Progressive Multifocal Leukoencephalopathy in Systemic Lupus Erythematosus: A Consequence of Patient-Intrinsic or -Extrinsic Factors?

Abstract

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.

Keywords: CDH7; GATA2; immunodeficiency; lymphopenia; polyomavirus.

Figure 1

Sequence of events in the SLE patient. D/C: Discontinuation; HCQ: hydroxychloroquine; PZ: prednisolone; WBC: white blood cells; AZA: azathioprine; MTX: methotrexate; CsA: cyclosporine; RTI: respiratory tract infection; IVIG: intravenous immune globulin.

Figure 2

Initial brain MRI of the patient with axial fluid-attenuated inversion recovery (FLAIR) (A–C), diffusion weighted imaging (DWI) (D), apparent diffusion coefficient (ADC) map (E), T2 (F–H), gradient echo (GRE) (I), and post-Gadolinium T1 (J) sections. A large, hyperintense, non- enhancing white matter lesion was revealed in the left frontoparietal area, with patchy, moderate restricted diffusion, along with local thinning and hemosiderin deposition of the adjacent cortex. Cerebral blood flow (CBF) map (K–M) derived from dynamic susceptibility contrast (DSC)-perfusion MRI showed decreased cerebral blood flow (CBF) in the involved parenchyma. Single-voxel spectroscopy (TE = 135 ms) (N) placed at the region of interest revealed the reduction in the N-acetyl aspartate (NAA)-to-creatine ratio (0.76), without a significant increase in the choline-to-creatine ratio (1.2) and presence of an inverted lactate peak. Magnetic resonance angiography (MRA) (O) of the brain was normal.

Figure 3

Axial T2 (A), FLAIR (B), DWI (C), ADC map (D), and post-Gadolinium T1 (E) sections of a follow-up brain MRI that was performed 1,5 months after the initial MRI, showed expansion of the pre-existing non-enhancing, T2 hyperintense, white matter lesion in the left frontoparietal area, with characteristic involvement of the U-fibers, lack of mass effect, and peripheral restricted diffusion, indicative of PML. Two months later, axial FLAIR (F,G), GRE (H), and pre- (I) and post-Gadolinium T1 (J) sections of a follow-up MRI showed further progression of the non-enhancing left frontoparietal lesion, a new lesion in the left thalamus, extending to the mesencephalon, and a subacute left parietal hematoma. Two more follow-up MRIs 5 months (axial FLAIR (K,L) and T2 (M)) and 10 months (axial FLAIR (N) and GRE (O)) later revealed new lesions in the right frontotemporal and parietal areas, with imaging characteristics also suggestive of PML, further loss of brain parenchyma and cortical hemorrhagic deposition in the left hemisphere, as well as bilateral frontoparietal subdural hematomas.

Figure 4

(A) GATA2 structure. The red arrow indicates the c.1132A>G variant position in exon 6. (B) Integrative Genomics Viewer (IGV) screenshot showing the GATA2 c.1132A>G variant.

Figure 5

(A) CHD7 structure. The red arrow indicates the c.8287_8295dup position in exon 38. (B) Integrative Genomics Viewer (IGV) screenshot showing the CHD7 c.8287_8295dup variant.

Figure 6

Disease-extrinsic and -intrinsic risk factors presumably linked to increased susceptibility for JC virus re-activation and PML in patients with SLE.