FRI0548 PREVALENCE AND THERAPY OF RHEUMATOLOGICAL ADVERSE EVENTS DUE TO IMMUNE CHECKPOINT INHIBITOR THERAPY
Authors: V. S. Schäfer, S. H. Verspohl, T. Holderried, C. Behning, P. Brossart
Journal: Annals of the Rheumatic Diseases (2020)

Background: Immune checkpoint inhibitors (ICIs) have improved cancer therapy and especially clinical outcomes for patients with many malignancies [ 1 ]. ICIs lead to a higher immune system activity and subsequent attack of tumor cells. However, this effect can cause rheumatological immune related adverse events (rh-irAE), which have not yet been extensively studied. Objectives: To determine the prevalence and type of rh-irAE in patients treated with ICIs. Additionally, our study focused on duration, severity and therapy of rh-irAE as well as the correlation between tumor response rate and patients with or without rh-irAE. Methods: We analysed 437 patients between January 2014 and October 2019, treated with ipilimumab (anti-CTLA-4) and/ or nivolumab (anti-PD-1) or pembrolizumab (anti-PD-1) at the Department of Oncology, Hematology and Rheumatology at the University Hospital in Bonn, Germany. Results: Of the 437 patients, 260 (60%) were males, 177 (40%) were females with a mean age of 64 years (SD ± 14) at the beginning of the ICI-therapy. 152 patients (34.8%) displayed at least one irAE. We identified 20 patients (4.6%) with a minimum of one rh-irAE due to ICI-therapy, seven of those had a pre-existing rheumatological disease. Those 20 patients were initially treated for melanoma, lung cancer, head and neck tumor and gastrointestinal carcinoma. Rh-irAE occurred in one patient (2.6%) with ipilimumab, in nine patients (4.8%) with nivolumab, in nine patients (5.7%) with pembrolizumab and in one patient (1.9%) with a combination of ipilimumab and nivolumab. Arthralgia developed most frequently in nine of the 20 patients (45%). Arthritis and myositis occurred with equal frequencies, in three cases each (3 patients, 15%). Furthermore, three of the 20 patients (15%) developed a psoriatic arthritis and one patient (5%) osteoarthritis. The time to the first rh-irAE after exposure to ICIs was in median 100 days (IQR 45 – 406 days). Most rh-irAE were classified as moderate severe (CTCAE [Common Terminology Criteria of Adverse Events] grade 2: 55%). 15 patients (75%) were treated with systemic corticosteroids. In three cases (15%) additional therapy with methotrexate and in one patient (5%) with tocilizumab was required. Other therapies including non-steroidal anti-inflammatory drugs and opioids were also used in eight patients. Even though patients benefited from ICI treatment, therapy had to be discontinued in nine of them (45%). Interestingly, patients with rh-irAE had a significantly higher tumor response rate compared to patients without any irAE (95% vs. 33%; p&lt;0,0001). Table 1. Independent risk factors of IFI in patients with SLE a Candidiasis Cryptococcosis Aspergillosis HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value Age&gt;50 1.77 (1.27-2.47) &lt;0.001 Diabetes mellitus 1.65 (1.16-2.35) 0.006 End-stage renal disease 1.76 (1.29-2.41) &lt;0.001 Stroke 1.77 (1.26-2.47) &lt;0.001 1.96 (1.09-3.53) 0.024 Mycophenolate mofetil 2.72 (1.60-4.61) &lt;0.001 4.02 (1.32-12.26) 0.015 Cyclosporin 4.94 (1.61-15.10) 0.005 Cyclophosphamide 1.50 (1.07-2.10) 0.019 Intravenous steroid 28.19 (21.17-37.52) &lt;0.001 63.51 (36.10-111.71) &lt;0.001 34.80 (15.09-80.24) &lt;0.001 a All factors with P &lt;0.05 in univariate analysis were selected for Cox multivariate analysis. CI, confidence interval; HR, hazard ratio. Figure 1. Incidence rate and incidence rata ratio of invasive fungal infection Figure 2. Kaplan-Meier curve of invasive fungal infection-free status in SLE versus non-SLE group. Conclusion: Our results show, that rh-irAE occur under ICI-therapy and in patients with higher tumor response. However, they are not the most frequent irAE after ICI exposure: 10.2% of all irAE were rheumatological (22 rh-irAE cases in 20 patients of a total of 216 irAE cases in 152 patients). As the use of ICIs is increasing for different malignancies the incidence of rh-irAE can be expected to increase. References: [1] Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science . 2018;359(6382):1350-1355. doi:10.1126/science.aar4060 [2] Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev . 2016;44:51-60. doi:10.1016/j.ctrv.2016.02.001 Acknowledgments Disclosure of Interests: None declared