State of the Art REVIEW
common other organ domains affected. 163 Further heterogeneity exists within each organ system; for example, multiple types of skin, joint, and renal disease are recognized. Neuropsychiatric lupus is less common, but also represents a broad catalogue of manifestations. 164 As recently reviewed, 165 cognitive dysfunction is commonly reported by patients with systemic lupus erythematosus, but a recent cross sectional study suggested a poor correlation between patient reported cognitive symptoms and objective findings. 161 Consistent with the multisystem nature of systemic lupus erythematosus, the list of other manifestations of systemic lupus erythematosus is long, and includes serositis, gastrointestinal disease, ocular disease, hepatitis, heart disease, and lung disease. Importantly, systemic lupus erythematosus is also heterogeneous in its time course, with some patients manifesting features all at once and others in an unpredictable series of steps over months or years. Similarly, the time course of disease activity varies greatly between patients, from relapse and remission in some to persistently active disease in others. 166 Of note, when systemic lupus erythematosus begins in childhood, it often takes a more severe form, characterized by higher rates of lupus nephritis, anti-dsDNA antibody positivity, and hemolytic anemia, as well as higher disease activity, morbidity, and mortality than adult onset systemic lupus erythematosus. 167 Antiphospholipid syndrome, in which autoantibodies to antigens with roles in the coagulation system (such as β 2 glycoprotein 1) are associated with clinical manifestations including arterial and venous thrombosis, pregnancy loss, and thrombocytopenia, can occur in patients with systemic lupus erythematosus as well as de novo (primary antiphospholipid syndrome). Please see the recent BMJ State of the Art review on this topic for more information. 168 As noted below in the guidelines section, a paucity of robust evidence and the clinical heterogeneity of the disease hamper the ability to provide clear guidance to practitioners on how to treat systemic lupus erythematosus; lupus nephritis is an exception in that several studies have compared treatment approaches for this manifestation. Treatment of systemic lupus erythematosus Goals of treatment The overarching goals of treatment for systemic lupus erythematosus are to reduce disease activity, prevent irreversible organ damage, and retain quality of life. These goals are achieved through seeking remission, or if remission cannot be attained, a state of low disease activity. As glucocorticoids contribute to the risk of long term harm in systemic lupus erythematosus, remission and low disease activity concepts in systemic lupus erythematosus combine the requirement for low disease activity with a requirement for low glucocorticoid doses. These goals are, unfortunately, not reflected in primary outcome measures used in systemic lupus erythematosus
clinical trials. As a result, translation of clinical trials into clinical practice is not directly guided by trial results and requires considerable interpretation by clinicians. Fortunately, the low disease activity and remission definitions have now been shown to be achievable and highly discriminatory in post hoc analysis of clinical trial datasets, 169-171 and, as a result, now appear as key secondary outcome measures in more recent trials 142 143 147 ; this should allow for a more direct application of trial outcomes to the goals of care in future. Due to the lack of evidence directly linking treatments to treatment goals, the information that follows is organized by drug class, with the general guidance that the least harmful treatment that maintains control of disease activity should be used. Antimalarials A core tenet of drug treatment for systemic lupus erythematosus is that treatment with an antimalarial (usually hydroxychloroquine) is recommended for all patients unless contraindicated. Although prospective studies are lacking, analysis of a longitudinal inception cohort of 1460 patients followed for 20 years indicated that antimalarials reduce the frequency of flares, 172 and another study of 6241 patients indicated that hydroxychloroquine use was associated with reduced mortality. 173 Confirming these results, a study of whole blood and serum hydroxychloroquine concentrations in 573 patients with systemic lupus erythematosus showed an association between drug level and avoidance of active disease 174 ; this and similar studies 175 also revealed high rates of non-adherence to standard treatment in patients with systemic lupus erythematosus that further complicate management. Adverse effects of hydroxychloroquine include rash, gastrointestinal discomfort, and uncommonly, skin pigmentation (incidence of approximately 7%) 176 and retinal toxicity (overall prevalence of 7.5%, with increase to 20% after 20 years of treatment). Retinal toxicity has led to a recommendation of a maximum dose of 5 mg/kg/day (actual body weight) based on a retrospective case-control study in 2361 patients with at least 5 years of exposure. 177 A joint statement of professional rheumatology, dermatology, and ophthalmology societies has highlighted the need for screening for retinal toxicity, but also the safety of long term hydroxychloroquine when appropriate precautions are taken. 178 A minority of patients have adequate control of disease with non-drug measures and antimalarials alone. Treatment guidelines 179 180 suggest the addition of glucocorticoids and immunosuppressants, or both, in this setting, and these drugs are often started when disease is moderately severe or severe at onset. Glucocorticoids Glucocorticoids are a mainstay of both acute and chronic treatment of systemic lupus erythematosus. Large multicenter multinational longitudinal cohort studies show that glucocorticoids are used
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doi: 10.1136/bmj-2022-073980 | BMJ 2023;383:073980 | the bmj
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