Primary progressive multiple sclerosis: evidence for uncoupling disease progression and inflammation

Objective: In MS patients following a primary progressive course (PPMS), there is limited evidence concerning the underlying mechanisms responsible for clinical deterioration. We therefore performed an exploratory longitudinal study to gain insight into the evolution of neurological disability in relation to MRI and immunological parameters.

Methods: Ten patients with PPMS were serially investigated at three time points over 18 months for clinical deficits using the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite score (MSFC). In parallel, brain MRI was performed to assess T1 and T2 lesion load, the occurrence of contrast enhancing lesions, and brain atrophy. Immunological parameters involved analysis of the T cell response towards the candidate self-antigen myelin basic protein (MBP) or the control antigen tetanus toxoid (TT), and of soluble TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), which is considered to have immunomodulatory capacity.

Results: Neurological disability gradually worsened during the observation period, as indicated by significant changes in EDSS and MSFC scores. MRI revealed a significant increase in T2 lesion load, while T1 lesion load showed a small, non-significant increase. Autoantigen-specific T cell response was very low compared to recall antigen reactivity and did not exhibit any relevant alterations. Similarly, the antiproliferative TRAIL showed a stable course.

Conclusions: In PPMS, the progressive decline of clinical functions occurs independent of inflammatory T cell response. This finding might explain the recently reported inefficacy of common immunomodulatory treatments and calls for other therapeutic strategies in this disease entity such as, e.g., neuroprotective concepts.