Prediction of Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors With a Panel of Autoantibodies: Protocol of a Multicenter, Prospective, Observational Cohort Study.

Introduction: Immune checkpoint inhibitor (ICI) therapy is markedly improving the prognosis of patients with several types of cancer. On the other hand, the growth in the use of these drugs in oncology is associated with an increase in multiple immune-related adverse events (irAEs), whose optimal prevention and management remain unclear. In this context, there is a need for reliable and validated biomarkers to predict the occurrence of irAEs in patients treated with ICIs. Thus, the main objective of this study is to evaluate the diagnostic performance of a sensitive routinely available panel of autoantibodies consisting of antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies to identify patients at risk of developing irAEs. Methods and Analysis: A multicenter, prospective, observational, cohort study has been designed to be conducted in patients diagnosed with cancer amenable to ICI therapy. Considering the percentage of ICI-induced irAEs to be 25% and a loss to follow-up of 5%, it has been estimated that a sample size of 294 patients is required to detect an expected sensitivity of the autoantibody panel under study of 0.90 with a confidence interval (95%) of no less than 0.75. For 48 weeks, patients will be monitored through the oncology outpatient clinics of five hospitals in Spain. Immune-related adverse events will be defined and categorized according to CTCAE v. 5.0. All the patients will undergo ordinary blood tests at specific moments predefined per protocol and extraordinary blood tests at the time of any irAE being detected. Ordinary and extraordinary samples will be frozen and stored in the biobank until analysis in the same autoimmunity laboratory when the whole cohort reaches week 48. A predictive model of irAEs will be constructed with potential risk factors of immune-related toxicity including the autoantibody panel under study. Ethics and Dissemination: This protocol was reviewed and approved by the Ethical Committee of the Basque Country and the Spanish Agency of Medicines and Medical Devices. Informed consent will be obtained from all participants before their enrollment. The authors declare that the results will be submitted to an international peer-reviewed journal for their prompt dissemination.

Association of immune-related adverse events induced by nivolumab with a battery of autoantibodies.

BACKGROUND: The aim of this study was to assess the diagnostic performance of an autoantibody battery in patients receiving immune checkpoint inhibitors who experienced immune-related adverse events (irAEs). METHODS: We retrospectively analyzed several variables potentially related to irAEs, namely, demographic, clinical, and laboratory characteristics, including an autoantibody battery (antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor). RESULTS: Sixty-nine patients (48 men; 61.8 ± 10.9 years at baseline) diagnosed with stage-4 solid-organ cancer and treated with nivolumab were followed up for 12 ± 10.3 months. Thirty-two irAEs were detected in 26 patients (37.5%). Adverse events occurred more commonly in women (62% vs. 27%, p = .006), and younger patients (irAEs: 58.1 ± 9.8, no irAEs: 64.1 ± 10.9 years, p = .024). Autoantibody battery results were available for 26 patients and were more frequently positive in patients with irAEs (87% vs. 30%, p = .009). The positive predictive value, negative predictive value, and diagnostic accuracy of the battery were 82.3%, 77.8%, and 80.8%, respectively. Among the 64 patients with an evaluable response, 23 (38.5%) experienced tumour progression, this being less frequent in patients with irAEs (19% vs. 48.5%, p = .03). Overall survival was higher in patients developing irAEs (HR = 1.88, p = .05). CONCLUSION: Positivity in a readily available autoantibody battery may be associated with the occurrence of irAEs.KEY MESSAGESPositivity in an accessible and inexpensive autoantibody battery including antinuclear, anti-neutrophil cytoplasmic, anti-thyroid antibodies and rheumatoid factor may be associated with the occurrence of immune-related adverse events.Patients with cancer on immune checkpoint inhibitors experiencing immune-related adverse events showed a lower risk of progression and better overall survival than patients not experiencing this type of adverse effect.

LAUDES Study: impact of digital ulcers on hand functional limitation, work productivity and daily activities, in systemic sclerosis patients.

The objective of this study was to evaluate the impact of digital ulcers (DUs) in daily life of systemic sclerosis (SSc) Spanish patients. We developed a multicenter observational study to compare functional disability in SSc patients with active DUs vs. those without DUs. An additional correlation between perception of patients and physicians on disability due to DUs was performed. A total of 199 patients were enrolled, 70 (35%) with DUs. Patients with DUs were younger (48 vs. 58 years; p < 0.001) and had more frequently the diffuse subtype of SSc (45 vs. 24%; p = 0.004) than patients without DUs. Patients with DUs showed significantly higher scores in the Cochin Hand Function Scale overall (p < 0.002) and for each of its five dimensions. They also showed higher scores in the Systemic Sclerosis Health Assessment Questionnaire items related to hand function such as, dress and self-care (p < 0.013), eat (p < 0.013) and grip (p < 0.03), and higher Visual Analogic Scale scores for pain (p < 0.013), trouble related with Raynaud's Phenomenon (p < 0.001) and sense of severity (p < 0.004). Impact on daily activities was significantly higher in patients with DUs (p = 0.002), with a non-significant trend to experience higher impact on work productivity (p = 0.07). A high correlation was found between DUs patients and physicians opinion on the impact of DUs (daily life: Pearson R = 0.86; work productivity: Pearson R = 0.87). Study findings show an impaired hand function and increased disability for daily life activities and work productivity in SSc patients with DUs compared with patients without DUs in Spanish population.

Length of exposure to antiphospholipid antibodies, rather than age, is a risk factor for thrombosis: a retrospective single-centre observational study.

To investigate the association of age and other factors with thrombosis risk in antiphospholipid antibody (aPL) carriers, a retrospective observational study was conducted in a cohort of patients with medium-high aPL titres recruited in a tertiary care hospital. Assuming an age difference of 9.8 years between patients with and without thrombosis, we estimated that a sample size of 70 participants was required. Several variables besides age including gender, vascular risk factors, inherited thrombophilias, non-thrombotic clinical manifestations, laboratory parameters, aPL profile, length of aPL exposure, antithrombotic drugs and partial aPL score were assessed by univariate analysis followed by multivariate logistic regression. Outcomes were analysed by whether thromboses occurred before (model 1) or after (model 2) aPL detection. Seventy patients [50 females; median (interquartile range) baseline age: 46.99 (39.39-66.20) years] were followed for 2.59 (0.67-5.86) years. Overall, 18 and 5 thromboses were diagnosed applying models 1 and 2, respectively. Time to thrombosis after aPL detection was 2.10 (1.03-8.24) years. Age did not differ between patients with and without thrombosis using models 1 (p = 0.92) or 2 (p = 0.67). Instead, we identified other predictors of thrombosis, namely, lack of thromboprophylaxis [odds ratio (OR) 13.50, 95%  confidence interval (95% CI) 1.02-178.05, p = 0.048] and length of aPL exposure (OR 1.41, 95% CI 1.04-1.92, p = 0.026) in model 2, while lupus anticoagulant showed a tendency to increase the risk (OR 7.10, 95% CI 0.86-58.78, p = 0.069) in model 1. Unlike age, lack of thromboprophylaxis, prolonged aPL exposure and lupus anticoagulant may increase the risk of thrombosis in aPL carriers.