Leonardo Punzi , Rhumatology Unit, Dpt Medicine, University of Padova, Italy

OSTEOARTHRITIS AND

HYALURONIC ACID

DISCLOSURES

Abbvie

Fidia SpA

Grunenthal

Menarini

Pfizer

MSD

Leonardo Punzi , Rhumatology Unit, University of Padova, Italy

• The most common form of chronic arthritis/joint disease

• Strongly related with age

radiological evidence in: 85% of aged at least 75 yrs, 50% of those over 65 yrs

radiographic OA of the knee joint: 70 % of the population over 60 yrs of age

• 15% of the population affected by symptomatic disease

• Most common reason for total hip and knee replacement

• Leading cause of chronic mobility disability

• Attributed annual costs (medical care and lost wages) ~ 65 millions in US

EPIDEMIOLOGY OF OSTEOARTHRITIS

Allen & Golyghty, Curr Opin Rheumatol, 2015

WARNINGS AND PRECAUTIONS

Al Ahabadi et al, SJGM 2016

BC guidelines, 2009

Oral NSAIDs

Guidelines for Elderly Patients with Osteoarthritis

Tramadol, Opioids, Duloxetin

KNEE OSTEOARTHRITIS IS A LOCAL DISEASE

…Needing (First) Local Treatments

• Topical NSAIDs

• Intra-articular corticosteroids

• Intra-articular hyaluronic acid

• Hyaluronic acid (HA) is a natural biological substance, a high-molecular weight

glycosaminoglycan

• It is a major component of ligament, tendon, and cartilage structure and of synovial fluid,

responsible for the visco-elastic properties of the latter.

• Since depolymerization of HA in the synovial fluid of OA was considered one of the main

causes of the mechanical pain, Balazs in 1960 first proposed to use the intra-articular (IA)

HA administration with the aim to restore the rheological properties of synovial fluid, called

visco-supplementation

• However many other mechanisms have been proposed, including an anti-inflammatory

effect

• Preclinical and clinical evidence support the hypothesis that this treatment modality can be

useful, and indeed, IA injections of HA have been shown to reduce pain and improve joint

function in OA in many studies

Peyron & Balazs, Pathol Biol, 1976

Punzi L et al, Clin Exp Rheumatol; 7:247-50, 1989

Kotevoglu N,et al. Rheumatol Int 2006;26:325–30

Petrella RJ, et al. Arch Intern Med 2002;162: 292–8

Tamir E, et al. Clin Exp Rheumatol 2001;19:265–70

INTRA-ARTICULAR HYALURONIC ACID

FDA APPROVED INTRA-ARTICULAR HYALURONIC ACID

Leonardo Punzi Cattedra ed Unità di Reumatologia, Azienda Ospedaliera Università di Padova

INTRA-ARTICULAR HYALURONIC ACID IN THE INTERNATIONAL RECOMMENDATIONS

OARSI recommended the usage of HA for knee and Hip OA

Part I: 2007

Part II: 2008

Part III: 2009

2014: uncertain recommendation for knee-only OA

Effect size (ES): 0.2=small, 0.5=moderate, > 0.8=large

Intra-articular Hyaluronic acid

in second line

• Longer-lasting pain control has been reported with IA HA compared with IA corticosteroids, possibly

delaying the need for total joint replacement

• No significant differences have been reported in symptom efficacy between IA HA and oral NSAIDs,

suggesting that IA HA might be a good alternative to oral NSAIDs in older patients with knee OA or in

those at a higher risk for NSAID-induced side effects

• A combination of IA HA and a corticosteroid often administered in the clinical setting, based on the

different mechanisms of action and trajectories of the two compounds:the rapid effect of corticosteroids

and the long-term effect of HA

• However, no clinical data are yet available from RCTs supporting such combined treatment

• The safety profile of IA HA has recently been questioned by a meta-analysis that reported a risk of side

effects (serious adverse events and local adverse events) in addition to therapeutic effects that barely

reached significance when the analysis was limited to a selected fraction of trials

• It is appropriate to point out that the considered studies were of poor methodological and reporting

quality, rendering questionable the final conclusion that IA HA is not safe

• Furthermore,this analysisis also in complete disagreement with the clinical setting,where only sporadic

flares and no severe systemic side effects have been reported after IA HA treatment.

COMMENTARY ON INTRA-ARTICULAR HYALURONIC ACID

Bannuru RR, et al. Osteoarthritis Cartilage 2011;19:611–9

Rutjes AW, et al. Ann Intern Med 2012;157:180–91

Bannuru RR, et al. Arthritis Rheum 2009;61:1704–11

Waddell DD,Bricker DC.J Manag Care Pharm 2007;13:113–21

Bannuru RR,et al. Semin Arthritis Rheum 2014;43:593–9

There are some problems…

• The lack of comprehensive comparative effectiveness studies that look at all modalities is making informed treatment decisions difficult

• Previous meta-analyses mostly looked at the efficacy of treatments vs. placebo only

– Oral NSAIDs vs. oral Placebo: 0.44 (0.34 to 0.55)

– IAHA vs. IA Placebo: 0.34 (0.22 to 0.46)

• In most treatment guidelines for knee OA, NSAIDs are recommended ahead of IA HA

• Not all IA HA are the same, in term of efficacy and safety

Forest plot of absolute treatment effects

0,00 5,00 10,00 15,00 20,00 25,00 30,00 35,00 40,00

Acetaminophen 19.55 (16.48, 22.85)

IA Placebo 21.97 (16.48, 27.46)

Celecoxib 22.85 (21.09, 24.83)

Naproxen 23.95 (21.53, 26.36)

Ibuprofen 25.27 (21.09, 29.44)

Diclofenac 27.02 (23.07, 30.76)

IA Corticosteroids 29.00 (22.63, 35.15)

IA Hyaluronic acid 29.44 (24.17, 34.93)

Red line at 20.00 represents the line of clinical significance.

Absolute Change from Baseline [ Scale, WOMAC (0-100)]

Effect size (ES): 0.2=small, 0.5=moderate, > 0.8=large