Background

Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear.

Methods

We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models.

Findings

In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS.

Interpretation

Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression.

Funding

F. Hoffmann-La Roche Ltd.

Background and objectives

The B cell-depleting anti-CD20 antibody ocrelizumab (OCR) effectively reduces MS disease activity and slows disability progression. Given the role of B cells as antigen-presenting cells, the primary goal of this study was to evaluate the effect of OCR on the T-cell receptor repertoire diversity.

Methods

To examine whether OCR substantially alters the molecular diversity of the T-cell receptor repertoire, deep immune repertoire sequencing (RepSeq) of CD4⁺ and CD8⁺ T-cell receptor β-chain variable regions was performed on longitudinal blood samples. The IgM and IgG heavy chain variable region repertoire was also analyzed to characterize the residual B-cell repertoire under OCR treatment.

Results

Peripheral blood samples for RepSeq were obtained from 8 patients with relapsing MS enrolled in the OPERA I trial over a period of up to 39 months. Four patients each were treated with OCR or interferon β1-a during the double-blind period of OPERA I. All patients received OCR during the open-label extension. The diversity of the CD4⁺/CD8⁺ T-cell repertoires remained unaffected in OCR-treated patients. The expected OCR-associated B-cell depletion was mirrored by reduced B-cell receptor diversity in peripheral blood and a shift in immunoglobulin gene usage. Despite deep B-cell depletion, longitudinal persistence of clonally related B-cells was observed.

Discussion

Our data illustrate that the diversity of CD4⁺/CD8⁺ T-cell receptor repertoires remained unaltered in OCR-treated patients with relapsing MS. Persistence of a highly diverse T-cell repertoire suggests that aspects of adaptive immunity remain intact despite extended anti-CD20 therapy.

Trial registration information

This is a substudy (BE29353) of the OPERA I (WA21092; NCT01247324) trial. Date of registration, November 23, 2010; first patient enrollment, August 31, 2011.