Long-term clinical and biomarker observations following rituximab exposure in two siblings with CSF1R-related leukoencephalopathy: a preliminary familial case series
Abstract
Background: Colony-stimulating factor 1 receptor ( CSF1R )-related leukoencephalopathy (CRL) is a rare microgliopathy, characterized by progressive neurodegeneration. Impaired STAT3 signaling reduces microglial numbers and limits their ability to clear cellular debris, leading to persistent inflammation and brain tissue damage that activates peripheral CD20⁺ B cells. These cells migrate into the CNS and secrete interleukin-6 (IL-6), amplifying inflammation and further disrupting STAT3 signaling in a self-reinforcing cycle that drives white-matter injury.
Methods: We describe two siblings from a single family, both carrying the same heterozygous CSF1R variant (c.2562 T > A, p.Asn854Lys), who received four infusions of rituximab (RTX;500 mg) on a compassionate, off-label basis between 2014-2017. The long-term disease trajectory was evaluated using standardized clinical rating scales and brain magnetic resonance imaging (MRI). As a secondary biomarker outcome, serum and CSF neurofilament light chain (NfL) concentrations were assessed.
Results: In both siblings, RTX exposure was followed by EDSS stability at 6.5 and 7.0, respectively, over 5 years, with mixed trajectories in other functional and cognitive domains. Over the 23-year MRI follow-up period, patients developed cerebral atrophy. During the post-treatment period, no new focal lesions were observed on brain MRI, and levels of CSF-NfL and CSF-CXCL13 were normalized.
Conclusions: In this preliminary familial case series of two siblings carrying the same CSF1R variant, RTX exposure was followed by long-term clinical stability and favorable biomarker trajectories. Patient 1 had a pre-treatment disease course of approximately 13 years, indicating an inherently slow disease progression that cannot be entirely separated from the treatment effect in an uncontrolled observation.
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BibTeX
@article{balevicius2026longterm,
title = {{Long-term clinical and biomarker observations following rituximab exposure in two siblings with CSF1R-related leukoencephalopathy: a preliminary familial case series}},
author = {Ramojus Balevicius and Lidija Marija Smertinaite and Mourad Kourie and Zbigniew Wszolek and Goda-Camile Mickeviciute and Robert Harris and Tobias Granberg and Nadezda Zhuravleva and Jinming Han and Virginija Danylaite Karrenbauer},
journal = {Communications Medicine},
year = {2026},
month = sep,
doi = {10.1038/s43856-026-01936-5},
url = {https://www.nature.com/articles/s43856-026-01936-5},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Long-term clinical and biomarker observations following rituximab exposure in two siblings with CSF1R-related leukoencephalopathy: a preliminary familial case series
AU - Ramojus Balevicius
AU - Lidija Marija Smertinaite
AU - Mourad Kourie
AU - Zbigniew Wszolek
AU - Goda-Camile Mickeviciute
AU - Robert Harris
AU - Tobias Granberg
AU - Nadezda Zhuravleva
AU - Jinming Han
AU - Virginija Danylaite Karrenbauer
PY - 2026
DA - 2026/09/30
JO - Communications Medicine
DO - 10.1038/s43856-026-01936-5
UR - https://www.nature.com/articles/s43856-026-01936-5
AB - Background: Colony-stimulating factor 1 receptor ( CSF1R )-related leukoencephalopathy (CRL) is a rare microgliopathy, characterized by progressive neurodegeneration. Impaired STAT3 signaling reduces microglial numbers and limits their ability to clear cellular debris, leading to persistent inflammation and brain tissue damage that activates peripheral CD20⁺ B cells. These cells migrate into the CNS and secrete interleukin-6 (IL-6), amplifying inflammation and further disrupting STAT3 signaling in a self-reinforcing cycle that drives white-matter injury. Methods: We describe two siblings from a single family, both carrying the same heterozygous CSF1R variant (c.2562 T > A, p.Asn854Lys), who received four infusions of rituximab (RTX;500 mg) on a compassionate, off-label basis between 2014-2017. The long-term disease trajectory was evaluated using standardized clinical rating scales and brain magnetic resonance imaging (MRI). As a secondary biomarker outcome, serum and CSF neurofilament light chain (NfL) concentrations were assessed. Results: In both siblings, RTX exposure was followed by EDSS stability at 6.5 and 7.0, respectively, over 5 years, with mixed trajectories in other functional and cognitive domains. Over the 23-year MRI follow-up period, patients developed cerebral atrophy. During the post-treatment period, no new focal lesions were observed on brain MRI, and levels of CSF-NfL and CSF-CXCL13 were normalized. Conclusions: In this preliminary familial case series of two siblings carrying the same CSF1R variant, RTX exposure was followed by long-term clinical stability and favorable biomarker trajectories. Patient 1 had a pre-treatment disease course of approximately 13 years, indicating an inherently slow disease progression that cannot be entirely separated from the treatment effect in an uncontrolled observation.
SN - 2730-664X
ER -