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

Evgenia Emmanouilidou; Despoina Kosmara; Efrosini Papadaki; Vasileios Mastorodemos; Pantelis Constantoulakis; Argyro Repa; Georgia Christopoulou; Christina Kalpadakis; Nestor Avgoustidis; Konstantinos Thomas; Dimitrios Boumpas; Prodromos Sidiropoulos; George Bertsias

doi:10.3390/jcm12216945

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

J Clin Med. 2023 Nov 6;12(21):6945. doi: 10.3390/jcm12216945.

Authors

Evgenia Emmanouilidou¹, Despoina Kosmara^{1

2}, Efrosini Papadaki^{3

4}, Vasileios Mastorodemos⁵, Pantelis Constantoulakis⁶, Argyro Repa¹, Georgia Christopoulou⁶, Christina Kalpadakis⁷, Nestor Avgoustidis¹, Konstantinos Thomas⁸, Dimitrios Boumpas^{8

9}, Prodromos Sidiropoulos^{1

2}, George Bertsias^{1

2}

Affiliations

¹ Rheumatology and Clinical Immunology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece.
² Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 71110 Heraklion, Greece.
³ Department of Radiology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece.
⁴ Computational Bio-Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology-Hellas, 71110 Heraklion, Greece.
⁵ Department of Neurology, University Hospital of Heraklion, 71110 Heraklion, Greece.
⁶ Genotypos Science Labs Medical SA, 11528 Athens, Greece.
⁷ Department of Laboratory Hematology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece.
⁸ 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Attikon University General Hospital, 12462 Chaidari, Greece.
⁹ Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece.

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.

Grants and funding

This research is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme “Human Resources Development, Education and Lifelong Learning” in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” (MIS-5000432), implemented by the State Scholarships Foundation (ΙΚΥ).