It Is the Time to Think About a Treat-to-Target Strategy for Knee Osteoarthritis.

Osteoarthritis (OA) is a rheumatic disease that affects the well-being of the patient, compromises physical and mental function, and affects other quality of life aspects. In the literature, several evidence-based guidelines and recommendations for the management of knee osteoarthritis (KOA) are available. These recommendations list the different therapeutic options rather than addressing a hierarchy between the treatments and defining the real target. Therefore, a question arises: are patients and physicians satisfied with the current management of KOA? Actually, the answer may be negative, thus suggesting a change in our therapeutic strategies. In this article, we address this challenge by suggesting that it is time to develop a "treat to target strategy" for KOA.

The discrepancy between recommendations and clinical practice for viscosupplementation in osteoarthritis: mind the gap!

Recently AAOS, ACR and OARSI revised their recommendations for the management of knee osteoarthritis (OA) and for hand, knee and hip joints. During ISIAT (International Symposium on Intra-Articular Treatments) 2013 round table on recommendations about the use of intra-articular Hyaluronic Acid (IAHA) in OA, several considerations were elaborated by the ISIAT Technical Expert Panel (TEP) regarding discrepancy between recommendations and clinical practice. The ISIAT TEP gathered the following eight suggestions regarding the drawing of recommendations on the use of IAHA in OA and its comparison with other treatments. It is necessary to merge data coming from both RCTs and registers. Only studies with a strong level of evidence should be taken into account. A common threshold of efficacy should be assessed for comparing treatments. Evaluation of hard outcomes is essential. The effect size of placebo as comparator should be attentively considered in RCTs. Particular attention should be given to different phenotypes of OA that may possibly respond differently to each treatment. Compliance and long-term side effects of different therapeutic approaches should be evaluated. Pharmacoeconomic evaluation should be performed on the long term.

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.

Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial.

AIM: To test the efficiency of tumour necrosis factor blockers (adalimumab) in patients with painful refractory (non-responders to analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)) hand osteoarthritis (OA). METHODS: We performed a randomised, double-blind, placebo-controlled, parallel group, multicentre study. Patients were randomised to: 1/1 adalimumab 40 mg for two subcutaneous injections at a 15-day interval or placebo and monitored for 6 months. The primary outcome was the percentage of patients with an improvement of more than 50% in global pain (Visual Analogue Scale) between week 0 (W0) and week 6 (W6). Secondary outcomes included the number of painful joints, swollen joints, morning stiffness duration, patient and practitioner global assessments, functional indexes for hand OA, and consumption of analgesics. Analysis on the mean primary outcome measure was done on patients who received at least one injection. RESULTS: 99 patients were recruited and 85 patients were randomised. Among them, 37 patients in the placebo group and 41 in the adalimumab group received at least one injection and were evaluated at W6 (n=78) on the main efficacy outcome. Mean age was 62 years, 85% were women, and mean level of pain was 62 mm at W0. At W6, 35.1% in the adalimumab group versus 27.3% in the placebo group had a pain reduction ≥50% (RR 1.12 (95% CI 0.82 to 1.54; p=0.48). There were no statistical differences for all secondary end points. The rate of adverse events was similar in the two groups. CONCLUSIONS: Adalimumab was not superior to placebo to alleviate pain in patients with hand OA not responding to analgesics and NSAIDs. TRIALS REGISTRATION NUMBER: NCT00597623.

[Thorn synovitis: Report of 2 cases]. / Synovites à piquants : à propos de deux cas.

INTRODUCTION: Thorn synovitis is related to plant or animal thorn punctures. We report two cases of thorn synovitis. CASE REPORTS: The first patient was a 41-year-old-woman who presented with recurrent arthritis of the right knee after needle fish injury. The immunological tests and cultures were negative. X-rays and MRI showed the foreign bodies in the soft parts on the outer side of the knee. An arthroscopy was performed and the thorn removed. Clinical outcome was favourable with complete symptoms resolution. The second patient was a 58-year-old-man, with a family history of spondylarthritis, who was admitted with a monoarthritis of the left wrist that occurred 10 weeks after palm tree thorn injury. Patient received unsuccessfully antibiotics and anti-inflammatory drugs. Immunological tests and cultures were negative. Wrist ultrasound showed erosive synovitis. Intra-articular lesion removal by arthroscopy allowed favourable outcome. CONCLUSION: Thorn synovitis diagnosis is based on the discovery of a foreign body. Treatment is based on their removal. Suspicion of infection with deficient pathogen, especially Pantoea agglomerans, remains difficult for the practitioner.

Early decrease of serum biomarkers of type II collagen degradation (Coll2-1) and joint inflammation (Coll2-1 NO2 ) by hyaluronic acid intra-articular injections in patients with knee osteoarthritis: a research study part of the Biovisco study.

To measure the evolution of the serum levels of specific Osteoarthritis (OA) biomarker, Coll2-1 and Coll2-1 NO2 in knee osteoarthritic patients after viscosupplementation (VS). Fifty-one patients with unilateral symptomatic knee were recruited for this prospective open label study. They received three intra-articular injections of 2 ml of hyaluronic acid (Hylan GF-20) and were followed for 3 months. Walking pain was evaluated and serum samples were taken at each visit. Coll2-1 and Coll2-1 NO2 were measured in the serum using specific immunoassays. Variations over time of each parameter and predictive factor of response were studied. Forty-five patients were analyzed. The serum concentrations of Coll2-1 and Coll2-1 NO2 were significantly higher in KL III/IV patients compared to KL I/II patients at baseline and decreased systematically over time after VS. Its effect was ever more pronounced in patients with KL III/IV. The serum concentration of Coll2-1 was significantly lower at baseline in responders than in non-responders. This study suggests a rapid slowdown of type II collagen degradation and joint inflammation after VS with Hylan G-20 and gives additional information for the validation of accurate biomarkers for OA. The serum level of Coll2-1 appeared to be a predictive factor for response to treatment.

Symptom and structure modification in osteoarthritis with pharmaceutical-grade chondroitin sulfate: what's the evidence?

OBJECTIVES: Osteoarthritis is a chronic disease characterized by irreversible damage to joint structures, including loss of articular cartilage, osteophyte formation, alterations in the subchondral bone and synovial inflammation. It has been shown that chondroitin sulfate interferes with the progression of structural changes in joint tissues and is used in the management of patients with osteoarthritis. METHODS: This review summarizes data from relevant reports describing the mechanisms of action of chondroitin sulfate that may explain the beneficial effects of the drug and examines the evidence for clinical efficacy of oral chondroitin sulfate in osteoarthritis. Data included in the review were derived from a literature search in PubMed. Literature searches were performed in PubMed using the search terms 'chondroitin sulfate', 'pharmaceutical-grade', 'osteoarthritis', 'randomized clinical trials', 'humans'. The MEDLINE database was searched from January 1996 through August 2012 for all randomized controlled trials, meta-analyses, systematic reviews, and review articles of chondroitin sulfate in osteoarthritis. RESULTS: Chondroitin sulfate exerts in vitro a beneficial effect on the metabolism of different cell lines: chondrocytes, synoviocytes and cells from subchondral bone, all involved in osteoarthritis. It increases type II collagen and proteoglycan synthesis in human articular chondrocytes and is able to reduce the production of some pro-inflammatory factors and proteases, to reduce the cellular death process, and improve the anabolic/catabolic balance of the extracellular cartilage matrix (ECM). Clinical trials have reported a beneficial effect of chondroitin sulfate on pain and function. The structure-modifying effects of chondroitin sulfate have been reported and analyzed in recent meta-analyses. The results in knee osteoarthritis demonstrate a small but significant reduction in the rate of decline in joint space width. Because chondroitin sulfate quality of several nutraceuticals has been found to be poor, it is recommended that pharmaceutical-grade chondroitin sulfate is used rather than food supplements in the treatment of OA. Chondroitin sulfate is recommended by several guidelines from international societies in the management of knee and hip OA. Furthermore, its safety profile is favorable when compared with many other therapies used in OA. CONCLUSION: Chondroitin sulfate is an effective and safe treatment option for patients with osteoarthritis.

Serum cartilage oligomeric matrix protein (COMP) level is a marker of disease activity in relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis (RP) is a rare and severe disease which may lead to destruction of elastic cartilages. Until now, no reliable biomarker of disease activity in RP has been available. This study was designed to measure serum levels of cartilage biomarkers during both active and inactive phases of the disease. METHODS: Serum levels of cartilage oligomeric matrix protein (COMP), chondroitin sulfate 846 epitope (CS846) of proteoglycan aggrecan and collagen type II collagenase cleavage neoepitope (C2C) were measured retrospectively in 21 subjects with RP. The Wilcoxon matched-pairs signed-rank test was used for statistical comparisons of biomarker levels in active and inactive phases of RP. RESULTS: Only the serum level of COMP was significantly increased during disease flares. Steroids did not alter the serum cartilage-related biomarker levels. However, during the active phase, C2C levels were significantly higher in steroid treated patients compared with non-steroid treated patients. CONCLUSIONS: This study suggests that serum COMP level may be useful for monitoring disease activity of RP. Further prospective studies are required to confirm this result.

Intermediate term functional outcome prediction following full thickness rotator cuff tear reparative or not reparative surgery.

UNLABELLED: Although simple suturing repair of a full thickness cuff tear can be performed when the preoperative fatty degeneration index (FDI) is 2 or less, it is not known if the functional results will be better than palliative surgical treatment. The aim of this study is to describe and validate a method to predict the intermediate term unweighted Constant scores of different surgical treatments based on preoperative FDI. The hypothesis of this study is that the preoperative and final follow-up ratios FDI/final follow-up Constant scores regression lines, established on a previous "reference study"[5] (a series of 29 shoulders with cuff tears and sutured intact rotator cuff), could be used for this purpose. MATERIAL: The present study included seven series of sutured cuffs (five, which resulted in intact cuffs and two in recurrent tears) and one series of cuffs treated with palliative surgery. Knowledge of the preoperative FDI and the location of the recurrent or unrepaired tears were required criteria for these series inclusion in the study. METHOD: For each of the series in this study the Constant scores and selected score items were compared to scores calculated with the same mathematical formulas previously used to determine the regression lines in the reference study series (resulting in Constant scores in relation to preoperative and final follow-up FDI). RESULTS: The calculated Constant scores were similar to those reported by the authors, which validate the proposed method. DISCUSSION: Because of the small size of the series of sutured cuffs with recurrent tears and of cuffs that underwent palliative surgery and arthroscopic treatment it is impossible to definitely confirm the validity of this method. CONCLUSION: The intermediate term results of different surgical treatments can reasonably be predicted for full thickness tendon tears based on the preoperative FDI and the location of these tears. With this method the best treatment should be chosen for a rotator cuff tear on a case-by-case basis. LEVEL OF EVIDENCE: Level IV.

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.

OBJECTIVES: The primary objective was to compare a single, 6 ml, intra-articular injection of hylan G-F 20 with placebo in patients with symptomatic knee osteoarthritis. The safety of a repeat injection of hylan G-F 20 was also assessed. METHODS: Patients with primary osteoarthritis knee pain were randomly assigned to arthrocentesis plus a 6 ml intra-articular injection of either hylan G-F 20 or placebo in a prospective, double-blind (one injector/one blinded observer) study. RESULTS: were evaluated at 4, 8, 12, 18 and 26 weeks post-injection. The primary outcome criterion was change from baseline over 26 weeks in Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index A pain. Secondary outcome measures included WOMAC A1 and C, patient global assessment (PGA) and clinical observer global assessment (COGA) and Outcome Measures in Rheumatology, Osteoarthritis Research Society International responder rates. A 4-week, open, repeat treatment phase evaluated safety only. Results: A total of 253 patients (Kellgren-Lawrence grade II or III) was randomly assigned. Patients receiving hylan G-F 20 experienced statistically significantly greater improvements in WOMAC A pain scores (-0.15, SE 0.076, p = 0.047), and several of the secondary outcome measures (WOMAC A1, PGA and COGA), than patients receiving placebo. There was no difference between the safety results of the two groups. No increased risk of local adverse events was observed in the open, repeat treatment phase. CONCLUSIONS: This placebo-controlled study demonstrated that, in patients with knee osteoarthritis, a single 6 ml intra-articular injection of hylan G-F 20 is safe and effective in providing statistically significant, clinically relevant pain relief over 26 weeks, with a modest difference versus placebo.

Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee. METHODS: Patients with OA of the knee were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients. RESULTS: Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after intraarticular injection was approximately 4 hours. CONCLUSION: Anakinra was well tolerated as a single 50-mg or 150-mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

Prospective, multi-centre, randomised evaluation of the safety and efficacy of five dosing regimens of viscosupplementation with hylan G-F 20 in patients with symptomatic tibio-femoral osteoarthritis: a pilot study.

INTRODUCTION: Viscosupplementation by repeated intra-articular injections of hyaluronic acid (HA) is used widely in the treatment of symptomatic knee osteoarthritis (OA). The number of injections required can limit the availability of treatment and affect patient compliance. The aim of this study was to assess different dosing regimens of hylan G-F 20, a high molecular-weight cross-linked derivative of HA, in the treatment of pain due to knee OA. MATERIALS AND METHODS: Pilot, prospective, multi-centre, open-label, randomised trial in 100 patients with unilateral, symptomatic, tibio-femoral OA (Kellgren-Lawrence grade II or III), aged > or =40 years. Patients were randomised to receive varying dosing regimens of hylan G-F 20 (1 x 6 mL, 1 x 4 mL, 2 x 4 mL 2 weeks apart, 3 x 4 mL 1 week apart, or 3 x 2 mL 1 week apart). Adverse events (AE's) were monitored throughout the study. The primary efficacy endpoint was the change from baseline in the patient-rated knee OA pain assessment (100 mm visual analogue scale (VAS)) at 24 weeks. The secondary efficacy criteria included the WOMAC index, patient and physician global assessments using a 100 mm VAS, and knee OA pain assessment at all other visits. Concomitant use of permitted rescue medications (paracetamol) was also assessed. RESULTS: The treatment was well tolerated overall. Patients in the 3 x 4 mL group reported the highest percentage of device-related local AE's (30%) while patients in the 1 x 6 mL and 3 x 2 mL groups reported only 10%. There were no serious device-related AEs. There was a statistically significant improvement from baseline at week 24 in all efficacy endpoints for all treatment regimens. The 1 x 6 and 3 x 4 and 3 x 2 mL treatment groups showed the greatest mean improvements (-34.9, -32.6 and -36.7 mm respectively) in the patient-rated knee OA pain assessment VAS. CONCLUSION: This study suggests that a single 6 mL injection of hylan G-F 20 may be as efficacious, and as well tolerated, as 3 x 2 mL one week apart. A double-blind, controlled trial is needed to confirm these data.

Acute myeloid leukemia after infliximab: a case report.

Concern has arisen regarding a possible increase in the risk of malignant diseases such as lymphoproliferative disorders in a patient taking TNF-alpha antagonists for the treatment of chronic inflammatory diseases. The evidence of a causal link remains unclear. We report a case of 60-year-old male patient who developed acute myeloid leukemia during infliximab therapy for ankylo-sing spondylitis.

[Wells' cellulitis and bacterial necrotizing cellulitis induced by anakinra]. / Cellulite de Wells et dermohypodermite bactérienne nécrosante induites par l'anakinra.

BACKGROUND: Anakinra is a recombinant form of the naturally occurring human interleukin-1 receptor antagonist. It is used in the treatment of rheumatoid arthritis. The most frequent side effects are injection site reactions, which seem to have a toxic mechanism. PATIENTS AND METHODS: We report two unusual cases of injection site reactions with anakinra: a woman presented Wells' cellulitis of the thigh and a man developed serious bacterial cellulitis distinguished by deep necrosis at the site of the latest anakinra subcutaneous injection. DISCUSSION: The cases are examples of serious side effects that can occur during treatment with anakinra and underline the need for careful use of this new biological agent.

Natural chondroitin sulphates increase aggregation of proteoglycan complexes and decrease ADAMTS-5 expression in interleukin 1 beta-treated chondrocytes.

OBJECTIVE: To assess the effect of natural chondroitin sulphate (CS) on the ability of neosynthesized sulphated proteoglycans (PGs) to aggregate in cultured chondrocytes treated with interleukin (IL)1 beta. METHODS: Primary cultured rabbit articular chondrocytes were treated or not with IL1 beta alone or with concentrations of CS for 20 h. Neosynthesized PGs were labelled by incorporation of [35SO(4)]-sulphate and analysed by chromatography on Sepharose 2B columns. Gelatinolytic activity was measured by zymography, and matrix metalloproteinase (MMP)1 mRNA level in chondrocytes underwent real-time PCR. Expression of ADAMTS (for "a disintegrin and metalloproteinase with thrombospondin motifs") -4 and -5 was analysed by real-time PCR and western blotting. RESULTS: The production of [35SO(4)]-labelled PGs was significantly increased with 10 microg/ml CS in the cellular pool rather than in the incubation medium. The addition of CS to IL1 beta-treated cells inhibited in part the disaggregation of sulphated PGs induced by IL1 beta. This inhibitory effect of CS is associated with a significant decrease in ADAMTS-5 expression at the mRNA and protein levels. No effect of CS was observed on IL1 beta-induced gelatinolytic activity, MMP1 mRNA expression or ADAMTS-4 expression. CONCLUSION: CS increases the production of functional sulphated PGs in the direct environment of chondrocytes in vitro. This beneficial effect of CS in IL1 beta-treated cells is associated with decreased expression of ADAMTS-5.