State of the Art REVIEW
patients with systemic lupus erythematosus was 2.6. 208 After some improvements in survival were observed in the second half of the 20th century, 209 a study of over 11 million people in a UK NHS dataset 210 showed no improvement in survival of patients with systemic lupus erythematosus this century. The leading causes of death in patients with systemic lupus erythematosus include infection related to immunosuppression, renal disease, and cardiovascular disease. 209 In a prospective cohort study of 3811 patients, socioeconomic factors and smoking were identified as risk factors for mortality, alongside disease activity and glucocorticoid exposure. 211 Poor health related quality of life, rated among the highest concerns of patients with systemic lupus erythematosus, 162 has been shown in many studies, as summarized in a recent review. 212 The evidence of poor outcomes for patients with systemic lupus erythematosus underlines the need for improved treatments, and treatment strategies, for this disease. Emerging medicines are based on a deepening understanding of the biology of systemic lupus erythematosus. Treat-to-target approaches While new medicines will be needed, improvements in outcome in systemic lupus erythematosus can also be achieved through better use of current treatments. Stemming from two papers in 2014 outlining consensus on the need for treat-to-target strategies in systemic lupus erythematosus and a pathway to develop them, 213 214 treat-to-target approaches are now reflected in treatment guidelines for systemic lupus erythematosus. These approaches require not only low or absent disease activity but also, given the evidence of long term harm from their use, ceilings in glucocorticoid dose. The definition of remission in systemic lupus erythematosus (DORIS) group reported a consensus definition of remission which rests on the absence of clinical disease activity and a prednisolone (or equivalent) ceiling of 5 mg/day. 215 As remission is infrequently achieved in systemic lupus erythematosus, LLDAS (embodying the absence of severe disease activity or flare), and a low treatment burden with a prednisolone ceiling of 7.5 mg/day, have also been defined. 216 These goals of treatment have been validated in cohort studies and prospective studies as protective from organ damage accrual, mortality, and loss of quality of life, 205 211 217 218 including in a 1735 patient multicenter prospective study. 219 220 In the prospective cohort study of 3811 patients mentioned above, attainment of LLDAS or remission was protective from mortality, and steroid free remission was markedly more protective. 211 Attainment of remission or LLDAS has been shown to be associated with improved health related quality of life in a 1422 patient cross sectional study, 218 and in post hoc analysis of clinical trials of belimumab and anifrolumab. 171 221 Formal prospective strategy trials are needed to show whether treat-to-target approaches (eg, adjusting treatment in a metric based way based
safe in lupus nephritis patients with reduced renal function, which is not yet confirmed for calcineurin inhibitors such as voclosporin (see below). In parallel, the importance of the innate immune system in systemic lupus erythematosus has been confirmed by trials of anifrolumab, an antibody to the type I interferon receptor. After a positive phase 2 randomized trial in 305 patients, 199 two phase 3 trials were completed. The first, in 457 patients, was a negative study based on the primary outcome measure of SRI, although numerous secondary outcome measures were nominally positive 113 ( table 2 ). The second, using a different endpoint, was positive for the primary and many secondary outcomes, 112 and anifrolumab was approved in 2021-22 in multiple jurisdictions. Subsequent post hoc analyses suggest efficacy across multiple organ domains, reduction in flares, and glucocorticoid sparing effects of anifrolumab. 111 200 201 Safety considerations for anifrolumab include increased herpes zoster reactivation and upper respiratory infections. 202 Importantly, a long term extension study in which 547 patients from the phase 3 trials were re-randomized to placebo or anifrolumab 300 mg monthly if they had been on placebo, or continued on anifrolumab 300 mg monthly if they had been on anifrolumab, showed no new safety signals compared with the first year of treatment, as well as long term trends towards both reduced disease activity and reduced glucocorticoid dosing in anifrolumab treated patients. 203 A phase 2 trial of anifrolumab in 147 patients with lupus nephritis was negative, 154 but suggestions of efficacy in secondary outcome measures have prompted a phase 3 trial to be initiated in this indication. Finally, the novel calcineurin inhibitor voclosporin was shown to be effective compared with placebo in a phase 3 study of 357 patients with lupus nephritis 153 in which all patients also received mycophenolate mofetil, and this drug received regulatory approval in 2021. The actions of voclosporin include effects on T lymphocytes and podocytes. These results come after several encouraging studies of an older calcineurin inhibitor, tacrolimus; for example, a study of 150 patients showing non-inferiority compared with mycophenolate mofetil. 204 Outcomes with current treatment Despite recent approvals of new treatments, outcomes for patients with systemic lupus erythematosus remain poor. A longitudinal cohort study of over 3300 patients identified that up to one- third do not achieve treatment goals, and that failure to do so is associated with worse outcomes in terms of irreversible organ damage, health related quality of life, and mortality. 205 This finding is supported by smaller studies showing that failure to achieve low disease activity soon after diagnosis is associated with increased mortality and organ damage. 206 207 In an international meta-analysis representing data from Asia, Europe, and North America from 1999 to2020, the overall standardized mortality ratio for
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doi: 10.1136/bmj-2022-073980 | BMJ 2023;383:073980 | the bmj
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