No abstract

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.

No abstract

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.

Number of figures/tables: 2 figures, 3 tables Number of references: 26 Research in context Evidence before this study We conducted two PubMed searches (with no date restrictions) of English language publications reporting clinical trials of tofacitinib monotherapy or methotrexate withdrawal in patients with psoriatic arthritis (PsA). The first search utilised the terms (('tofacitinib' [All Fields] OR 'tofacitinib' [MeSH Terms]) AND ('monotherapy' [All Fields]) AND ('psoriatic arthritis' [All Fields] OR 'arthritis, psoriatic' [MeSH Terms]) AND (Clinical Trial [Publication Type])). The second search utilised the terms (('tofacitinib' [All Fields] OR 'tofacitinib' [MeSH Terms]) AND ('methotrexate' [All Fields] OR 'methotrexate' [MeSH Terms]) AND ('withdrawal' [All Fields] OR 'withdrawn' [All Fields] OR 'discontinu*' [All Fields] OR 'monotherapy' [All Fields]) AND ('psoriatic arthritis' [All Fields] OR 'arthritis, psoriatic' [MeSH Terms]) AND (Clinical Trial [Publication Type])). No relevant publications were retrieved.