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Background:While some risk factors for severe COVID have been identified for patients with rheumatic diseases,1 few studies have investigated whether outcomes differ based on the type of rheumatoid arthritis (RA) treatment. Most existing reports have been limited to individual centers or voluntary reporting registries.2,3Objectives:To compare the occurrence of hospitalizations following COVID-19 diagnosis among patients with RA treated with various classes of DMARDs.Methods:A cohort of patients with confirmed COVID-19 (ICD10 diagnosis code or positive PCR or antigen test result) were identified within a large US electronic health record (EHR) dataset (Optum, Inc.) during the time period Feb 1, 2020 through Oct 14, 2020. From these, we identified RA patients (ICD10 RA diagnosis code) with treatment (most recent of JAK inhibitor [JAKi], biologic [bDMARD] or conventional synthetic [csDMARD] only) within the 12 months prior to COVID-19 diagnosis (i.e., index). The primary outcome was any hospitalization on or within 30 days after COVID-19 diagnosis. Multivariable logistic regression models compared users of JAKi’s to non-TNFi bDMARDs and csDMARDs (separately), as well as users of TNFi’s to non-TNFi bDMARDS and csDMARDs (separately), and were adjusted for age, gender, index month and baseline corticosteroid use. Sensitivity analyses included restriction of prevalent treatment use to within 180 days prior to COVID-19 diagnosis and restriction of csDMARDs to a group without hydroxychloroquine or chloroquine.Results:The study included 910 RA patients on DMARD treatment who were diagnosed with COVID-19 (mean age ± SD: 61±15, 80% female, 62% white. Of those, 26% (n=240) were hospitalized on or within 30 days after COVID-19 diagnosis. The proportion of patients hospitalized was highest in non-TNFi bDMARD users (37/87; 43%), followed by csDMARDs users (161/581; 28%) and lowest in JAKi (13/68; 19%) and TNFi users (29/174; 17%). In multivariable-adjusted models, no differences in risk of hospitalization were found comparing JAKi users to csDMARD users (aOR=0.71; 95% CI 0.37-1.36) or TNFi users to csDMARD users (aOR=0.67; 95%CI 0.43-1.06). Compared to non-TNFi bDMARD users, JAKi use and TNFi use was associated with reduced risk of hospitalization (JAKi aOR=0.32; 95%CI 0.14-0.71; TNFi aOR=0.34; 95%CI 0.18-0.62). Age and corticosteroid use were positively associated with 30-day hospitalization in all models. Results of sensitivity analyses were consistent with the main findings.Conclusion:In this study, roughly a quarter of RA patients with recent DMARD treatment were hospitalized within 30 days after COVID diagnosis. Patients treated with JAKi and TNFi therapies experienced the lowest risk of hospitalization, with risk of hospitalization significantly lower than non-TNFi bDMARDs. However, recent therapy recorded in the EHR may not reflect exposure at time of COVID-19 diagnosis and small sample size per treatment may limit interpretation.References:[1]Hyrich KL, Machado PM. Nat Rev Rheumatol 2020;1-2. doi:10.1038/s41584-020-00562-2[2]Gianfrancesco MA, et al. Lancet Rheumatol 2020;2(5):e250-e253. doi:10.1016/S2665-9913(20)30095-3[3]Veenstra J, et al. J Am Acad Dermatol 2020;83(6):1696-1703.Acknowledgements:Jonathan Johnson of Optum, Inc. provided dataset guidance and conducted data analyses. AbbVie funded this study, contributed to its design, participated in data collection, analysis, and interpretation of the data, and in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship.Disclosure of Interests:Lani Wegrzyn Shareholder of: AbbVie, Employee of: AbbVie, Kevin Winthrop Consultant of: Pfizer, AbbVie, UCB, Eli Lilly & Company, Galapagos, GSK, Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca, Novartis, Grant/research support from: BMS, Pfizer, Seoyoung Kim Grant/research support from: institutional research grants from Pfizer, AbbVie, Roche, BMS for unrelated studies, Yizhou Ye Shareholder of: AbbVie, Employee of: AbbVie, Carrie Huisingh Shareholder of: AbbVie, Employee of: AbbVie, Whitney Krueger Shareholder of: AbbVie, Employee of: AbbVie, anna maniccia Shareholder of: AbbVie, Employee of: AbbVie, Ryan Kilpatrick Shareholder of: AbbVie, Employee of: AbbVie.

Recent advances in oncotherapies and immunotherapies have markedly expanded melanoma treatment options. Nevertheless, the benefits of these treatments are often short-lived due to the development of resistance. We have previously established the onco-protective effect of the K63-ubiquitin (K63-Ub) deubiquitinating enzyme CYLD. In this study, we studied the role of the K63-Ub ubiquitin enzyme UBE2N and its functionally essential partners, UBE2V1 and UBE2V2, in melanoma growth and progression. We found that UBE2N and UBE2V2 were expressed and activated at elevated levels in malignant melanoma cell lines compared to normal melanocytes. Inhibition of UBE2N either pharmacologically or genetically via CRIPSR-mediated gene deletion and shRNA-mediated gene-silencing markedly decreased melanoma cell growth and sensitized cells to decarbonize and radiation treatments in vitro. In addition, we found that knockdown of UBE2V2 but not UBE2V1 significantly increased melanoma cell apoptosis and inhibited cell growth and migration. Surprisingly, gene silencing of UBE2N and UBE2V2 increased activation of the AKT and JNK pathways, and sensitized A375 melanoma cells to AKT and JNK inhibitors. In agreement with the in vitro data, subcutaneous tumor growth analysis showed that A375 melanoma cells with UBE2N and UBE2V2 knockdowns displayed significantly reduced tumor growth compared with cells with UBE2V1 knockdown or non-silencing control. Moreover, tumors with UBE2N or UBE2V2 knockdown expressed markedly elevated levels of E-cadherin and cleaved caspase 3. Further examination of the lung tissues revealed that UBE2N or UBE2V2 knockdown abolished pulmonary metastasis. These results indicate that UBE2N and UBE2V2 are crucial for melanoma growth, progression, and survival. We are currently using proteomic approaches to understand the molecular mechanisms mediating these effects.