THU0024 Treatment with immune checkpoint inhibitors and the break of b-cell tolerance to autoantigens
Authors: E.C. de Moel, L. Rozeman, A. Grummels, E.M.E. Verdegaal, J.A. Bakker, E.H. Kapiteijn, T.W.J. Huizinga, J.B. Haanen, R.E.M. Toes, D. van der Woude
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The field of autoimmunity may benefit from the knowledge gained by studying immune checkpoint inhibitors. These agents, which have proven remarkably successful in treating various types of cancer, inhibit negative costimulatory signals to T-cells, thereby enhancing anti-tumour T-cell responses. This can come at the cost of severe immune-related adverse effects (irAEs) including arthritis, colitis, endocrine diseases, hepatitis, and various skin abnormalities. However, it is currently unknown to which extent or to which autoimmune disease-associated autoantigens autoantibodies are formed (as a reflection of breaking of tolerance to self-antigens) under checkpoint inhibitor therapy and whether this is associated with irAEs. <h3>Objectives</h3> To investigate whether patients treated with immune checkpoint inhibitors develop autoantibodies, and whether this trait is associated with irAEs. <h3>Methods</h3> In pre- and (12 weeks) post-treatment sera of 133 patients with Stage III or IV melanoma treated with ipilimumab (anti-CTLA-4), we determined antibodies associated with rheumatoid arthritis (RF IgM, anti-CCP2), autoimmune hepatitis (anti-smooth muscle, anti-mitochondria, anti-liver-kidney-microsome), thyroiditis (anti-thyroid peroxidase (TPO), anti-thyroglobulin (TG)), Coeliac's disease (anti-endomysium, anti-gliadine IgG), adrenal insufficiency (anti-adrenal cortex), and autoimmune connective tissue diseases (anti-nuclear antibodies, anti-dsDNA, anti-ENA, and specific ENA tests: anti-SSA, anti-SSB, anti-RNP70, anti-U1RNP, anti-Sm, anti-Jo1, anti-CENP, anti-PMSCL, anti-RNA polymerase 3, anti-Scl70). We used McNemar's exact test for paired data to test whether autoantibody positivity increased post-treatment, and investigated by Fisher's exact tests whether developing autoantibodies was associated with system-specific (Grade 3 or 4) irAEs. <h3>Results</h3> In total, post-treatment positivity for any autoantibody was seen in 19.2% (19/99) of patients that were fully autoantibody-negative pre-treatment (p&lt;0.0001). A significant association was observed between development of any autoantibodies and any irAEs: 14/19 (73.7%) patients that developed autoantibodies had irAEs, versus 37/80 (46.3%) patients that did not develop autoantibodies (OR: 3.3 [95% CI: 1.1 to 9.9]). Regarding specific autoantibodies, predominantly anti-TPO (4.8%, 6/125) and anti-TG antibodies (6.0%, 8/132) developed in patients negative for these autoantibodies at baseline (p=0.03 and p=0.008, respectively). However, development of these antibodies was not associated with development of thyroid disease. For most other autoantibodies, including RA-associated antibodies, post-treatment positivity increased only marginally and was not associated with occurrence of irAEs in the organ system related to the specificity of the autoantibody. <h3>Conclusions</h3> Breaking of humoral tolerance as measured by development of autoantibodies is relatively common under treatment with ipilimumab and is associated with the development of irAEs. The nature of the autoantigens towards which tolerance is broken is not reflected in the phenotype of the irAEs. <h3>Disclosure of Interest</h3> None declared