State of the Art REVIEW
kappa by keratinocytes. 115 158 Interestingly, ultraviolet light exposure to the skin can also drive local and systemic type I interferon responses via cGAS/STING activation. 103 Overall, growing evidence over the past decade confirmed by clinical trials of interferon-targeting treatments suggests that dysregulation of the innate immune system is crucial in the initiation and perpetuation of systemic lupus erythematosus, with potentially multiple distinct paths to innate immune system dysregulation converging on the clinical systemic lupus erythematosus phenotypes. It remains to be seen whether different origins of innate immune overactivation relate to different clinical phenotypes within the overall systemic lupus erythematosus diagnostic category and, as such, require different treatment approaches. Clinical phenotypes of systemic lupus erythematosus Setting aside the challenge of problematic classification of a heterogeneous set of phenotypes under a single diagnostic rubric, patients classified with systemic lupus erythematosus have highly heterogeneous clinical manifestations. Constitutional symptoms such as fever, brain fog, and especially fatigue affect most patients; fatigue is rated by patients among the highest impact features of their disease and is a major driver of low quality of life reported by patients with systemic lupus erythematosus. 161 162 Inflammatory arthropathy and mucocutaneous disease are seen in most patients, while glomerulonephritis and hematological disease, each seen in about 50% of patients, are the most
plasmacytoid dendritic cells are a major source of type I interferon in patients with systemic lupus erythematosus remains unresolved. 114 In fact, recent evidence has suggested that circulating plasmacytoid dendritic cells from patients with systemic lupus erythematosus are dysfunctional, and display a senescent phenotype. 115 Beyond type I interferon production, plasmacytoid dendritic cells could play additional roles in systemic lupus erythematosus pathogenesis, as these cells produce other proinflammatory cytokines including interleukin 6, interferon lambda, and chemokines, and can function as antigen presenting cells. 116 However, as noted in table 2 , the monoclonal antibody litifilimab, which targets the plasmacytoid dendritic cell surface marker BDCA2, has shown promise in phase 2 clinical trials in systemic lupus erythematosus, 144 145 and reduces interferon signatures in systemic lupus erythematosus patient blood and skin .156 Alongside plasmacytoid dendritic cells, other cell types have emerged as potential sources of type I interferons in systemic lupus erythematosus, including monocytes/macrophages, follicular dendritic cells, and keratinocytes. 157-160 Caielli et al recently showed the removal of dysfunctional mitochondria in mature red blood cells from patients with systemic lupus erythematosus. These mitochondria carrying red blood cells can stimulate type I interferon production through the cGAS/STING cytoplasmic DNA sensor pathway after undergoing antibody mediated phagocytosis by macrophages. 160 The skin is also likely to contribute to type I interferon production, mainly via the expression of interferon
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Fig 2 | Timeline of treatments for systemic lupus erythematosus, and a roadmap for future progress. Many drugs forming the standard of care for systemic lupus erythematosus have been in use since the 1950s, with no new treatments being approved for decades until the approval of belimumab in 2011. Improving on this history requires that research be specifically focused on doing so, including a patient centered and biologically grounded approach to the study of systemic lupus erythematosus, evidence based decision making in clinical practice, as well as improved measurements to increase the utility of clinical trial data, even negative data. NSAID=non-steroidal anti-inflammatory drug. †Approved for lupus nephritis
the bmj | BMJ 2023;383:073980 | doi: 10.1136/bmj-2022-073980
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