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Are there any differences in the response to apheresis therapy for steroid refractory relapses among patients with histologically defined immunopathological patterns of multiple sclerosis?
This cohort study of 69 patients defined 3 patterns of multiple sclerosis and observed functional improvement after apheresis therapy in patients with histological pattern 1 (31%) and pattern 2 (55%), but not in patients with pattern 3. Secondary outcome parameters (magnetic resonance imaging and expanded disability status scale improvement) strongly supported the primary outcome.
Response to apheresis therapy may be associated with immunopathological patterns and thus with pathological mechanisms of lesion development.
Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell– and macrophage–associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response.
To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis.
Design, Setting and Participants
This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded.
Main Outcomes and Measures
The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters.
The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], −1.43; 95% CI, −3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01).
Conclusions and Relevance
This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions.
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Corresponding Author: Imke Metz, MD, Institute of Neuropathology, University Medical Center Goettingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany (firstname.lastname@example.org).
Accepted for Publication: September 15, 2017.
Published Online: February 5, 2018. doi:10.1001/jamaneurol.2017.4842
Author Contributions: Dr Metz and Ms Stork had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Metz, Brück and Lucchinetti.
Acquisition, analysis, or interpretation of data: Stork, Ellenberger, Metz, Brück.
Drafting of the manuscript: Stork, Ellenberger, Metz.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Ellenberger, Beißbarth, Friede.
Obtained funding: Brück, Metz.
Administrative, technical, or material support: Lucchinetti, Brück, Metz.
Study supervision: Metz.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by the German Federal Ministry of Education and Research (Bunderministerium fur Bildung und Forschung) and the German Competence Network Multiple Sclerosis (Kompetenznetz Multiple Sklerose), Pattern Multiple Sclerosis/Neuromyelitis Optica (Drs Metz and Brück).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We acknowledge Sven Müller, Institute of Neuropathology, University Medical Center, Goettingen, Germany, for his outstanding administrative support. No compensation from a funding sponsor was involved in his contribution.
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