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Background: Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy. Methods: Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-β-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARα related to cartilage degeneration. Findings: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients. Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. Interpretation: These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment.

Simvastatin treatment is associated with moderate clinical improvement in patients with active RA. Immunological changes produced by simvastatin in peripheral blood are complex and may reflect both its anti- and pro-inflammatory properties.

BackgroundThere is growing evidence that mast cells (MCs) play a role in knee osteoarthritis (OA). H1-antihistamines block H1-receptors of histamine, which is an important mediator of MCs. There is a lack of data on whether H1-antihistamines can influence OA. We hypothesized that the use of H1-antihistamines may be linked to the reduced prevalence of knee OA.MethodsBaseline data from the Osteoarthritis Initiative cohort were analysed cross-sectionally. Unadjusted and adjusted logistic regression models were performed to compare the prevalence of knee OA in H1-antihistamine users and non-users. Generalized estimating equations were used to adjust for the correlation between knees. Knee OA was defined as (1) Kellgren-Lawrence (KL) grade ≥ 2 or total joint replacement or (2) KL grade ≥ 2 and joint space narrowing or total joint replacement.ResultsThe analysed sample consisted of 8545 knees (664 knees of H1-antihistamine users and 7881 knees of H1-antihistamine non-users). The use of H1-antihistamines was associated with reduced prevalence of knee OA in unadjusted and adjusted models using both the first (adjusted OR, 0.77; 95% CI, 0.62, 0.96; P < 0.02) and second (adjusted OR, 0.75; 95% CI, 0.62, 0.93; P < 0.008) definitions of knee OA.ConclusionsH1-antihistamines are associated with a reduced prevalence of knee OA. The findings indicate that this class of drugs should be further evaluated for possible structure-modifying properties in knee OA.

In recent years, peroxisome proliferator-activated receptors (PPARs) have received growing interest due to the broad spectrum of their biological activities. PPARα, an isoform of PPAR, plays an important role in lipid homeostasis and inflammation, which makes it a potential target for the treatment of chronic inflammatory disorders, including RA. This paper reviews studies on the properties of PPARα agonists which may be pertinent to the treatment of RA. These properties include effects on lipid metabolism, inflammation, and angiogenesis, as well as interference with glucocorticoid effects, and a potential role in gender dimorphism of autoimmune disorders. However, current clinical experience with this class of drugs in RA is limited. New studies are needed to elucidate whether PPARα agonism may be an effective treatment strategy for RA patients.

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Hand osteoarthritis (HOA) is a common condition associated with high disease burden and frequently accompanied by comorbidities including dyslipidemia, atherosclerosis and obesity. The most debilitating HOA phenotype is erosive HOA (EHOA), characterized by synovial inflammation, formation of erosions, and substantial decline in hand function. Currently, there is no proven symptomatic treatment for the EHOA. Due to their broad spectrum effects directed on lipid metabolism, inflammation and pain, the agonists of peroxisome proliferator-activated receptor alpha or fibrates are a candidate class of drugs for the treatment of EHOA. In this study, we assessed the influence of fenofibrate treatment on clinical efficacy parameters, in vivo cytokine and adipokine production and concentrations of endothelial progenitor cells (EPC) in patients with EHOA. Fourteen patients received treatment with 145 mg of fenofibrate/day for 12 weeks. Fenofibrate treatment was associated with significant decreases in pain score, tender joint count, duration of morning stiffness, disease activity score, Cochin index, and ESR. Eight (57.14 %) patients developed Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society response at the end of treatment. Paracetamol consumption did not change during the treatment course. There was a significant reduction in triglyceride levels. No changes were detected in serum pro-inflammatory cytokine and adipokine concentrations while circulating IL-10 levels significantly decreased. There were no differences in circulating EPC numbers before and after the treatment. Fenofibrate was well tolerated, no patient experienced disease flare during the treatment. In conclusion, in EHOA patients, fenofibrate is associated with pleiotropic effects on pain, inflammation, and lipid profile. Larger, controlled studies are needed to confirm these results.

Peroxisome proliferator-activated receptors α (PPARα) agonists, or fibrates, are used in the treatment for dyslipidemia. Experimental data suggest that fibrates have anti-inflammatory properties, and PPARα is essential for the differentiation of endothelial progenitor cells (EPC) which diminished pool in rheumatoid arthritis (RA) contributes to accelerated atherosclerosis. The data on fibrates' effects in patients with RA are limited. The aim of this study was to investigate changes in disease activity, inflammatory markers, lipid profile, and circulating EPC in active RA patients treated with fenofibrate. Twenty-seven patients with active RA taking traditional disease-modifying antirheumatic drugs (DMARDs) were prescribed fenofibrate (145 mg/day) for 3 months. All patients received background traditional DMARDs in stable doses. The outcomes measured were clinical disease activity variables, circulating cytokines, adipokines, lipids, and EPC. Twenty-five patients completed the study. At the end of treatment, there was a significant reduction in DAS28, all individual DAS28 components except tender joint count, the duration of morning stiffness, and in the patient's assessment of disease activity. Fifteen (60 %) patients achieved good/moderate EULAR response, while 10 (40 %) patients satisfied ACR20 response criteria. Treatment with fenofibrate resulted in significant decrease in CRP and IL-6 concentrations and improvement in lipid profile. There was no change in the concentrations of circulating EPC. In conclusion, fenofibrate treatment is associated with reduced inflammation and improved lipid profile in RA patients. Large randomized controlled studies are needed to confirm these results and to define the role of fibrates in the treatment for RA.