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The prevalence of osteoarthritis (OA) and the burden associated with the disease are steadily increasing worldwide, representing a major public health challenge for the coming decades. The lack of specific treatments for OA has led to it being recognized as a serious disease that has an unmet medical need. Advances in the understanding of OA pathophysiology have enabled the identification of a variety of potential therapeutic targets involved in the structural progression of OA, some of which are promising and under clinical investigation in randomized controlled trials. Emerging therapies include those targeting matrix-degrading proteases or senescent chondrocytes, promoting cartilage repair or limiting bone remodelling, local low-grade inflammation or Wnt signalling. In addition to these potentially disease-modifying OA drugs (DMOADs), several targets are being explored for the treatment of OA-related pain, such as nerve growth factor inhibitors. The results of these studies are expected to considerably reshape the landscape of OA management over the next few years. This Review describes the pathophysiological processes targeted by emerging therapies for OA, along with relevant clinical data and discussion of the main challenges for the further development of these therapies, to provide context for the latest advances in the field of pharmaceutical therapies for OA.In this Review, the authors describe the pathophysiological targets and clinical effects of new drugs currently being investigated for the treatment of osteoarthritis.

Gout, the most prevalent inflammatory arthritis worldwide, is associated with cardiovascular and renal diseases, and is an independent predictor of premature death. The frequencies of obesity, chronic kidney disease (CKD), hypertension, type 2 diabetes, dyslipidaemias, cardiac diseases (including coronary heart disease, heart failure and atrial fibrillation), stroke and peripheral arterial disease have been repeatedly shown to be increased in gout. Therefore, the screening and care of these comorbidities as well as of cardiovascular risk factors are of outmost importance in patients with gout. Comorbidities, especially CKD, and drugs prescribed for their treatment, also impact gout management. Numerous epidemiological studies have shown the association of asymptomatic hyperuricaemia with the above-mentioned diseases and cardiovascular risk factors. Animal studies have also produced a mechanistic approach to the vascular toxicity of soluble urate. However, causality remains uncertain because confounders, reverse causality or common etiological factors might explain the epidemiological results. Additionally, these uncertainties remain unsolved despite recent studies using Mendelian randomisation or therapeutic approaches. Thus, large randomised placebo-controlled trials are still needed to assess the benefits of treating asymptomatic hyperuricaemia.

Gout is a common arthritis caused by deposition of monosodium urate crystals within joints after chronic hyperuricaemia. It affects 1–2% of adults in developed countries, where it is the most common inflammatory arthritis in men. Epidemiological data are consistent with a rise in prevalence of gout. Diet and genetic polymorphisms of renal transporters of urate seem to be the main causal factors of primary gout. Gout and hyperuricaemia are associated with hypertension, diabetes mellitus, metabolic syndrome, and renal and cardiovascular diseases. Non-steroidal anti-inflammatory drugs and colchicine remain the most widely recommended drugs to treat acute attacks. Oral corticosteroids could be an alternative to these drugs. Interleukin 1β is a pivotal mediator of acute gout and could become a therapeutic target. When serum uric acid concentrations are lowered below monosodium urate saturation point, the crystals dissolve and gout can be cured. Patient education, appropriate lifestyle advice, and treatment of comorbidities are an important part of management of patients with gout.

Biologic agents have been used successfully to treat rheumatoid arthritis, but are less effective in osteoarthritis. Chevalier et al . discuss the use of cytokine blockers, inhibitors of nitrogen oxide production, and growth factors to treat osteoarthritis—clinical trial data has been overwhelmingly negative but glimmers of hope still exist. 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. Key Points Targeted therapy against β-nerve growth factor (β-NGF) in knee osteoarthritis (OA) has resulted in dramatic improvements in symptoms but reports of unexpected, rapid, destructive arthropathies suggest major safety concerns Anti-IL-1β therapy using either intra-articular injection or systemic administration failed to demonstrate any clinical improvement in patients with knee OA Systemic and subcutaneous injections have been used to deliver anti-TNF therapy in patients with polyarticular hand OA and knee OA, respectively; neither strategy has resulted in structural effects or clinical improvement Therapies targeting nitrogen oxide synthesis (administered orally) or local delivery of growth factors in patients with knee OA did not show clinical or structural improvements Future strategies should differentiate between those agents aiming to reduce pain, such as anti-β-NGF treatments, and those targeting structural evolution, which have had disappointing results Emerging therapies should fit the natural progression of OA, focus on early disease where changes might be reversible, and take into account the location and heterogeneity of the disease

The ACR has published an update to its guideline on gout management, which was mostly based on the results of randomized controlled trials (RCTs). Although rigorous, the methodology used for these recommendations can be called into questioned given the lack of robust data from RCTs on all aspects of gout.

Purpose There has been much debate regarding the use of intra-articular injections of platelet-rich plasma (PRP) as symptomatic treatment for knee osteoarthritis. The objective of this consensus was to develop guidelines for PRP injections in knee osteoarthritis according to the French National Authority for Health recommendations. Methods Fifteen physicians from different French-speaking countries (10 rheumatologists, 4 specialists in rehabilitation and sports medicine and 1 radiologist) were selected for their expertise in the areas of PRP and osteoarthritis. A comprehensive literature review was conducted on Medline including all published therapeutic trials, open studies, meta-analysis and systematic reviews focusing on the effects of PRP in knee OA, as well as fundamental studies concerning the characteristics of the various types of PRP and their mechanisms, indexed before April 2019. Using the method recommended by the French National Authority for Health inspired by the Delphi consensus process, 25 recommendations were finally retained and evaluated. The recommendations were classified as appropriate or not appropriate, with strong or relative agreement, or uncertain if a consensus was not achieved. Results Among the 25 recommendations selected, the main ones are the following: (1) Intra-articular injections of PRP are an effective symptomatic treatment for early to moderate knee osteoarthritis. This recommendation was considered appropriate with a relative agreement (Median = 8; rank = 6–9). Level of evidence 1A. (2) A PRP treatment sequence in knee osteoarthritis may include 1–3 injections. This recommendation was considered appropriate with a strong agreement (Median = 9; rank = 7–9). Level of evidence 1A. (3) Leucocytes-poor PRP should be preferred in knee osteoarthritis. This recommendation was considered appropriate with a relative agreement (Median = 8; rank = 5–9). Level of evidence 5. (4) Intra-articular PRP knee injections should be performed under ultrasound or fluoroscopic guidance. This recommendation was considered uncertain with no consensus (Median = 8; rank = 3–9). Level of evidence 5. (5) PRP should not be mixed with an anesthetic or intra-articular corticosteroid. This recommendation was considered appropriate with a relative agreement (Median = 9; rank = 6–9). Level of evidence 5 Conclusion Those 25 recommendations should standardize and facilitate the use of IA PRP injections, which are considered by experts as an effective treatment especially in early or moderate knee OA. Although a strong or relative agreement from the experts was obtained for most of the recommendations, many of them had a very low level of evidence (Level 5) and were principally based on the clinical experience of the experts.

Deposition of monosodium urate and calcium pyrophosphate (MSU and CPP) micro-crystals is responsible for painful and recurrent inflammation flares in gout and chondrocalcinosis. In these pathologies, the inflammatory reactions are due to the activation of macrophages responsible for releasing various cytokines including IL-1β. The maturation of IL-1β is mediated by the multiprotein NLRP3 inflammasome. Here, we find that activation of the NLRP3 inflammasome by crystals and concomitant production of IL-1β depend on cell volume regulation via activation of the osmo-sensitive LRRC8 anion channels. Both pharmacological inhibition and genetic silencing of LRRC8 abolish NLRP3 inflammasome activation by crystals in vitro and in mouse models of crystal-induced inflammation. Activation of LRRC8 upon MSU/CPP crystal exposure induces ATP release, P2Y receptor activation and intracellular calcium increase necessary for NLRP3 inflammasome activation and IL-1β maturation. We identify a function of the LRRC8 osmo-sensitive anion channels with pathophysiological relevance in the context of joint crystal-induced inflammation. Formation of urate and calcium pyrophosphate micro-crystals is responsible for painful inflammatory flares in gout and chondrocalcinosis. Here the authors show that the osmo-sensitive LRRC8 anion channel is involved with macrophage inflammasome activation by crystals involving cell volume regulation and ATP release leading to P2Y receptor activation.

Objectives To evaluate the efficacy and safety of rituximab in patients with primary Sjögren's syndrome (pSS). Methods The AutoImmune and Rituximab registry has included 86 patients with pSS treated with rituximab, prospectivey followed up every 6 months for 5 years. Results Seventy-eight patients with pSS (11 men, 67 women), who already had at least one follow-up visit, were analysed. Median age was 59.8 years (29–83), median duration of disease was 11.9 years (3–32). Indications for treatment were systemic involvement for 74 patients and only severe glandular involvement in four patients. The median European Sjögren's Syndrome disease activity index (ESSDAI) was 11 (2–31). 17 patients were concomitantly treated with another immunosuppressant agent. Median follow-up was 34.9 months (6–81.4) (226 patient-years). Overall efficacy according to the treating physician was observed in 47 patients (60%) after the first cycle of rituximab. Median ESSDAI decreased from 11 (2–31) to 7.5 (0–26) (p<0.0001). Median dosage of corticosteroid decreased from 17.6 mg/day (3–60) to 10.8 mg/day (p=0.1). Forty-one patients were retreated with rituximab. Four infusion reactions and one delayed serum sickness-like disease resulted in rituximab discontinuation. Three serious infections (1.3/100 patient-years) and two cancer-related deaths occurred. Conclusions In common practice, the use of rituximab in pSS is mostly restricted to patients with systemic involvement. This prospective study shows good efficacy and tolerance of rituximab in patients with pSS and systemic involvement.

Objective The aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese. Methods All patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Results On comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8–40.1], P  < 0.0001), female sex (OR 333 [40–43,453], P  < 0.0001), allopurinol for asymptomatic hyperuricemia (OR 955 [120–125,847], P  < 0.0001), allopurinol starting dose > 150 mg (OR 316 [101–122], P  < 0.0001), diuretics intake (OR 304 [35–40,018], P  < 0.0001), eGFR < 60 ml/min/1.73 m 2 (OR 100 [32–353], P  < 0.0001), history of allopurinol-induced skin reaction (OR 78 [6–10,808], P  = 0.004), and HLA-B*58:01 carriage (OR 147 [45–746], P  < 0.0001). HLA-B*58:01 allele frequency in controls was 7.3%. For MCARs ( n  = 74), risk factors were eGFR < 60 ml/min/1.73 m 2 (OR 4.9 [1.61–14.6], P  = 0.006), history of allopurinol-induced skin reaction (OR 27 [2–3777], P  = 0.01), and asymptomatic hyperuricemia (OR 27 [2–3777], P  = 0.01). Conclusion This study confirmed 8 risk factors, including HLA-B*58:01, for SCARs and identified 3 risk factors for MCARs in Kinh Vietnamese. HLA-B*58:01 genotyping could guide the indication for allopurinol in Kinh Vietnamese patients with gout.

Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved as monotherapy or in combination with methotrexate for treating adults with moderate-to-severe active rheumatoid arthritis (RA) and provides improvements in clinical signs, symptoms and patient-reported outcomes. Currently, baricitinib is approved for treating RA in more than 75 countries. In several pivotal Phase II and III RA trials (RA-BALANCE, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BEYOND), up to seven years of baricitinib treatment was well tolerated and provided rapid and sustained efficacy, which was confirmed in real-world settings. Safety signals for another JAK inhibitor, tofacitinib, have emerged, as observed in the post-marketing Phase IIIb/IV trial Oral Rheumatoid Arthritis Trial (ORAL) Surveillance; safety signals were subsequently highlighted in a retrospective study of baricitinib and consequently new recommendations and warnings and precautions for all JAK inhibitors have been issued. Ongoing studies to further characterise and clarify the benefit:risk of JAK inhibitors include registries and controlled trials. This capstone review summarises clinical and real-world data outlining the benefit:risk profile of baricitinib, confirming that the improved disease activity and physical function of patients with RA treated with this JAK inhibitor observed in clinical trials is translated into effectiveness in clinical practice, with a low rate of discontinuations.