Differences in the Reponses to Apheresis Therapy of Patients With 3 Histopathologically Classified Immunopathological Patterns of Multiple Sclerosis

Abstract

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.

Utility and safety of plasma exchange in paediatric neuroimmune disorders

“…While the delay likely reflects the time required for equilibration between the CNS and systemic vascular component across the complex blood brain barrier, the heterogeneity of clinical response is likely to reflect differences in immunopathology. In an intriguing recent study, responsivity to TPE in patients with multiple sclerosis relapse was superior in those with a neuropathological pattern of humoral involvement (immunoglobulin and complement deposition) on brain biopsy . Furthermore, the presence of ring‐enhancing lesions on imaging predicts beneficial response to TPE across a range of CNS inflammatory demyelinating disorders …”

“…In an intriguing recent study, responsivity to TPE in patients with multiple sclerosis relapse was superior in those with a neuropathological pattern of humoral involvement (immunoglobulin and complement deposition) on brain biopsy. 9 Furthermore, the presence of ring-enhancing lesions on imaging predicts beneficial response to TPE across a range of CNS inflammatory demyelinating disorders. 10 Where present, the immediate benefits of TPE in our cohort were generally mild or stabilizing, as reflected by the relatively modest improvements in mRS score between initiation and completion of TPE, demonstrated in 22% of children only.…”

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns

“…The clinical relevance of these immunopathological patterns has been shown previously: Apheresis is a second-line therapy for MS relapses. Whereas pattern III patients do not respond to apheresis therapy, > 50% of pattern II patients benefit from this treatment [32,75]. Thus far, patterns I-III can only be determined by histopathological analysis of brain biopsies.…”

“…Antibodies directed against the water channel AQP4 are used as a diagnostic biomarker and play a pathogenic role in lesion development [4,38,82]. Several lines of evidence suggest that antibodies are also involved in lesion development in MS [32,42,48,75]. Indeed, antibodies binding the myelin oligodendrocyte glycoprotein (MOG) were identified in a small subgroup of MS patients [22,63,72].…”

Mitoxantrone treatment in a patient with multiple sclerosis and pattern III lesions

“…In contrast, pattern III lesions show signs of an oligodendrogliopathy . Apart from pattern I and, in particular, pattern II lesions, which have been identified to be predictive for a therapeutic response to apheresis therapies, knowledge about the correlation of histological patterns and efficacy of treatment regimens is sparse …”