State of the Art REVIEW
recommended for all patients with systemic lupus erythematosus unless contraindicated. Additional treatments are guided by broad categories of severity of active disease. Mild disease, characterized as constitutional symptoms, mild rash or arthritis, and thrombocytopenia with a platelet count no less than 50 000/mm 3 , is recommended to be treated with the addition of glucocorticoids. Moderate disease activity, characterized as rheumatoid-like arthritis, more severe skin disease or cutaneous vasculitis affecting <18% of body surface area, serositis, or thrombocytopenia with a platelet count no less than 20 000/mm 3 , is recommended to be treated with the addition of immunosuppressives to antimalarials and glucocorticoids (options include methotrexate, azathioprine, mycophenolate, or calcineurin inhibitors, with the addition of belimumab in refractory cases). Severe disease activity, categorized as major organ threatening disease such as kidney and central nervous system disease, is recommended to be treated with the addition of mycophenolate, cyclophosphamide, or rituximab. These categories of severity are also listed according to the systemic lupus erythematosus disease activity index (SLEDAI) and British Isles lupus assessment group (BILAG) disease activity measures, but these are rarely used outside the research setting; the guidelines also highlight that most of these recommendations are not derived from level A evidence. Glucocorticoids are recommended across the entire spectrum of disease, which reflects a paucity of safe effective alternatives for the treatment of systemic lupus erythematosus. Similar guidelines were also published in 2019 for childhood onset systemic lupus erythematosus, 234 albeit with an even shallower evidence base. Conclusion We look forward to a future where optimism can replace the guarded prognostic discussions that still characterize our conversations with patients with systemic lupus erythematosus today. Notwithstanding ongoing concerns with trial and endpoint design, the information in table 2 highlights a remarkable increase in clinical development activity in systemic lupus erythematosus over the past two decades but, unfortunately, successes leading to new product approvals are uncommon. To improve our ability to deliver better outcomes for patients, research efforts should shift towards a focus on just that: improving the lives of patients. This shift requires patient centered approaches, application of advances in pathogenic understanding to identification and testing of therapeutic targets, evidence based decision making in clinical practice, and improved robustness of outcome measures used in trials to improve the utility of both positive and negative results ( fig 2 ). Reclassification of systemic lupus erythematosus into subsets based on biological profiles could help in the assignment of individual patients to the treatments best suited to them, which potentially include combinations of adaptive and innate immune targeting medicines; importantly, this approach could
also result in reclassification of autoimmune diseases as a class into a system based on molecular profiles rather than clinical clusters. 11 Alternatively, single organ studies with specific readouts could result in a variety of basket trial approaches, some of which are now being cautiously introduced (NCT05162586). Antigen specific approaches have had proof of concept in other autoimmune diseases 235 and could lead to a patient-by-patient approach; alternatively, the discovery that GILZ mediates the effects of glucocorticoids in systemic lupus erythematosus but lacks metabolic toxicity 51 53 could lead to a broad spectrum approach obviating the need for detailed immune profiling. Regardless, as outcomes including death in systemic lupus erythematosus are closely linked to socioeconomic factors, future advances in treatment must be made available to patients around the world. Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: EFM receives research funding from the National Health and Medical Glossary of abbreviations • SLICC: systemic lupus international collaborating clinics • EULAR: European Alliance of Associations for Rheumatology • PTPN22: protein tyrosine phosphatase non-receptor type 22 • GILZ: glucocorticoid induced leucine zipper • BAFF: anti-B cell activating factor • NETs: neutrophil extracellular traps • TLRs: toll-like receptors • cGAS/STING: GMP-AMP synthase/stimulator of interferon genes • LLDAS: lupus low disease activity state • SRI: systemic lupus erythematosus responder index • DORIS: definition of remission in systemic lupus erythematosus group • TYK2: tyrosine kinase 2 • CAR-T: chimeric antigen receptor T cell • SLEDAI: systemic lupus erythematosus disease activity index • BILAG: British Isles lupus assessment group Questions for future research • Should systemic lupus erythematosus and related autoimmune diseases be reclassified using biological, rather than clinical, descriptors? • Should we continue to study treatments in pooled patients with systemic lupus erythematosus, or in organ specific patient groups or biologically determined subsets? • How should we measure treatment response in systemic lupus erythematosus trials in the future? • Will the combination of innate plus adaptive immune targeting be necessary to completely control disease activity in systemic lupus erythematosus, or does the link between them mean that targeting one is sufficient?
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doi: 10.1136/bmj-2022-073980 | BMJ 2023;383:073980 | the bmj
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