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  • 1. Natalizumab • Continuous treatment (monthly infusions) • Very high efficacy; high NEDA rates and significant proportion of treated subjects improve. • Prevents end-organ damage (reduced brain atrophy yr-2) • Reversible treatment effect • Infusion reactions uncommon • No short-term generalised immunosuppression • Reduced immune surveillance increases risk of CNS infections; in particular PML if JCV-seropositive • Breakthrough disease • Re-baseline at 3-6 months • Neutralizing antibodies to natalizumab reduce efficacy and cause infusion reactions • Suboptimal or failure to respond • NEDA reliable metric for efficacy • Rebound activity • Highly likely, can be life threatening • Pregnancy • Not recommended, natalizumab crosses placenta and has transient effects in baby • No secondary autoimmunity • No obvious secondary malignancy risk • Monitoring: yes, blood and liver function tests early on, anti-natalizumab antibodies, JCV serology and annual MRI • No potential for a cure • Rebound Alemtuzumab • Short-course pulsed therapy (2-5 annual cycles of treatment) • Very high efficacy; significant proportion of treated subjects improve. Reported NEDA rates low, but not measured in correct epoch • Prevents end-organ damage (reduced brain atrophy yr-2) • Irreversible treatment effect • Infusion reactions the norm • Short-term generalised immunosuppression (8-12 weeks post infusion) • Low risk of CNS and other infections after immune system reconstitution • Breakthrough disease • Re-baseline at 24 months • Antibodies to alemtuzumab are transient and don’t appear to inhibit activity of drug • Marker for retreatment • NEDA unreliable to assess efficacy • Rebound activity • Less likely, unlikely to be life-threatening • Pregnancy • Fine once immune system reconstituted • Potential for autoantibodies to cross placenta, for example neonatal hyperthyroidism • Secondary autoimmunity; ~50% of patients with long-term follow-up - mainly thyroid related. • Potential, but undefined, secondary malignancy risk • Monitoring: yes, monthly blood and urine tests for secondary autoimmunity and annual MRI • Potentially curative • Long-term remission established in about 50% of treated patients • Ongoing 15-20 year experiment, analogous to BMT