Background: Immune checkpoint inhibitors (ICIs) improved cancer therapy by inducing a higher immune system activity. This effect can cause rheumatic immune-related adverse events (rh-irAEs), which have not yet been extensively studied. Methods: We analysed 437 patients between 2014 and 2019, treated with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) or pembrolizumab (anti-PD-1) at the Clinic for Internal Medicine III, Oncology, Haematology and Rheumatology at the University Hospital Bonn, Germany. Results: Of the 437 patients 60% were males. Patients were mainly treated for melanoma, lung cancer, head and neck tumour and urothelial carcinoma. At least one immune-related adverse event (irAE) was observed in 163 patients (37.3%), including rh-irAE. Most common side effects were rash, colitis and hepatitis. We identified 19 patients (4.3%) with a minimum of one rh-irAE due to ICI therapy; three of those had a pre-existing rheumatic disease. Arthralgia developed most frequently in eight patients (42.1%). Other rh-irAEs were: arthritis ( n = 7; distinguished in rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis and undifferentiated arthritis), myalgia ( n = 2) and myositis ( n = 3). Most rh-irAEs were classified as moderately severe (Common Terminology Criteria of Adverse Events grade 2: 68.4%). Median time between starting ICI therapy and the occurrence of rh-irAE was 109 days (interquartile range 40–420 days). Fifteen patients (78.9%) were treated with glucocorticosteroids. In four cases additional therapy with methotrexate or tocilizumab was required. Even though patients benefited from ICI treatment, therapy had to be discontinued in six of the participants due to rh-irAE. Interestingly, patients with rh-irAE had a significantly higher tumour response compared with patients without rh-irAE (94.4% versus 43.5%; p < 0.0001). Conclusion: Rh-irAEs occur under ICI therapy, especially in patients with higher tumour response. However, they are not the most frequent irAE after ICI exposure: 9.3% of all irAEs were rheumatic (20 rh-irAE cases in 19 patients of a total of 215 irAE cases in 163 patients).

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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<0,0001).Table 1.Independent risk factors of IFI in patients with SLEaCandidiasisCryptococcosisAspergillosisHR (95% CI)PvalueHR (95% CI)PvalueHR (95% CI)PvalueAge>501.77 (1.27-2.47)<0.001Diabetes mellitus1.65 (1.16-2.35)0.006End-stage renal disease1.76 (1.29-2.41)<0.001Stroke1.77 (1.26-2.47)<0.0011.96 (1.09-3.53)0.024Mycophenolate mofetil2.72 (1.60-4.61)<0.0014.02 (1.32-12.26)0.015Cyclosporin4.94 (1.61-15.10)0.005Cyclophosphamide1.50 (1.07-2.10)0.019Intravenous steroid28.19 (21.17-37.52)<0.00163.51 (36.10-111.71)<0.00134.80 (15.09-80.24)<0.001aAll factors withP<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 infectionFigure 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.2016.02.001AcknowledgmentsDisclosure of Interests:None declared

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