Florent Eymard

Biologic agents in osteoarthritis: hopes and disappointments

New treatment options are needed for osteoarthritis (OA) to slow down the structural progression of the disease; current therapies mostly target pain and function with minimal effectiveness. OA results from an imbalance between catabolic and anabolic factors, and biologic agents either target specific catabolic proinflammatory mediators, such as cytokines, nitric oxide synthesis, or affect anabolism more generally. Biologic agents have dramatic effects in other rheumatic inflammatory diseases such as rheumatoid arthritis; they were hoped to have similar effects in the treatment of OA. In this Review, we will discuss the three main types of cytokine blockers used in knee and hand OA, which target β-nerve growth factor (β-NGF), IL-1β or TNF. We will also discuss inhibitors of nitrogen oxide production and the use of growth factors to treat OA. Among the targeted agents, anti-β-NGF therapy has shown promising results, although cases of rapid destructive arthropathy caution against its widespread use. The future of therapies targeting cytokines, nitrogen oxide synthesis and growth factors in OA is questionable, as results from clinical trials have been repeatedly negative. Strategies in OA therapy need to be reconsidered. New molecules emerging from preclinical data should focus on treating the early phase of the disease where damage may be reversible, and treatment should be modified to fit each patient.

Diabetes is a risk factor for knee osteoarthritis progression

PURPOSE Recent studies have suggested that metabolic factors (obesity, diabetes, hypertension and dyslipidemia) and their clustering in metabolic syndrome (MetS) might be involved in the pathophysiology of knee osteoarthritis (OA). We investigated their impact on radiographic progression by an annualised measure of the joint space narrowing (JSN) of the medial tibiofemoral compartment. METHODS 559 patients older than 50 years with symptomatic knee OA were recruited for the placebo arm of the SEKOIA trial. The presence of diabetes, hypertension and dyslipidemia was determined at baseline interview. Body mass index (BMI) was calculated, obesity was considered >30 kg/m(2). MetS was defined by the sum of metabolic factors ≥ 3. Minimal medial tibiofemoral joint space on plain radiographs was measured by an automated method at baseline and then annually for up to 3 years. RESULTS The mean age of patients was 62.8 [62.2-63.4] years; 392 were women. A total of 43.8% was obese, 6.6% had type 2 diabetes, 45.1% hypertension, 27.6% dyslipidemia and 13.6% MetS. Mean annualised JSN was greater for patients with type 2 diabetes than without diabetes (0.26 [-0.35 to -0.17] vs 0.14 [-0.16 to -0.12] mm; P = 0.001). This association remained significant after adjustment for sex, age, BMI, hypertension and dyslipidemia (P = 0.018). In subgroup analysis, type 2 diabetes was a significant predictor of JSN in males but not females. The other metabolic factors and MetS were not associated with annualised JSN. CONCLUSION Type 2 diabetes was a predictor of joint space reduction in men with established knee OA. No relationships were found between MetS or other metabolic factors and radiographic progression.

Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias

Background The effectiveness of intra-articular hyaluronic acid (IAHA) injection for knee osteoarthritis (KOA) is debated. Objectives To evaluate the effect of IAHA for patients with KOA by analysing data from trials of IAHA versus placebo with low risk of bias, to provide the highest level of evidence. Methods A systematic review and meta-analysis was conducted. Randomised controlled trials (RCTs) with a low risk of bias (adequate randomisation and concealment and double-blind design) that investigated IAHA versus placebo (saline solution) injection were eligible. The primary efficacy measure was pain intensity and secondary outcome function at 3 months. The treatment effect was summarised with the standardised mean difference (SMD) calculated from differences in means of pain and function measures between treatment and control groups at 3 months. Trials were pooled by a random-effects model with DerSimonian and Laird weights. Statistical heterogeneity was explored by a visual exploration of forest plots and the I2 statistic. Results A total of eight RCTs (2 199 randomised patients) met our inclusion criteria. IAHA significantly reduced the pain intensity (SMD=−0.21, 95% CI (95% CI) −0.32 to −0.10) and improved function (SMD=−0.12, 95% CI −0.22 to −0.02). Trials showed no heterogeneity. Conclusions This meta-analysis of high-quality trials of IAHA versus placebo shows that IAHA provides a moderate but real benefit for patients with KOA.

Inflammation of the infrapatellar fat pad.

The infrapatellar fat pad (IFP) of Hoffas fat pad is the main adipose structure within the knee joint. It is located between the joint capsule and the synovial membrane, which lines its posterior aspect. The IFP is composed chiefly of adipocytes and receives an abundant supply of blood vessels and nerves. Immune cells can infiltrate the IFP, which can become a major source of numerous proinflammatory mediators (cytokines and adipokines). The physiological role for the IFP remains unclear but may involve shock absorption and the protection of adjacent tissues. Hoffas disease is characterized by inflammation, hypertrophy, and fibrosis of the pad in response to repetitive trauma. Anterior knee pain is the most common symptom. In advanced forms, metaplasia of the IFP may result in the development of a sometimes sizable osteochondroma. The IFP may also contribute to the pathophysiology of knee osteoarthritis, in particular via procatabolic and proinflammatory effects on its synovial lining. Finally, in patients with knee osteoarthritis, inflammation of the IFP may be a source of pain.

Safety and efficacy of intra-articular injections of a combination of hyaluronic acid and mannitol (HAnOX-M) in patients with symptomatic knee osteoarthritis: Results of a double-blind, controlled, multicenter, randomized trial.

BACKGROUND To compare both safety and efficacy of a novel intra-articular viscosupplement made of intermediate molecular weight (MW) hyaluronic acid (HA) mixed with high concentration of mannitol with a marketed high MW HA, in patients with knee osteoarthritis (OA). METHODS Patients with symptomatic knee OA, with radiological OARSI grades 1 to 3, were enrolled in a controlled, double-blind, parallel-group, non-inferiority trial. They were randomized to receive three intra-articular injections, at weekly intervals, of either HAnOX-M made of a combination of HA (MW one to 1.5MDa, 31mg/2ml) and mannitol (70mg/2ml) or Bio-HA (MW 2.3 to 3.6MDa, 20mg/2ml). The primary outcome was six-month change in the WOMAC pain subscale (0 to 20). Sample size was calculated according to a non-inferiority margin of 1.35. Secondary endpoints included six-month change in function and walking pain, analgesic consumption and safety. RESULTS The intention-to-treat (ITT) and per-protocol (PP) populations consisted of 205 and 171 patients. HAnOX-M and Bio-Ha groups did not differ statistically at baseline. The primary analysis was conducted in the PP population, then in the ITT population. The average WOMAC pain score at baseline was 9.5 in both groups. Mean (SD) variations in WOMAC pain score were -4.4 (3.8) and -4.5 (4.3) mm, for HAnOX and Bio-HA respectively, satisfying the claim for non-inferiority. Similar results were obtained for all other secondary endpoints. CONCLUSION Treatment with of HAnOX-M is effective to alleviate knee OA symptoms and to improve joint function over six months, with similar safety than conventional HA viscosupplement.

Obesity and radiological severity are associated with viscosupplementation failure in patients with knee osteoarthritis

Viscosupplementation (VS) is still controversial. One of the key points is the lack of well‐identified factors of response. We aimed to identify clinical and radiological factors associated with lack of relevant response after intra‐articular (IA) hyaluronic acid (HA) injections in symptomatic knee osteoarthritis patients. A post hoc analysis of the HAV‐2012 trial, a controlled, multicentre, double‐blind, randomized, non‐inferiority trial comparing 3 weekly IA injections of HA (HAnox‐M or BioHA) for symptomatic tibiofemoral OA was performed. At inclusion, demographic, anthropometric, clinical data (WOMAC score, patient global assessment, presence of knee effusion), and radiological data (OARSI grade, patello‐femoral involvement) were recorded. VS response was defined according to OMERACT–OARSI response criteria at month 6. Predictors of response were investigated in univariate then in multivariate analysis. One hundred and sixty‐six patients with full available data were included. As baseline characteristics and treatment effectiveness were similar between the 2 HA groups, their data were pooled. The mean age was 65.2 [63.7–66.8] years; 101 (60.8%) were women; 73 (44.0%) had severe TF space narrowing. At 6 months, 113 patients (68.1%) were responders. Multivariate analysis showed that obesity (BMI ≥30 kg/m2) and radiological severity (OARSI grade 3) were significantly associated with VS failure (p = 0.001 and p = 0.008, respectively). Moreover, the association of obesity and severe TF space narrowing significantly increased the risk of VS failure. Baseline pain intensity and functional impairment were not associated with VS response. Consequently, IA injection of HA for knee OA should mainly be considered in subjects with low BMI and mild TF space narrowing.

Predictors of response to viscosupplementation in patients with hip osteoarthritis: results of a prospective, observational, multicentre, open-label, pilot study

BackgroundTo identify predictive factors of response to viscosupplementation (VS) in patients with hip osteoarthritis (HOA).MethodsProspective, multicentre, open-label trial, achieved in daily practice conditions. Patients with HOA were treated with a single intra-articular injection of a cross-linked hyaluronic acid combined with mannitol (HAnox-M-XL), using imaging guidance. WOMAC pain and function scores and patient global assessment (PGA) were assessed at baseline and day 90. Improvement, satisfaction and efficacy were self-assessed at day 90.Hip radiographs at baseline were scored using Kellgren-Lawrence grade and Osteoarthritis Research Society International (OARSI) score. Associations between clinical and radiological features and response to VS (pain improvement > 50% at day 90) were assessed in univariate analysis, and then using logistic regression, adjusted for confounding factors.ResultsThe intent-to-treat (ITT) population included 97 patients (57 females, mean age 63). Ninety completed the follow-up and 80 had full clinical and radiological data. Response to VS was achieved in 47.8% of patients. In univariate analysis, the only clinical outcome statistically and negatively related to response was PGA at baseline (p = 0.047). Radiologically, response to VS was negatively correlated with joint space narrowing (JSN) score (JSN < 2 vs. JSN ≥ 2, p = 0.01) and was related to the patterns of femoral head migration (p = 0.008). In multivariate analysis, only JSN grade (p = 0.03) remained significantly related to a poor response.ConclusionThis pilot study, which needs further confirmation by larger scale trials, suggests that radiological features might be of importance for the decision of VS in patients with HOA.Trial registration numberID RCB N°2013-A00165-40. Registered 31 January 2013.

Statin use and knee osteoarthritis progression: Results from a post-hoc analysis of the SEKOIA trial

OBJECTIVE Epidemiological and experimental studies have suggested that lipid disorders might be involved in the pathophysiology of knee osteoarthritis (OA). Studies assessing the effect of statins on knee OA progression have shown conflicting results. We investigated the impact of statin use on radiological progression in patients with radiological and symptomatic knee OA. METHODS In total, 336 patients from the placebo arm of SEKOIA trial completed the 3-year follow-up and were included in this post-hoc analysis. Statin use was recorded at baseline interview. Minimal medial tibiofemoral joint space was measured on plain radiographs by an automated method at baseline and then annually. Radiologic progression was defined as joint space narrowing≥0.5mm over 3 years. RESULTS Overall, 71 patients were statin users (21.1%). They had a higher BMI (31.1±5.3 vs. 29.3±5.2kg/m2, P=0.008), a higher sum of metabolic factors (≥3 factors: 43.7% vs 7.2%; P for trend<0.001) and a higher rate of radiological progression (49.3% vs. 32.1%, P=0.007) as compared to statin non-users. The significant association between radiological progression and statin use was independent of age, gender, WOMAC global score, disease duration, baseline joint space width, hypertension, type 2 diabetes, obesity (BMI>30kg/m2) and cardiovascular diseases [relative risk 1.49 (95% CI: 1.10-2.02), P=0.010]. CONCLUSION Among patients with knee OA, statin use was associated with radiological worsening over 3 years, regardless of other potential confounding factors (obesity, type 2 diabetes, hypertension, disease duration, symptom intensity and radiological severity).

Addition of Mannitol to Hyaluronic Acid may Shorten ViscosupplementationOnset of Action in Patients with Knee Osteoarthritis: Post-Hoc Analysis of ADouble-blind, Controlled Trial

Objectives: To compare the speed of action of three weekly intra-articular injections of a combination of hyaluronic acid and mannitol (HAnox-M) with that of hyaluronic acid alone (BioHA), in patients with knee osteoarthritis (OA). Methods: Post-hoc analysis of a randomized, double blind, controlled trial demonstrating the non-inferiority of an association HAnox-M compared to BioHA at month 6 after injections. Data from 205 patients with symptomatic knee OA (Intent-to-Treat population) were retrospectively analyzed. The primary outcome was 1 and 2 week change in the WOMAC pain subscale (0-20). The number and percentage of improved patients at week 1 and 2 were also studied, as well as the level of improvement. Results: HAnox-M and BioHA groups were not statistically different at baseline and month 6. The median WOMAC pain score at baseline was 9 in both groups. It was 6.0 and 5.0 in the HAnox-M group at Week 1 and Week 2 respectively. It was 7.0 and 6.0 in the BioHA group, namely a decrease of 1 more point in favor of HANOX, obtained from as soon as the 1st injection. At month 3 and 6 the results were identical (5.0 and 4.0 respectively) for both groups. In subjects with grade 3 joint space narrowing (N=84) the decrease of pain (SD) was significantly greater at week 3 in patients treated with HAnox-M than in those treated with Bio-HA:-4.2 (3.2) versus -2.8 (2.6) respectively (p=0.048). Conclusion: In patients with symptomatic knee osteoarthritis, addition of mannitol to HA may shorten the onset of action of viscosupplementation, chiefly in patients with advanced stage of the disease.