JAMA Neurology | Transdermal Application of Myelin Peptides in Multiple Sclerosis Treatment

Importance  Demonstration of efficacious antigen-specific therapy in multiple sclerosis.
Objective  To assess the safety and efficacy of transdermally applied myelin peptides in patients with relapsing-remitting multiple sclerosis.
Design  One-year double-blind, placebo-controlled cohort study.
Setting  Referral center.
Participants  Thirty outpatients aged 18 to 55 years with relapsing-remitting multiple sclerosis.
Intervention  Skin patch with a mixture of 3 myelin peptides, MBP85-99, MOG35-55, and PLP139-155.
Main Outcomes and Measures  Cumulative number of active gadolinium-enhanced (Gd+) lesions per patient per scan, mean volume of Gd+ lesions, cumulative number of new T2 lesions, and T2 lesion and T1 lesion volume change from baseline to the end of the study. Total number of relapses during the year of the study per patient (annual relapse rate), proportion of relapse-free patients, and proportion of patients with 3 months of confirmed disability worsening on the Expanded Disability Status Scale at month 12.
Results  All patients completed the study. Compared with placebo, treatment with a myelin peptide skin patch (1 mg) showed a 66.5% reduction in the cumulative number of Gd+ lesions (P = .02) during the 12 months of the study. The annual relapse rate in patients treated with a mixture of myelin peptides (1 mg) was significantly lower compared with the placebo group (0.43 vs 1.4; P = .007). Treatment with a myelin peptide skin patch was well tolerated and no serious adverse events were reported.
Conclusions and Relevance  In patients with relapsing-remitting multiple sclerosis, treatment with a myelin peptide skin patch significantly reduced both magnetic resonance imaging and clinically defined measures of disease activity and was safe and well tolerated.

Induction of antigen-specific tolerance in multiple sclerosis (MS) remains the ultimate goal of therapy for this disease. The pathogenesis of MS is thought to result from antigen-specific autoimmunity where autoreactive immune cells, T and B lymphocytes, directed at myelin-related peptides mediate the destruction of myelin within the central nervous system. All currently available therapies in MS attenuate global function of the immune system without discrimination of antigen specificity. This approach has led to some success for MS therapy but at the same time exposes patients to the risk of increased susceptibility to infectious agents, the induction of opportunistic infections, and increased risk for cancer. In contrast, antigen-specific therapy aims to selectively target cells specific for a given antigen, thus disabling only a small part of the immune system responsible for an autoimmune response, which for MS includes antigens associated with the myelin sheath.

In MS, several antigens have been linked with autoimmunity. Among them, a prominent role has been proposed for peptides from 3 major myelin proteins, myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP). Mapping and sequencing studies identified immunogenic peptide epitopes within these proteins as potentially responsible for the induction of an autoimmune response in MS. However, immunogenic peptides, if applied in an altered form in an appropriate environment and at low concentrations, might not induce an immune response but instead might lead to immune tolerance.The skin is a key first line of immune defense protecting us from pathogen invasion and the external environment. Thus, the immune system of the skin possesses large numbers of immune cells controlling both the induction of an immune response and immunotolerance. Transdermal application of myelin antigens in animals sensitized for experimental autoimmune encephalomyelitis showed an attenuating effect on disease expression.Thus, the transdermal route of antigen application might prove to be effective in the development of antigen-induced immune tolerance in humans.

In this study, we conducted a double-blind, placebo-controlled trial with 3 myelin peptides, MBP85-99, PLP139-151, and MOG35-55, applied transdermally as a skin patch in 30 patients with relapsing-remitting MS over the course of 1 year. We tested the hypothesis that a mixture of these peptides would decrease disease activity in MS as assessed by an effect on magnetic resonance imaging (MRI) and clinical outcomes. We also assessed the safety and tolerability of transdermal application of myelin peptides.

No comments: