Complement Driven Vasculopathy Underlies Neuropsychiatric Lupus Save

Neuropsychiatric lupus (NPSLE) is a diagnostic challenge as its clinical manifestations are protean and the pathophysiology is poorly understood.

A study published in the current issue of Rheumatology uses unique methodology to compare brain histopathology and ex vivo imaging in lupus patients with and without NPSLE and controls.

Cohen D, et al, from Leiden University used cerebral autopsy tissue from SLE patients both with and without NP manifestations. These patients had been autopsied between 1971-2010 and archived in a Dutch histo- and cytopathology database. Brain sections with stained with H&E, and also for complement components (C1q, MBL, C4d-C5b-9). Sections were evaluated by a neuropathologist for evidence of microinfarction, macroinfarction, large hemorrhage, microbleeds, cerebral infection, vasculitis and vasculopathy. Their search yielded brain tissue from 16 NPSLE and 18 SLE subjects, with 24 controls who had died of acute cardiac events.

They found that diffuse vasculopathy, microinfarction, macroinfarction, vasculitis and microthrombi occurred significantly more often in NPSLE compared to SLE patients, and was not seen in controls.

Complement deposition was also associated with NPSLE and SLE but not with controls. Interestingly, C4d and C5b-9 (membrane attack complex) were strongly associated with microthrombi within the NPSLE group.

For 3 patients, whole formalin-fixed brains were available, and ex-vivo 7-Tesla MRI was used to directly compare imaging findings to histopathology. This sophisticated imaging modality utilizes ultrahigh-field-strength technology to allow for higher resolution compared to standard MRI, however the authors found that 7-T MRI was unable to detect most small vessel injury that was seen histopathologically.

This study shows that histopathology from NPSLE lesions range from non-specific lesions to more specific lesions, including C4d and C5b-9deposition associated with microthrombi and diffuse vasculopathy.

NPSLE will remain a poorly understood manifestation of SLE, but this study reinforces the idea that there may be hope for manipulating the complement pathway as a therapeutic target in NPSLE and SLE.