Does the addition of triamcinolone to viscosupplementation (1) improve first-week pain and function compared with viscosupplementation alone, (2) diminish adverse effects of viscosupplementation alone, and (3) alter 6-month pain and function of viscosupplementation alone?
Our study had some limitations. First, we did not limit the use of analgesics or any other nonpharmacologic treatment. We believe that viscosupplementation is a procedure that should not exclude any other type of treatment for OA, therefore, patients received usual care but were asked to keep track of the use of analgesics, with no differences between groups. Second, clinical scores, such as the WOMAC™ and Lequesne, cannot distinguish one knee from another when the patient has bilateral OA. Therefore, patients with bilateral disease had both knees treated with the same drug and only the knee reported as the worst by the patient was considered and classified with the Kellgren and Lawrence grade. Third, we had no saline injection placebo group. Several studies [3, 7, 8, 11, 22] have compared viscosupplementation versus placebo and intraarticular corticosteroid versus placebo [6, 15, 26] (Table 5). We also were able to have a control group that received treatment (VS), conducting a study without the ethical issues of using a placebo group. Fourth, most of the HA products are supposed to be administered three to five times on a weekly injection basis. The regimen adopted for this study was a single injection of 6 mL of hylan GF-20, which is accepted only for this particular product . Fifth, there was concern regarding the chondrotoxicity of intraarticular corticosteroid injections , but after a review of the literature [6, 15] we concluded there was enough safety evidence on this matter. One 2-year followup randomized clinical trial showed no loss of joint space width after the intraarticular injection of triamcinolone hexacetonide at 3-month intervals . Sixth, no objective methods were performed to evaluate disease progression, such as joint space width  or MRI [9, 17]. It would bring complexity and the necessity of a longer followup.
We observed improvement in all patients, but the VAS and WOMAC™ scores decreased to lower levels and sooner in Group VS + T. This phenomenon can be explained by the faster pain relief and function improvement for intraarticular corticosteroid injections [4, 6, 15]. The charts (Fig. 2) showed two different curve patterns for each group until Week 4, probably owing to the effect of the corticosteroid. Group VS showed a smoother curve, denoting the more modulating mechanism of action of the HA.
Adverse events, such as knee effusion, pain, heat, and erythema, may occur in approximately 4.2% of the patients . HA injections also may lead to an acute arthritis  owing to an allergic reaction or foreign body reaction. The addition of triamcinolone should reduce the frequency and severity of such reactions. In our study, one patient from Group VS had a severe reaction. Both groups had a higher rate of pain and similar rate of effusions, as seen in the literature (ranging from 0.1% to 8.1% [3, 7, 19]). However, there was no difference between the groups regarding adverse events. Since the pseudoseptic reaction is a rare event , it might be necessary to have a larger number of patients to reach any conclusion on that matter.
We found no differences in WOMAC™, VAS, and Lequesne values at 6 months’ followup. Despite the similar clinical outcomes, we do not know whether the addition of steroids will affect the disease modification effect of the HA. The osteoarthritic chondrocytes are deficient in glucocorticoid receptors, and a poor response to circulating steroids may be one of the factors involved with the higher levels of cytokines and metalloproteinases in an osteoarthritic joint . Therefore, in addition to improving first-week pain and function scores of viscosupplementation, one can speculate that triamcinolone could positively affect the action in disease progression. More studies are needed on this matter. Regarding the type of HA used for viscosupplementation, there is no convincing evidence of one product being superior over another regarding molecular weight, concentration, or the number of crosslinks [3, 11]. We believe that our results can be extrapolated to the viscosupplementation procedure in general.
The addition of 1 mL of triamcinolone hexacetonide improved the first-week symptom and functional scores of viscosupplementation, and it did not alter its adverse effects or the 6-month symptom and functional improvement.
We thank Rogerio Ruscitto do Prado MSc, for helping with the statistical analysis.
1. Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., Christy, W., Cooke, TD., Greenwald, R., Hochberg, M. et al.
Development of criteria for the classification and reporting of osteoarthritis: classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum.
1986; 29: 1039-1049. 10.1002/art.1780290816
2. Balazs, EA., Watson, D., Duff, IF. and Roseman, S. Hyaluronic acid in synovial fluid: I. Molecular parameters of hyaluronic acid in normal and arthritis human fluids. Arthritis Rheum.
1967; 10: 357-376. 10.1002/art.1780100407
3. Bannuru, RR., Natov, NS., Dasi, UR., Schmid, CH. and McAlindon, TE. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis: meta-analysis. Osteoarthritis Cartilage.
2011; 19: 611-619. 10.1016/j.joca.2010.09.014
4. Bannuru, RR., Natov, NS., Obadan, IE., Price, LL., Schmid, CH. and McAlindon, TE. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum.
2009; 61: 1704-1711. 10.1002/art.24925
5. Bellamy, N., Buchanan, WW., Goldsmith, CH., Campbell, J. and Stitt, LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol.
1988; 15: 1833-1840.
6. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev
7. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev
8. Chevalier, X., Jerosch, J., Goupille, P., Dijk, N., Luyten, FP., Scott, DL., Bailleul, F. and Pavelka, K. 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: 113-119. 10.1136/ard.2008.094623
9. Conaghan, PG., Hunter, DJ., Maillefert, JF., Reichmann, WM. and Losina, E. Summary and recommendations of the OARSI FDA osteoarthritis Assessment of Structural Change Working Group. Osteoarthritis Cartilage.
2011; 19: 606-610. 10.1016/j.joca.2011.02.018
10. DiBattista, JA., Martel-Pelletier, J., Wosu, LO., Sandor, T., Antakly, T. and Pelletier, JP. Glucocorticoid receptor mediated inhibition of interleukin-1 stimulated neutral metalloprotease synthesis in normal human chondrocytes. J Clin Endocrinol Metab.
1991; 72: 316-326. 10.1210/jcem-72-2-316
11. Divine, JG., Zazulak, BT. and Hewett, TE. Viscosupplementation for knee osteoarthritis: a systematic review. Clin Orthop Relat Res.
2007; 455: 113-122. 10.1097/BLO.0b013e31802f5421
12. Goldberg, VM. and Coutts, RD. Pseudoseptic reactions to hylan viscosupplementation: diagnosis and treatment. Clin Orthop Relat Res.
2004; 419: 130-137. 10.1097/00003086-200402000-00021
13. Gomis, A., Miralles, A., Schmidt, RF. and Belmonte, C. Intra-articular injections of hyaluronan solutions of different elastoviscosity reduce nociceptive nerve activity in a model of osteoarthritic knee joint of the guinea pig. Osteoarthritis Cartilage.
2009; 17: 798-804. 10.1016/j.joca.2008.11.013
14. Guidolin, DD., Ronchetti, IP., Lini, E., Guerra, D. and Frizziero, L. Morphological analysis of articular cartilage biopsies from a randomized, clinical study comparing the effects of 500-730 kDa sodium hyaluronate (Hyalgan) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthritis Cartilage.
2001; 9: 371-381. 10.1053/joca.2000.0398
15. Hepper, CT., Halvorson, JJ., Duncan, ST., Gregory, AJ., Dunn, WR. and Spindler, KP. The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: a systematic review of level I studies. J Am Acad Orthop Surg.
2009; 17: 638-646.
16. Hollander, JL., Brown, EM, Jr, Jessar, RA. and Brown, CY. Hydrocortisone and cortisone injected into arthritic joints: comparative effects of and use of hydrocortisone as a local antiarthritic agent. JAMA.
1951; 147: 1629-1635. 10.1001/jama.1951.03670340019005
17. Hunter, DJ., Zhang, W., Conaghan, PG., Hirko, K., Menashe, L., Li, L., Reichmann, WM. and Losina, E. Systematic review of the concurrent and predictive validity of MRI biomarkers in OA. Osteoarthritis Cartilage.
2011; 19: 557-588. 10.1016/j.joca.2010.10.029
18. Kellgren, JH. and Lawrence, JS. Radiological assessment of rheumatoid arthritis. Ann Rheum Dis.
1957; 16: 485-493. 10.1136/ard.16.4.485
19. Kemper, F., Gebhardt, U., Meng, T. and Murray, C. Tolerability and short-term effectiveness of hylan G-F 20 in 4253 patients with osteoarthritis of the knee in clinical practice. Curr Med Res Opin.
2005; 21: 1261-1269. 10.1185/030079905X56501
20. Lequesne, MG. The algofunctional indices for hip and knee osteoarthritis. J Rheumatol.
1997; 24: 779-781.
21. Lussier, A., Cividino, AA., McFarlane, CA., Olszynski, WP., Potashner, WJ. and Medicis, R. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol.
1996; 23: 1579-1585.
22. Navarro-Sarabia, F., Coronel, P., Collantes, E., Navarro, FJ., Serna, AR., Naranjo, A., Gimeno, M. and Herrero-Beaumont, G. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis.
2011; 70: 1957-1962. 10.1136/ard.2011.152017
23. Ozturk, C., Atamaz, F., Hepguler, S., Argin, M. and Arkun, R. The safety and efficacy of intraarticular hyaluronan with/without corticosteroid in knee osteoarthritis: 1-year, single-blind, randomized study. Rheumatol Int.
2006; 26: 314-319. 10.1007/s00296-005-0584-z
24. Papachristou, G., Anagnostou, S. and Katsorhis, T. The effect of intraarticular hydrocortisone injection on the articular cartilage of rabbits. Acta Orthop Scand Suppl.
1997; 275: 132-134.
25. Prieto, JG., Pulido, MM., Zapico, J., Molina, AJ., Gimeno, M., Coronel, P. and Alvarez, AI. Comparative study of hyaluronic derivatives: rheological behaviour, mechanical and chemical degradation. Int J Biol Macromol.
2005; 35: 63-69. 10.1016/j.ijbiomac.2004.12.003
26. Raynauld, JP., Buckland-Wright, C., Ward, R., Choquette, D., Haraoui, B., Martel-Pelletier, J., Uthman, I., Khy, V., Tremblay, JL., Bertrand, C. and Pelletier, JP. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum.
2003; 48: 370-377. 10.1002/art.10777
27. Reichmann, WM., Maillefert, JF., Hunter, DJ., Katz, JN., Conaghan, PG. and Losina, E. Responsiveness to change and reliability of measurement of radiographic joint space width in osteoarthritis of the knee: a systematic review. Osteoarthritis Cartilage.
2011; 19: 550-556. 10.1016/j.joca.2011.01.023
28. Wang, CT., Lin, YT., Chiang, BL., Lin, YH. and Hou, SM. High molecular weight hyaluronic acid down-regulates the gene expression of osteoarthritis-associated cytokines and enzymes in fibroblast-like synoviocytes from patients with early osteoarthritis. Osteoarthritis Cartilage.
2006; 14: 1237-1247. 10.1016/j.joca.2006.05.009
29. Wang, Y., Hall, S., Hanna, F., Wluka, AE., Grant, G., Marks, P., Feletar, M. and Cicuttini, FM. Effects of Hylan G-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial. BMC Musculoskelet Disord.
2011; 12: 195. 10.1186/1471-2474-12-195
30. Yasuda, T. Hyaluronan inhibits prostaglandin E2 production via CD44 in U937 human macrophages. Tohoku J Exp Med.
2010; 220: 229-235. 10.1620/tjem.220.229
31. Zhang, W., Nuki, G., Moskowitz, RW., Abramson, S., Altman, RD., Arden, NK., Bierma-Zeinstra, S., Brandt, KD., Croft, P., Doherty, M., Dougados, M., Hochberg, M., Hunter, DJ., Kwoh, K., Lohmander, LS. and Tugwell, P.OARSI recommendations for the management of hip and knee osteoarthritis: Part III. Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage.
2010; 18: 476-499. 10.1016/j.joca.2010.01.013