Natalizumab Promotes Activation of Peripheral Monocytes in Patients With Multiple Sclerosis.

OBJECTIVES: Natalizumab (NTZ), a monoclonal antibody against very late antigen-4 (VLA-4), is one of the most efficient therapies to prevent acute relapses in multiple sclerosis (MS). VLA-4 is the key adhesion molecule for peripheral immune cells, especially lymphocytes to enter the CNS. While its blockade thus virtually abrogates CNS infiltration of these cells, long-term exposure to natalizumab may also affect immune cell function. METHODS: In this study, we report that in patients with MS, NTZ treatment is associated with an enhanced activation status of peripheral monocytes. RESULTS: Expression of 2 independent activation markers, CD69 and CD150, was significantly higher on blood monocytes from NTZ-treated patients when compared with those from matched untreated patients with MS, while other properties such as cytokine production remained unchanged. DISCUSSION: These findings consolidate the concept that peripheral immune cells remain fully competent on NTZ treatment, an excellent asset rare among MS treatments. However, they also suggest that NTZ may exert nondesirable effects on the progressive aspect of MS, where myeloid cells and their chronic activation are attributed a prominent pathophysiologic role.

A Milestone in Multiple Sclerosis Therapy: Monoclonal Antibodies Against CD20-Yet Progress Continues.

Multiple sclerosis (MS), which is a chronic inflammatory disease of the central nervous system, still represents one of the most common causes of persisting disability with an early disease onset. Growing evidence suggests B cells to play a crucial role in its pathogenesis and progression. Over the last decades, monoclonal antibodies (mabs) against the surface protein CD20 have been intensively studied as a B cell targeting therapy in relapsing MS (RMS) as well as primary progressive MS (PPMS). Pivotal studies on anti-CD20 therapy in RMS showed remarkable clinical and radiological effects, especially on acute inflammation and relapse biology. These results paved the way for further research on the implication of B cells in the pathogenesis of MS. Besides controlling relapse development in RMS, ocrelizumab (OCR) also showed clinical benefits in patients with PPMS and became the first approved drug for this disease course. In this review, we provide an overview of the current anti-CD20 mabs used or tested for the treatment of MS-namely rituximab (RTX), OCR, ofatumumab (OFA), and ublituximab (UB). Besides their effectiveness, we also discuss possible limitations and safety concerns especially in regard to long-term treatment, both for this class of drugs overall as well as for each anti-CD20 mab individually. Additionally, we elucidate to what extent anti-CD20 therapy may alter the function of other immune cells, both directly or indirectly. Finally, we cover the current knowledge on repopulation of CD20+ cells after cessation of anti-CD20 treatment and discuss future aspirations towards alternative, further developed B cell silencing therapies.