Dybowski, SarahSarahDybowskiTorke, SebastianSebastianTorkeWeber, MartinMartinWeber2023-08-092023-08-092023https://publica.fraunhofer.de/handle/publica/44784810.1001/jamaneurol.2022.53322-s2.0-8515217142036780171Importance: Currently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell-depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell-directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK). Observations: BTK is centrally involved in the B cell receptor-mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety. Conclusions and Relevance: While the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.enreview