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ABSTRACT & COMMENTARY
Treating Small Vessel PCNSV with Cyclophosphamide
July 1, 2025 4 minutes read
By Samuel S. Bruce, MD
Synopsis: In this single-center study, 26 adults with biopsy-confirmed small vessel primary central nervous system vasculitis (PCNSV) were followed for a median of 49 months. Patients receiving early treatment with cyclophosphamide within three months of immunosuppression initiation achieved remission faster than those receiving conservative initial treatment with corticosteroids, either as monotherapy or with azathioprine, mycophenolate, or methotrexate. Retrospective design, treatment selection bias, small sample size, and clinicopathologic heterogeneity limit therapeutic inferences and highlight the need for prospective trials.
Source: Reddy SP, LaHue SC, Goglin S, et al. Biopsy-confirmed small vessel primary CNS vasculitis: Clinical features and impact of early intensive treatment on remission. Neurol Neuroimmunol Neuroinflamm. 2025;12(4):e200397.
Primary central nervous system vasculitis (PCNSV) is an idiopathic immune-mediated vasculopathy affecting the blood vessels of the brain or spinal cord. Although PCNSV may affect vessels of all calibers, small vessel PCNSV is distinct from medium and large vessel variants in multiple ways: Small vessel PCNSV changes are only detected by biopsy, being below the resolution of angiography, and small vessel PCNSV is more likely than its larger vessel counterparts to present with cognitive decline, seizures, cerebrospinal fluid (CSF) abnormalities, and contrast enhancement on brain magnetic resonance imaging (MRI). Despite these differences, many clinical studies on PCNSV include small, medium, and large vessel variants together.
Management approaches to small vessel PCNSV can be highly variable in practice and often are extrapolated from data that include all patients with PCNSV as well as non-CNS, systemic vasculitides. First-line treatment typically involves high-dose glucocorticoids with or without additional immunosuppressive medications such as azathioprine, mycophenolate, or methotrexate. There is a lack of consensus regarding initiation of potent second-line agents, such as cyclophosphamide, early after first-line treatment vs. reserving such treatments only for escalation therapy if first-line treatment proves ineffective.
The authors conducted a single-center, retrospective cohort study of adults from 2009-2023 undergoing treatment for biopsy-proven small vessel PCNSV, with secondary etiologies excluded. Twenty-six patients in total were included (50% female, median age at symptom onset 55.5 years), including seven cases of amyloid beta-related angiitis (ABRA) and 19 cases of non-amyloid small vessel PCNSV. There was significant heterogeneity in histopathologic, CSF, and radiographic features. All patients began high-dose corticosteroids and were classified into two treatment groups: Those who received cyclophosphamide within three months and continued it for at least three months were classified as early intensive treatment (EIT) (n = 12), whereas patients in the escalation treatment (ESC) group (n = 14) received initial treatment with corticosteroids, alone or in conjunction with azathioprine, mycophenolate, or methotrexate. Five of the 14 patients in the ESC group eventually received cyclophosphamide a median of nine months from treatment initiation. The primary endpoint was time from treatment initiation to remission, defined by both clinical quiescence and absence of new MRI lesions.
Despite somewhat comparable baseline demographics, histopathology, and treatment delays, EIT was associated with faster and more universal disease control. All 12 EIT patients achieved remission vs. 11/14 (78.6%) in the ESC group. The median time to remission was five months with EIT compared with 19 months for ESC (hazard ratio, 0.24; 95% confidence interval, 0.10 to 0.63; P < 0.005). Over a median 49-month follow-up, relapses occurred in four patients (19%), two in each treatment group. The EIT group had a higher proportion with improvement in modified Rankin Scale score over two years, but this did not achieve statistical significance. Cumulative corticosteroid exposure remained high in both cohorts.
Commentary
This single-center series provides preliminary evidence that early induction with cyclophosphamide may be associated with a shorter time to remission in biopsy-proven small vessel PCNSV than a more conservative escalation-based approach. However, multiple factors limit one’s ability to draw firm conclusions about these competing treatment strategies. First, the sample size is small, with only 26 patients included. Second, the study population is heterogeneous, including patients with varying histopathological subtypes (lymphocytic, granulomatous, necrotizing, and ABRA), unilateral vs. bilateral hemispheric involvement, and with or without spinal cord disease. Any of these variables conceivably could affect the disease trajectory at least as strongly as treatment strategy, but the study is unequipped to fully adjust for their effects. Finally, these are retrospective observational data with nonrandomized treatment assignment and, therefore, there is strong treatment selection bias. Most patients in the ESC group had specific reasons for not receiving early cyclophosphamide, including diagnostic uncertainty, poor functional status, patient preference, and pregnancy.
This study also has clear strengths of biopsy-proven diagnosis and a long follow-up time. Considering these strengths, this study demonstrates the breadth of clinical, imaging, laboratory, and histopathologic phenotypes of small vessel PCNSV that are encountered in clinical practice. This work underscores important future priorities in this disease: harmonized outcome definitions, systematic assessment of clinicopathologic subtypes, and prospective multicenter protocols that directly compare immunosuppressive strategies while minimizing steroid exposure.
Samuel S. Bruce, MD, is Assistant Professor of Neurology, Weill Cornell Medicine.
In this single-center study, 26 adults with biopsy-confirmed small vessel primary central nervous system vasculitis (PCNSV) were followed for a median of 49 months. Patients receiving early treatment with cyclophosphamide within three months of immunosuppression initiation achieved remission faster than those receiving conservative initial treatment with corticosteroids, either as monotherapy or with azathioprine, mycophenolate, or methotrexate. Retrospective design, treatment selection bias, small sample size, and clinicopathologic heterogeneity limit therapeutic inferences and highlight the need for prospective trials.
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