018 Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

Abstract

Anti-TNFs have become a benchmark in the treatment of numerous autoimmune diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. However, TNF blockade as a therapy has its limitations. Besides an increased susceptibility to infections, 0.2-1% of patients develop anti-TNF induced lupus erythematosus (ATIL). Moreover, anti-TNFs are associated with increased frequencies of anti-drug antibodies (ADA). We have previously shown that TNF inhibition shifts the equilibrium of TNF and type I interferons towards an excessive type I interferon response. Here, we show that a similar pathomechanism underlies B cell-mediated autoimmunity and the formation of ADA during anti-TNF treatment. In fact, adalimumab but not the anti-IL12/23 ustekinumab was associated with an increase of antinuclear antibodies (ANA) in psoriasis patients. In-vitro, anti-TNF treated plasmacytoid dendritic cells propelled B cell-activation and enhanced IgG-production, an effect that was critically dependent on type I interferon. In a mouse model of lupus, anti-TNF accelerated ANA formation, led to early glomerular IgG-deposition and serum-creatinine increase, suggesting a pathogenic role for the dysbalance of TNF and type I interferon in ATIL. Besides increased ANA, adalimumab also showed a significantly higher frequency of ADA as compared to ustekinumab, despite similar immunogenicity of the antibodies. ADA correlated with interferon-alpha serum levels in patients receiving adalimumab and, in a mouse model, the activation of the type I interferon pathway led to accelerated ADA formation during anti-TNF treatment. These findings indicate that, in patients treated with anti-TNFs, unabated type I interferon production might unleash B cell-mediated autoimmunity and facilitates ADA formation and secondary loss of efficacy.

Janus kinase inhibitors in autoimmune bullous diseases

“…Animal models play a crucial role in understanding the mechanism of JAK inhibitors in treating AIBDs. However, there is a lack of research specifically using JAK inhibitors to treat AIBDs in mouse models, despite the existence of numerous reports on AIBDs in mouse models induced by antibody transfer, lymphocyte transfer, and immunization (38,39). Interestingly, in veterinary medicine, oclacitinib, a selective JAK1 inhibitor for dogs, has shown promise in treating AIBDs like PF (40,41).…”