Association between Changes in the Patterns of Antinuclear Autoantibodies during Immune Checkpoint Inhibition Therapy and the Development of Severe Immune Related Adverse Events

Abstract

Immune-related adverse events (irAEs) are unpredictable autoimmune-like toxicities induced by immune checkpoint inhibitors (ICI). irAEs are a consequence of a breakdown in self-tolerance. ICIs can induce autoantibody formation, and the presence of antinuclear autoantibodies (ANAs) has been reported in patients who developed irAEs. Our goal was to compare ANA patterns by indirect immunofluorescence at different timepoints before (baseline) and after the initiation of ICI treatment and to analyze the role of ANA pattern changes as predictors of irAEs. This is a 2-year-follow-up prospective study of 152 consecutive patients with solid tumors treated with anti-PD-(L)1 blockade agents. They were included from September 2018 until March 2020 in the Hospital de la Santa Creu I Sant Pau (Barcelona, Spain). We grouped patients into three groups: ANA de novo (patients who showed new ANA patterns at any time after ICI initiation), ANA (ANA positive at baseline without changes in the ANA patterns after initiation of treatment) and non-ANA (ANA negative at baseline and after ICI initiation). We did not find any association between the appearance of ANAs and irAE rates or the number and types of irAEs. However, patients in the ANA de novo group showed higher severe irAE rates (grade ≥ 3) than the other groups. Additionally, in most of the patients with severe irAEs (83.3%), changes in ANA patterns preceded irAE onset. In conclusion, we found ANA induction during ICI therapies in 22 patients and our results suggest that the appearance of ANAs may predict the severity of the irAE.

A multidisciplinary approach to treating a unique case of recurrent metastatic thymic carcinoma: case report

“…Studies have not established a clear relationship between elevated autoantibodies and incidence of irAEs, and contradictory results exist regarding their impact on patient outcomes. 19,21,22 Notably, our patient initially presented with Raynaud's phenomenon, which is typically associated with mixed connective tissue disease. 23 It is challenging to determine whether our patient's Raynaud's phenomenon was related to the immune dysregulation of TC or represented a predisposition to autoimmunity that was further exacerbated with immune checkpoint inhibitors.…”

Immune‐related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity

“…Toi et al 44 found that the presence of pre‐treatment anti‐nuclear autoantibodies (ANA), RF or anti‐thyroid autoantibodies predicted irAEs overall, independent of organ type, suggesting that the presence of autoantibodies may be a harbinger of a predisposition toward irAEs. Yet there is also an observation that the development of autoantibodies after ICI treatment may portend more severe irAEs, this has been described in most depth in the context of ANA seroconversion 45 . Lastly, there is also evidence that ICI influence the B‐cell compartment and that these changes may promote ICI‐induced irAEs 46 .…”

“…Yet there is also an observation that the development of autoantibodies after ICI treatment may portend more severe irAEs, this has been described in most depth in the context of ANA seroconversion. 45 Lastly, there is also evidence that ICI influence the B-cell compartment and that these changes may promote ICI-induced irAEs. 46 Das et al 47 observed a reduction in circulating B cells in patients with melanoma after ICI therapy and that this was associated with greater risk of ICI-induced irAEs as well as irAE severity.…”

Non-Invasive Predictive Biomarkers for Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors

“…However, the results were somewhat inconsistent when investigating which specific autoantibody was the main contributor to the association with irAEs. The most promising and well-studied autoantibody was anti-nuclear antibody [ 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], followed by rheumatoid factor [ 13 , 22 ], both studied in multiple types of solid tumors, including malignant melanoma and NSCLC. Some studies suggested a positive association between pre-existing autoantibodies and the development of any irAE [ 14 , 16 , 17 , 18 , 19 ], but some reported no association [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

“…The most promising and well-studied autoantibody was anti-nuclear antibody [ 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], followed by rheumatoid factor [ 13 , 22 ], both studied in multiple types of solid tumors, including malignant melanoma and NSCLC. Some studies suggested a positive association between pre-existing autoantibodies and the development of any irAE [ 14 , 16 , 17 , 18 , 19 ], but some reported no association [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. In summary, the evidence is conflicting, and they do not seem to be a reliable predictor for irAE in general when used alone.…”