Systemic autoimmune diseases arise from a heterogeneous interplay of genetic, epigenetic, and environmental factors that culminates in loss of tolerance, chronic inflammation, and tissue injury. Among the pathways linking susceptibility to effector disease, CD40-CD40L is a central regulator of antigen presentation, T-B cell collaboration, and germinal centre responses, while also contributing to extrafollicular autoantibody production. In this review, we first introduce the disease-specific rationale for targeting CD40-CD40L interactions, with a particular focus on systemic lupus erythematosus, Sjögren's disease, and rheumatoid arthritis. We then summarize the multifaceted roles of CD40-CD40L signalling across adaptive immunity, innate immune priming, tissue inflammation, and platelet-driven thrombo-inflammation. Finally, we review the therapeutic translation of this pathway, highlighting insights from early trials of anti-CD40/CD40L antibodies and recent advances in Fc-silent antibody engineering that preserve target binding while minimizing platelet activation. Together, these data support CD40-CD40L blockade as a renewed and promising mechanism-based strategy in systemic autoimmune rheumatic diseases.

Knee osteoarthritis (OA) is the most prevalent form of OA and a leading cause of chronic pain and disability worldwide. Its growing burden, driven mainly by ageing and obesity, is associated with major societal costs and increased cardiovascular mortality. Knee OA is now recognized as a heterogeneous whole-joint disease involving biomechanical, metabolic, inflammatory, osteochondral and neurovascular mechanisms. This complexity helps to explain why existing analgesics have modest efficacy and why disease-modifying OA drug development has repeatedly faltered. The therapeutic landscape is nevertheless evolving rapidly. Emerging symptomatic strategies include incretin-based therapies (semaglutide is the first to show substantial benefits for pain and function), neurotrophin modulation, extended-release intra-articular glucocorticoids, lubricating injectables and image-guided neurovascular interventions. In parallel, candidate disease-modifying OA drugs target cartilage anabolism, Wnt signalling, matrix-degrading enzymes, subchondral bone remodelling, immunometabolic pathways and local gene therapy. Several treatments, including locally administered GLP1 receptor agonists, the anabolic agent TPX-100 and intra-articular IL-1 receptor antagonist gene therapy, have shown encouraging signals, whereas mesenchymal stromal cell therapies have thus far demonstrated inconsistent efficacy across phase III clinical trials, highlighting the need for further standardization of mesenchymal stromal cell products and optimization of patient selection. Recent advances signal a shift towards a more diverse therapeutic landscape for knee OA, with emerging opportunities to target both symptoms and the underlying mechanisms of disease.

Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic condition in older adults. Glucocorticoids (GCs) remain the cornerstone of treatment, but many people with PMR relapse during tapering and are exposed to prolonged GC therapy with associated toxicity. There is therefore a need for evidence-based strategies that optimize disease control while minimizing GC-related harm. This guideline was developed in line with the British Society for Rheumatology's Creating Clinical Guidelines Protocol (v6.0), using GRADE and AGREE II frameworks, and supersedes previously published 2009 BSR/BHPR PMR guidelines. Several key recommendations have been included in this guideline update. These include when to discuss or refer people with PMR to rheumatology; initiation of GCs and tapering with options for a faster GC taper; consideration of early methotrexate; IL-6 receptor antagonist use in people with PMR who are unable to taper GCs or have had an inadequate response; and bone protection in all people with PMR. Furthermore, the guideline emphazises the importance of ongoing patient education and counselling, monitoring for glucocorticoid toxicity and suggestions for when to refer people with PMR to secondary care. This guideline aims to support clinicians in delivering safe, effective and individualized care for people with PMR, while promoting judicious use of GCs and timely introduction of GC-sparing therapies where appropriate.

Trained immunity is a form of innate immune memory mediated by metabolic and epigenetic reprogramming that promotes sustained inflammatory responses. Accumulating evidence implicates a role for maladaptive trained immunity in sustaining inflammation and promoting disease progression across distinct forms of inflammatory joint disease, including rheumatoid arthritis, gout, calcium pyrophosphate deposition disease and osteoarthritis. Inflammatory cytokines, damage-associated patterns and metabolic signals can induce long-lasting inflammatory programmes in both immune cells, such as monocytes and macrophages, and non-immune cells within the joint, such as chondrocytes and synovial-like fibroblasts. Trained immunity also provides a potential mechanistic link between joint inflammation and associated systemic complications, including increased cardiovascular risk. Therapeutic strategies targeting the metabolic and epigenetic pathways that underlie trained immunity could offer opportunities to limit chronic inflammation, prevent structural damage and reduce disease-associated comorbidities.