27 Translational insights into the pathogenesis transforming SLE treatment

Systemic lupus erythematosus (SLE) is a heterogeneous disease characterized by abnormalities in cellular and humoral immunity. Key disturbances comprise abnormal cytokine production (increased type I IFN, IL-6, IL-17, IL-12 and IL-23, BAFF) and B lineage cell abnormalities. In the light of the recent SARS-Cov2 pandemic, the role of type I IFN and humoral immunity became of great interest and a number of similarities, but also subtle differences, to SLE became apparent and will be addressed based on recent data.Inflammatory cytokines or their corresponding cytokine receptors have been identified as therapeutic targets. Since these cytokines activate various intracellular pathways, such as Jak/Stat signaling, activation of the NfκB or BCR signaling pathways (i.e. spleen tyrosine kinase [Syk]), Bruton’s tyrosine kinase (BTK), small molecules inhibiting these pathways are being investigated in various clinical studies permitting a concept of multiple targeting therapy.1 Recent study experiences blocking Jak1/Jak2 pathways with baricitinib showed clinical improvements over 24 weeks2 and identified a number of molecules downstream of Stat1, Stat2, and Stat4 correlating with SLE activity.3 A Phase Ib/IIa trial using tofacitinib as Jak1/Jak3 selective inhibitor in SLE has also been reported limited to safety but also mechanistic insights.4The recent identification of hyporesponsive but not hyperresponsive B cell functions among SLE and other autoimmune diseases (RA, Sjögren’s) require consideration of anergic post-activated (APA) B cells with increased phosphatase activity and responding to CD40 stimulation most pronounced in SLE.5 As a result, inhibitors of preferred B cell activation pathways (BTK4, Syk etc.) that generated hope based on experiences with anti-CD20 therapy failed in various SLE and rheumatoid arthritis trials, including a Phase 2 study with the BTK inhibitor fenebrutinib (GDC-0853)4 and evobrutinib (e-ACR 2020). Notably, evobrutinib was very efficacious in RRMS5 which also opens new avenues of the understanding of a differential pathogenesis6 of the two diseases. Thus, consideration of APA B cells in certain autoimmune diseases responding to CD40 activation may guide the development of successful new therapies in SLE and other diseases.Learning ObjectivesDiscuss the translational rationale and distinct mechanisms of action for novel therapeutic targets in SLE within the context of APA B cellsExplain the significance of certain signaling pathways,