Elsevier

Journal of Autoimmunity

Volume 96, January 2019, Pages 1-13
Journal of Autoimmunity

Systemic lupus erythematosus: Diagnosis and clinical management

https://doi.org/10.1016/j.jaut.2018.11.001Get rights and content

Highlights

  • Classification criteria are a helpful diagnostic framework to confirm clinical judgement.

  • Hydroxychloroquine is the cornerstone of medical therapy in lupus.

  • Immunosuppression and targeted therapies are paramount for renal and severe extra-renal lupus manifestations.

  • New therapies targeting the Th17, BAFF, JAK/STAT, and calcineurin pathways showed positive phase 2b trial results.

Abstract

Systemic lupus erythematosus (SLE) is a worldwide chronic autoimmune disease which may affect every organ and tissue. Genetic predisposition, environmental triggers, and the hormonal milieu, interplay in disease development and activity. Clinical manifestations and the pattern of organ involvement are widely heterogenous, reflecting the complex mosaic of disrupted molecular pathways converging into the SLE clinical phenotype. The SLE complex pathogenesis involves multiple cellular components of the innate and immune systems, presence of autoantibodies and immunocomplexes, engagement of the complement system, dysregulation of several cytokines including type I interferons, and disruption of the clearance of nucleic acids after cell death. Use of immunomodulators and immunosuppression has altered the natural course of SLE. In addition, morbidity and mortality in SLE not only derive from direct immune mediated tissue damage but also from SLE and treatment associated complications such as accelerated coronary artery disease and increased infection risk.

Here, we review the diagnostic approach as well as the etiopathogenetic rationale and clinical evidence for the management of SLE. This includes 1) lifestyle changes such as avoidance of ultraviolet light; 2) prevention of comorbidities including coronary artery disease, osteoporosis, infections, and drug toxicities; 3) use of immunomodulators (i.e. hydroxychloroquine and vitamin D); and 4) immunosuppressants and targeted therapy. We also review new upcoming agents and regimens currently under study.

Introduction

Systemic lupus erythematosus (SLE) is the quintessential autoimmune disease. A complex interaction of impaired apoptotic clearance, upregulation of innate and adaptive immune system, complement activation, immune complexes, and tissue inflammation culminates in a self-sustained autoimmune process. Multiple pathogenic mechanisms likely can converge toward the clinical phenotypes that we call SLE. In fact, while many organs and tissues may be affected by SLE, the pattern of clinical manifestations and autoimmune phenomena is heterogenous among patients and even changes over time in individual patients. For this reason, diagnosis is often difficult or delayed and relies on keen clinical expertise to combine clinical and immunological findings. Here, we review classification criteria and current and future treatments with a mechanistic and evidence-based point of view.

Section snippets

Epidemiology

Lupus is a worldwide disease with a striking predilection for women of childbearing age. In women between the age of 15 and 44 years, the female to male ratio is up to 13:1 while it is only 2:1 in children and in the elderly [[1], [2], [3]]. While present across ethnicities, it is more prevalent in non-Caucasians. While prevalence in Europe and United States is higher in people of African descent, SLE is infrequent in Africa [4,5]. In the United States, it is more common in African-Americans,

Pathogenesis overview

The clinical onset of SLE requires an interaction of genetic predisposition, environmental precipitants, immunological and hormonal factors. In such a permissive environment, along with proinflammatory stimuli such as type 1 interferons and other cytokines, immune tolerance to self-antigens is lost [11]. Autoimmunity then follows driven by a complex interplay of defective clearance of apoptotic waste and immune complexes along with neutrophil extracellular traps, sensing of nucleic acids,

Diagnosis

The diagnosis of systemic lupus erythematosus is made based on a combination of typical clinical manifestations and positive serologies. Given the wide heterogeneity of clinical manifestations, several sets of classification criteria have been developed over time for epidemiological and research purposes. However, some, such as the SLICC classification criteria, which are more sensitive, and therefore particularly useful in early diagnosis, can be useful as a diagnostic framework to confirm

Principles

The goals of treatment in lupus are 1) maintain lowest degree of activity using immunomodulators, immunosuppression as appropriate and avoiding known triggers, 2) prevent organ damage from active lupus, 3) reduce comorbidities secondary to lupus and its treatment, especially accelerated atherosclerosis, the major cause of death, and 4) address fatigue and pain, which often are not associated with active lupus. Early initiation of treatment as well as partnership with the patient towards these

Future perspectives and personalized medicine

The more granular understanding of the molecular basis of lupus pathogenesis has led to several new promising treatments that are undergoing late phase clinical testing. These recent phase 2 trials underlined how targeting a specific pathway may elicit dramatically different responses in patient subgroups. Precise characterization of disease phenotypes based on molecular and clinical features is crucial to design personalized treatment. The Accelerated Medicine Partnership (AMP), for example,

Funding

The Hopkins Lupus Cohort is funded by NIH AR 69572.

Disclosures

None.

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