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.

ESDR013 - Unabated type I interferon expedites B-cell autoimmunity and anti-drug antibody formation during anti-TNF therapy

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING