Neurological Disease in Lupus: Toward a Personalized Medicine Approach

Abstract

The brain and nervous system are important targets for immune-mediated damage in systemic lupus erythematosus (SLE), resulting in a complex spectrum of neurological syndromes. Defining nervous system disease in lupus poses significant challenges. Among the difficulties to be addressed are a diversity of clinical manifestations and a lack of understanding of their mechanistic basis. However, despite these challenges, progress has been made in the identification of pathways which contribute to neurological disease in SLE. Understanding the molecular pathogenesis of neurological disease in lupus will inform both classification and approaches to clinical trials.

Keywords: interferon type I; lupus erythematosus; neurolupus; personalized medicine; systemic; targeted therapy.

Figure 1

The spectrum of neurological disease in lupus. Lupus can affect all levels of the nervous system, including the brain and spinal cord, as well as the peripheral nervous system. See text for detailed descriptions of individual syndromes.

Figure 2

Classifying neurological disease in lupus. Both the brain and kidney can be severely affected in up to 10% of patients with lupus. (A) While lupus nephritis can present with different clinical syndromes, it is largely defined by a pathological classification of the renal biopsy. Image created with Biorender. (B) In contrast, neurological forms of lupus are usually classified according to neurological syndrome, and pathological material is rarely obtained. (C) We have an increasingly precise understanding of the syndrome previously described as “lupus myelopathy,” T2-weighted magnetic resonance imaging of long inflammatory lesion in person with lupus shown, with high signal from within the thoracic spinal cord. A proportion of such spinal cord presentations are driven by antibodies directed against aquaporin-4, a glial water channel (21). Other cases are caused by spinal cord inflammation without these antibodies, while some cases are associated with spinal cord ischemia (22, 23). Each of these causes may require consideration of differing therapeutic approaches. As such, what was previously considered a single disease entity can be caused by differing pathogenic mechanisms, with implications for treatment and clinical trial design.

Figure 3

Magnetic resonance imaging (MRI) imaging in lupus brain disease. (A,B) Fluid-attenuated inversion recovery MRI scan of a representative individual with lupus, showing accelerated cerebral small vessel disease, highlighted red arrows. (C,D) Advanced MRI techniques such as diffusion tensor imaging and tractography can allow identification of individual white matter tracts and parameters such as mean diffusivity can identify microstructural disease. Tractography images of lupus patient shown, each line represents individual white matter tract. Credit: Mark Bastin, Joanna Wardlaw, and Stewart Wiseman.

Figure 4

A stratified medicine approach for neurolupus. Brain disease in lupus is clinically heterogeneous (left), but may be driven by certain molecular pathways (e.g., type I interferon pathway, pathogenic autoantibodies), allowing stratification of populations. Improvements in biomarkers will allow identification of aberrant pathways in patients, such that they can be directed to clinical trials targeted at the specific pathway. Central to the success of such a strategy is the development of brain biomarkers (e.g., magnetic resonance imaging scans, markers of brain damage) to supplement clinical assessment.