Xavier Chevalier

Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial

Background Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. Methods Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5–5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). Results The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: −0.23 (SD 0.56) mm; 2 g/day: −0.27 (SD 0.63) mm; placebo: −0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. Conclusions Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.

Immunohistological study of entheses in spondyloarthropathies: comparison in rheumatoid arthritis and osteoarthritis

OBJECTIVE To determine which inflammatory cell types are present in entheses from patients with spondyloarthropathy (SpA) compared with patients with rheumatoid arthritis (RA) or osteoarthritis (OA). METHODS Enthesis specimens were obtained during orthopaedic procedures in eight patients with SpA, four with RA, and three with OA. After decalcification, the lymphocyte subsets (CD3, CD4, CD8, CD20) in the bone marrow component of each enthesis were measured by an immunohistochemical technique. RESULTS Oedema and an inflammatory infiltrate were present in all the SpA specimens, being clearly predominant in the bone marrow component of the entheses. The density of all cell types in the bone marrow was significantly higher in the SpA group than in the two other groups. The cell type CD3+ showed the greatest difference between the SpA and RA groups, being increased fivefold in the SpA group. Within the SpA group, CD3+ cells were considerably more numerous than CD20+ cells—a difference from the RA group—and the predominant T cells were CD8+. CONCLUSION Persistent oedema with an inflammatory infiltrate composed predominantly of CD8+ cells was noted in the entheses of patients with SpA, being predominant in the bone marrow. These results suggest that CD8+ cells may have a key role in local inflammation in SpAs.

Benefits of massive weight loss on symptoms, systemic inflammation and cartilage turnover in obese patients with knee osteoarthritis

Objective To investigate the effect of massive weight loss on (1) knee pain and disability, (2) low-grade inflammation and metabolic status and (3) joint biomarkers in obese patients with knee osteoarthritis (OA). Methods 140 patients involved in a gastric surgery programme were screened for painful knee OA, and 44 were included (age 44 ± 10.3 years, body mass index (BMI) 50.7 ± 7.2 kg/m2). Clinical data and biological samples were collected before and 6 months after surgery. Results Before surgery, interleukin 6 (IL-6) levels were correlated with levels of high-sensitivity C reactive protein (hsCRP) (p=0.006) and Helix-II (p=0.01), a biomarker of cartilage turnover, and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score (p=0.03). Surgery resulted in substantial decrease in BMI (−20%). Levels of insulin and insulin resistance were decreased at 6 months. Knee pain decreased after surgery (24.5 ± 21 mm vs 50 ± 26.6 mm; p<0.001), and scores on all WOMAC subscales were improved. Levels of IL-6 (p<0.0001), hsCRP (p<0.0001), orosomucoid (p<0.0001) and fibrinogen (p=0.04) were decreased after surgery. Weight loss resulted in a significant increase in N-terminal propeptide of type IIA collagen levels (+32%; p=0.002), a biomarker of cartilage synthesis, and a significant decrease in cartilage oligomeric matrix protein (COMP) (−36%; p<0.001), a biomarker of cartilage degradation. Changes in COMP concentration were correlated with changes in insulin levels (p=0.02) and insulin resistance (p=0.05). Conclusion Massive weight loss improves pain and function and decreases low-grade inflammation. Change in levels of joint biomarkers with weight loss suggests a structural effect on cartilage.

The Infrapatellar Fat Pad in Knee Osteoarthritis: An Important Source of Interleukin-6 and Its Soluble Receptor

OBJECTIVE Obesity is a potent risk factor in knee osteoarthritis (OA). It has been suggested that adipokines, secreted by adipose tissue (AT) and largely found in the synovial fluid of OA patients, derive in part from the infrapatellar fat pad (IFP), also known as Hoffas fat pad. The goal of this study was to characterize IFP tissue in obese OA patients and to compare its features with thigh subcutaneous AT to determine whether the IFP contributes to local inflammation in knee OA via production of specific cytokines. METHODS IFP and subcutaneous AT samples were obtained from 11 obese women (body mass index > or =30 kg/m2) with knee femorotibial OA. Gene expression was measured by real-time quantitative polymerase chain reaction. Cytokine concentrations in plasma and in conditioned media of cultured AT explants were determined by enzyme-linked immunosorbent assay or by Luminex xMAP technology. RESULTS In IFP tissue versus subcutaneous AT, there was a decrease in the expression of genes for key enzymes implicated in adipocyte lipid metabolism, whereas the expression levels of genes for AT markers remained similar. A 2-fold increase in the expression of the gene for interleukin-6 (IL-6), a 2-fold increase in the release of IL-6, and a 3.6-fold increase in the release of soluble IL-6 receptor (sIL-6R) were observed in IFP samples, compared with subcutaneous AT, but the rates of secretion of other cytokines in IFP samples were similar to the rates in subcutaneous AT. In addition, leptin secretion was decreased by 40%, whereas adiponectin secretion was increased by 70%, in IFP samples versus subcutaneous AT. CONCLUSION Our results indicate that the IFP cytokine profile typically found in OA patients could play a role in paracrine inflammation via the local production of IL-6/sIL-6R and that such a profile might contribute to damage in adjacent cartilage.

Management of nontuberculous infectious discitis. treatments used in 110 patients admitted to 12 teaching hospitals in France.

The optimal management of pyogenic discitis is not agreed on. No randomized clinical trials of short-course or oral antibiotic regimens have been published to date. To shed light on this issue, we reviewed the management of patients admitted for pyogenic discitis to one of 12 networked rheumatology departments. In this cross-sectional observational study, each department included the first ten patients admitted starting in January 1997 for treatment of pyogenic discitis. One hundred ten patients met the inclusion criteria, 67 men and 43 women, with a mean age of 60.6 +/- 13.7 years (range, 17-86 years). Mean time from symptom onset to diagnosis was 39.6 +/- 39.8 days (range, 24 h-240 days). Blood cultures were positive in 47.3% of patients, and the percutaneous discal and vertebral biopsy in 63.6% of cases; these two investigations identified the causative organism in 79 cases (72.8%). Mean duration of the rheumatology department stay was 31.3 +/- 14.1 days (range, 4-78 days). Antibiotics were given intravenously to 103 (93.6%) patients, for a mean of 25.5 +/- 17.6 days (range, 4-124 days); duration of intravenous antibiotic therapy was longer than 4 weeks in 36.5% of patients. Only seven (6.4%) patients received primary oral antibiotics with no parenteral antibiotics. One hundred patients were given oral antibiotics at the same time as and after intravenous antibiotics, for a mean duration of 87.2 +/- 43.6 day (range, 20-278 days); Bracing was used in 98 (89.1%) patients. Although antibiotic selection was rational and in agreement with current recommendations, wide differences were noted across centers regarding intravenous treatment duration, hospital stay duration, and total treatment duration.

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.

Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.

Effect of Hyaluronic Acid in Symptomatic Hip Osteoarthritis : A Multicenter, Randomized, Placebo-Controlled Trial

OBJECTIVE To evaluate the efficacy and tolerability of a single intraarticular (IA) injection of hyaluronic acid (HA) for the treatment of hip osteoarthritis (OA). METHODS A multicenter, randomized, parallel-group, placebo-controlled trial was conducted over 3 months. Patients (older than 30 years) with symptomatic hip OA (pain score of >40 mm on a visual analog scale [VAS]) and a Kellgren/Lawrence grade of 2 or 3 were randomly assigned to receive 1 fluoroscopically guided IA injection of HA (2.5 ml) or placebo (2.5 ml). Patients were followed up for 3 months. The main outcome measure was pain score on a VAS (100 mm) at month 3 compared with baseline. Secondary outcome measures were the proportion of responders defined by Osteoarthritis Research Society International criteria; Western Ontario and McMaster Universities Osteoarthritis Index subscores for pain, stiffness, and disability; and patient and physician global assessment. Randomization was computer generated. HA and placebo preparations were placed in numbered identical containers, and syringes were covered with masking tape. Physicians assessing outcomes were blinded with regard to group assignment. RESULTS Eighty-five patients were randomized to the HA group (n = 42) or placebo group (n = 43). Baseline characteristics were similar between the 2 groups. At 3 months, the decrease in pain score did not differ between the HA and placebo groups in the intent-to-treat analysis (mean +/- SD decrease 7.8 +/- 24.9 mm with HA versus 9.1 +/- 27.4 mm with placebo; P = 0.98). The responder rates were 33.3% and 32.6% in the HA and placebo groups, respectively (P = 0.94). Other secondary end points did not differ between the groups, nor did use of rescue medication or frequency of adverse events. CONCLUSION Our findings indicate that a single IA injection of HA is no more effective than placebo in treating the symptoms of hip OA.

Adherence to, and results of, physical therapy programs in patients with hip or knee osteoarthritis. Development of French clinical practice guidelines.

OBJECTIVE To develop recommendations regarding adherence to physical therapy programs by patients with hip or knee osteoarthritis. METHODS We used the method recommended by the French Society for Physical and Rehabilitation Therapy (SOFMER), which combines a systematic literature review, a practice survey, and validation by a multidisciplinary panel of experts. RESULTS When setting up exercise programs for patients with lower limb osteoarthritis, measures should be taken to increase effectiveness by optimizing adherence. Patient selection is among these measures, as exercise programs are more likely to succeed in patients with a history of being physically active, a positive view of the suggested program, and/or favorable social and material conditions. Regardless of the type of exercise, the program should be tailored to exercise capacity and pain level (professional consensus). Patient adherence can be improved by explaining the expected results to the patient, asking the patient to keep a self-evaluation diary, conducting long-term evaluations (by phone or mail), and providing follow-up visits. CONCLUSION Studies of adherence according to the type of exercise are needed. The relevance of widely used incentives in patients with hip or knee osteoarthritis should be evaluated in new therapeutic trials.

A randomised, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee osteoarthritis

Objectives To compare the effects of an intermediate molecular weight (MW) intra-articular hyaluronic acid (HA) with a low MW product on knee osteoarthritis (OA) symptoms. Methods Patients with symptomatic knee OA were enrolled inarandomised, controlled, double-blind, parallel-group, non-inferiority trial with the possibility to shift to superiority. Patients were randomised to GO-ON(MW 800–1500 kD, 25 mg/2.5 ml) or Hyalgan(MW 500–730 kD, 20 mg/2 ml) injected at 3-weekly intervals. The primary outcome was 6-month change in the WOMAC pain subscale (0–100 mm). Sample size was calculated on a non-inferiority margin of 9 mm, lower than the minimum perceptible clinical improvement. Secondary endpoints included OARSI-OMERACT responder rates Results The intention-to-treat (ITT) and per-protocol (PP) populations consisted of 217 and 209 patients and 171 and 172 patients in the GO-ON and Hyalgan groups, respectively. ITT WOMAC pain of 47.5±1.0(SE) and 48.8±1.0 mm decreased by 22.9±1.4 mm with GO-ON and 18.4±1.5 mm with Hyalgan after 6 months. The primary analysis was conducted in the PP population followed by the ITT population.Mean (95% CI) differences in WOMAC pain change were 5.2 (0.9 to 9.6)mm and 4.5 (0.5 to 8.5)mm, respectively,favouring GO-ON, satisfying the claim for non-inferiority (lower limit>−9 mm) and for statistical superiority (95% CI all>0, p=0.021). Ahigher proportion of OARSI/OMERACT responders was observed with GO-ONthan with Hyalgan (73.3% vs58.4%, p=0.001). Both preparations were well tolerated. Conclusions Treatment with 3-weekly injections of intermediate MW HA may be superior to low MW HA on knee OA symptoms over 6 months, with similar safety.