lnduction Therapies in Multiple Sclerosis - Clinical and immunological follow-up

Abstract: Multiple sclerosis (MS) is a chronic disease that damages the central nervous system. Its pathophysiology is complex, and consists of inflammation and degeneration from the disease onset. The treatment of MS has continuously been developed with improved efficacy. The classical escalation treatment strategy with chronic immunosuppression and thus, by extension, accumulated risk of side effects is challenged by immune reconstitution or induction therapies (IRT). IRT is given once or intermittently as short courses that causes transient immunosuppression followed by a "reboot" of the immune system and thus loss of previous autoimmunity. In this way, long-term disease control can be achieved even in treatment-free intervals, with reduced safety risks over time. Currently, there are 3 therapies that are considered as IRTs for treatment of relapsing-remitting MS (RRMS): autologous hematopoietic stem cell transplantation (AHSCT), alemtuzumab (ALZ) and cladribine therapy. The aim of this thesis was to study the long-term efficacy and safety of ALZ, and to compare its efficacy and safety with AHSCT. In addition, we evaluated a wide range of different methods and biomarkers to investigate the long-term effect of ALZ on inflammation and degeneration in RRMS. In study I, ALZ achieved a progression-free survival of 69%, cumulative no evidence of disease activity with three components (NEDA-3) of 33%, and reduced neurofilament light levels in RRMS, over a five-year follow-up. In study II, it appeared that ALZ's ability to mitigate neurodegeneration was essentially limited to RRMS without inflammatory disease activity. In them, we show signs of remyelination using quantitative measures of white matter volume and myelin content in the brain. In study III, AHSCT was associated with a greater probability than ALZ of exhibiting NEDA-3 during follow-up. Early adverse events (<100 days) were more common with AHSCT but late adverse events were more common with ALZ. In study IV, 40% of patients developed an ALZ-induced autoimmune thyroid disease (AITD), of these, 62% exhibited thyroid autoimmune antibodies (auto-Abs). Thyroid auto-Abs often proceeded AITD development and can be used to monitor the risk of thyroid disease after ALZ treatment. In conclusion, we confirm ALZ as a highly effective treatment in suppressing inflammatory disease activity in RRMS, and that this effect is maintained long-term, even during drug-free intervals. Slowed neurodegeneration appeared to be limited to RRMS patients without inflammatory disease activity, who even showed signs of remyelination. AHSCT was superior to ALZ in achieving remission of RRMS, and AITD was confirmed as the most common long-term side effect after ALZ. Finally, the surveillance of ALZ-induced AITD may be improved by monitoring thyroid auto-Abs.