Differences in the reponses to apheresis therapy of patients with 3 histopathologically classified immunopathological patterns of multiple sclerosis

Lidia Stork, David Ellenberger, Tim Beißbarth, Tim Friede, Claudia F Lucchinetti, Wolfgang Brück, Imke Metz

Research output: Contribution to journalArticle

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Abstract

IMPORTANCE 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. OBJECTIVE 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. RESULTS 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.

Original languageEnglish (US)
Pages (from-to)428-435
Number of pages8
JournalJAMA Neurology
Volume75
Issue number4
DOIs
StatePublished - Apr 1 2018

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Blood Component Removal
Multiple Sclerosis
Therapeutics
Demyelinating Diseases
Plasma Exchange
Humoral Immunity
Cohort Studies
Odds Ratio
Acute Disseminated Encephalomyelitis
Neuromyelitis Optica
Recurrence
Oligodendroglia
Brain Stem
Immunoglobulins

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Differences in the reponses to apheresis therapy of patients with 3 histopathologically classified immunopathological patterns of multiple sclerosis. / Stork, Lidia; Ellenberger, David; Beißbarth, Tim; Friede, Tim; Lucchinetti, Claudia F; Brück, Wolfgang; Metz, Imke.

In: JAMA Neurology, Vol. 75, No. 4, 01.04.2018, p. 428-435.

Research output: Contribution to journalArticle

Stork, Lidia ; Ellenberger, David ; Beißbarth, Tim ; Friede, Tim ; Lucchinetti, Claudia F ; Brück, Wolfgang ; Metz, Imke. / Differences in the reponses to apheresis therapy of patients with 3 histopathologically classified immunopathological patterns of multiple sclerosis. In: JAMA Neurology. 2018 ; Vol. 75, No. 4. pp. 428-435.
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abstract = "IMPORTANCE 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. OBJECTIVE 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. RESULTS 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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AU - Brück, Wolfgang

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N2 - IMPORTANCE 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. OBJECTIVE 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. RESULTS 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.

AB - IMPORTANCE 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. OBJECTIVE 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. RESULTS 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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