BackgroundMusculoskeletal (MSK) diseases are expected to have a growing impact worldwide.ObjectiveTo analyse the worldwide burden of MSK diseases from 2000 to 2015.MethodsDisability-adjusted life years (DALYs), which combines the years of life lost (YLLs) and the years lived with disability (YLDs), were extracted for 183 countries from the WHO Global Health Estimates Database. We analysed the median proportion of DALYS, YLLs and YLDs for MSK diseases (ICD-10: M00–M99) among the 23 WHO categories of diseases. Mixed models were built to assess temporal changes.ResultsWorldwide, the total number of MSK DALYs increased significantly from 80,225,634.6 in 2000 to 107,885,832.6 in 2015 (p < 0.001), with the total number of MSK YLDs increasing from 77,377,709.4 to 103,817,908.4 (p = 0.0008) and MSK diseases being the second cause of YLDs worldwide. YLLs due to MSK diseases increased from 2,847,925.2 to 4,067,924.2 (p = 0.03). In 2015, the median proportion of DALYs attributed to MSK diseases was 6.66% (IQR: 5.30 – 7.88) in Europe versus 4.66% (3.98 – 5.59) in the Americas (p < 0.0001 vs Europe), 4.17% (3.14 – 6.25) in Asia (p < 0.0001), 4.14% (2.65 – 5.57) in Oceania (p = 0.0008) and 1.33% (1.03 – 1.92) in Africa (p < 0.0001). We observed a significant correlation (r = 0.85, p < 0.0001) between the proportion of MSK DALYs and the gross domestic product per capita for the year 2015.ConclusionsThe burden of MSK diseases increased significantly between 2000 and 2015 and is high in Europe. These results are crucial to health professionals and policy makers to implement future health plan adjustments for MSK diseases.
From a 1-year survival of less than 50% before the discovery of glucocorticoids to over 90% at 10 years in most dedicated centres, the spectrum of SLE has profoundly evolved. Despite this improvement, several major challenges currently remain. The aim of this review is to analyse what are, according to us, the 10 most important contemporary challenges in the management of SLE. Among those are the need to treat to target to favour disease remission (or low disease activity), limit the use of glucocorticoids, derive more comprehensive tools for the evaluation of disease activity, develop more effective drugs (yielding successful trials), dissect the heterogeneity of the disease both at the molecular and genetic levels, identify relevant biomarkers for individualised treatment, manage fertility and pregnancy, tackle comorbidities such as cardiovascular risk, the prevention of infections and osteoporosis, improve the network of care (from the patients’ perspective), and favour a holistic approach (integrating fatigue, adherence to treatment, physical activity). Altogether, these 10 contemporary challenges in SLE may be considered as a roadmap for those involved in the daily care of patients with SLE, as well as for researchers who may wish to contribute to an improved management of this rare and complex disease.
Coinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls. However, the enhancement of BTLA expression after activation was significantly lower in SLE patients compared with that in healthy controls. Furthermore, we found an impaired capacity of BTLA to inhibit T cell activation in SLE due to a poor BTLA recruitment to the immunological synapse following T cell stimulation. Finally, we demonstrated that defective BTLA function can be corrected by restoring intracellular trafficking and by normalizing the lipid metabolism in lupus CD4+ T cells. Collectively, our results evidence that the BTLA signaling pathway is altered in SLE T cells and highlight the potential of targeting this pathway for the development of new therapeutic strategies in lupus.
Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-β and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab.
of SLE, and had active disease involving skin or joints. RNA isolated from whole blood at baseline and weeks 2, 4, 12, and 24 was analyzed using Affymetrix HTA2.0 array. Results Gene expression profiling demonstrated a statistically significant elevation of STAT1 and STAT2 gene expression at baseline in SLE patients. There was a significant association between the overexpression of STAT1 and STAT2 at baseline. Baricitinib 4-mg treatment resulted in modest reduction in STAT1, STAT2, and STAT4 expression, and a statistically significant reduction in multiple genes downstream of STAT1, STAT2, and STAT4. The reduction in expression of STAT-associated genes with baricitinib treatment correlated with clinical improvement in SLE patients using SLEDAI-2K measurements (table 1). Conclusions Baricitinib may partially mediate its effect in SLE through changes in STAT-related gene expression, with changes associated with clinical improvement in SLE. Acknowledgements Funded by Eli Lilly and Company.
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