What is already known about this topic? Preliminary data suggest increased type 2 cytokines during the COVID-19 cytokine storm. However, it remains unclear how COVID-19 outcomes differ between patients with atopic dermatitis (AD) on type 2etargeting agents (dupilumab) and those treated with other systemics or topical treatments.What does this article add to our knowledge? This is the first study to directly compare the severity of COVID-19 symptoms in patients with moderate-to-severe AD on different treatments, shedding important light on the treatment of patients with AD during the pandemic and beyond.How does this study impact current management guidelines? Our results suggest that type 2 targeting with dupilumab may attenuate COVID-19 responses, supporting the safety of specific type 2etargeting agents in patients with AD during the COVID-19 pandemic, and potentially extending to other viral infections.BACKGROUND: In the SARS-CoV-2/COVID-19 pandemic, we need to understand the impact of immunomodulatory medications on COVID-19 symptom severity in patients with inflammatory diseases, including the type 2/Th2 polarized skin disease, atopic dermatitis (AD). OBJECTIVE: Because it is believed that type 1/Th1 immunity controls viral infections and that there is a Th1/Th2 counterregulation, we hypothesized that Th2 targeting with the IL-4Ra-antagonist, dupilumab, in patients with moderate-to-severe AD would rebalance the Th1/Th2 axis, potentially leading to attenuated COVID-19 symptoms. METHODS: A total of 1237 patients with moderate-to-severe AD in the Icahn School of Medicine at Mount Sinai Department of Dermatology were enrolled in a registry. Patients were screened for COVID-19-related symptoms and assigned a severity score (asymptomatic [0]-fatal [5]). Scores were compared among 3 treatment groups: dupilumab (n [ 632), other systemic treatments (n [ 107), and limited/no treatment

IMPORTANCE Persistent erythema multiforme (PEM) is poorly understood and lacks effective therapies other than glucocorticoids.OBJECTIVE To report outcomes following treatment of PEM with Janus kinase (JAK) inhibition and to elucidate cytokine drivers of erythema multiforme (EM). DESIGN, SETTING, AND PARTICIPANTSThis was a retrospective case series of 4 patients with PEM treated with tofacitinib and/or upadacitinib in 2015 to 2021 at the dermatology clinics of 2 major tertiary referral centers. Four consecutive patients with PEM refractory to multiple treatment approaches were treated. In 1 patient, skin biopsy specimens were obtained for RNA sequencing and proteomic analysis before and during treatment. Molecular findings were validated through RNA in situ hybridization analysis of cytokine expression in biopsy specimens from a total of 12 patients with EM (3 treated with tofacitinib in this study and 9 historic samples).INTERVENTIONS Treatment with tofacitinib, 5 to 10 mg, twice daily or upadacitinib, 15 mg, once daily.MAIN OUTCOMES AND MEASURES Change in PEM activity was assessed in all 4 patients treated with a JAK inhibitor. Median (range) follow-up was 20.5 months (10.0-36.0 mo). RESULTSThe study population of 4 female patients had a mean (SD) age of 46.2 (13.7) years and a mean (SD) disease duration of 21.75 (11.30) years. Marked clinical improvement was noted in all 4 patients. In 1 patient with a robust improvement following treatment with tofacitinib, RNA sequencing identified interferon gamma (IFN-γ) and interleukin 15 (IL-15) as cytokines with activity both highly upregulated at baseline in lesional skin and subsequently suppressed following tofacitinib treatment. Measurement of IFNG-and IL15-positive cells in additional EM biopsy specimens of 12 patients showed significant upregulation of IFNG (8.72 cells per mm; 95% CI, 2.60-14.84) and IL15 (14.13 cells per mm; 95% CI, 0.14-28.11) compared with normal skin (P = .008 and P = .045, respectively). CONCLUSIONS AND RELEVANCEThe results of this case series study suggest that JAK inhibition may be effective in treating PEM and that IFN-γ and IL-15 may be important cytokine mediators of the disease.

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BackgroundCancer-associated neoantigens (neoAg) derived from tumor genomic sequencing and predictive algorithms for mutated peptides are a promising basis for therapeutic vaccines under investigation. Although these are generally designed to bind major histocompatibility complex class I and induce CD8 cytolytic T lymphocyte (CTL) activity, results from preclinical and clinical studies demonstrate that the majority of neoAg vaccines efficiently induce CD4 T helper (Th) responses but not CTL. Despite this, these vaccines have demonstrated clinical efficacy. Therefore, understanding the mechanisms of CD4 + T cell-mediated tumor protection is critical to optimizing this immunotherapeutic strategy.MethodsWe investigated this phenomenon in the mineral oil-induced plasmacytoma (MOPC).315.BM (MOPC315) mouse model of multiple myeloma, a malignancy of plasma cells. MOPC315 cells express in their lambda chain a unique tumor-specific neoAg, an idiotypic (Id) peptide. We generated a vaccine formulated with this Id peptide fused to a heat shock protein HSC70 binding (HSB) motif co-delivered with poly (I:C). The immunogenicity of the Id-vaccine was measured in splenocytes by ELISpot. Mice were challenged with MOPC315 cells and antitumor immunity was assessed by co-incubating splenocytes and bone marrow mononuclear cells derived from vaccinated mice and controls, with the Id antigen and irradiated MOPC315 cells. The frequency of activated CD4 and CD8 T cells and their phenotype were characterized by flow cytometry.ResultsId-vaccine efficiently induced antigen-specific CD4 Th activity and antitumor immunity, protecting mice from MOPC315 tumor growth. CD4 cytolytic activity was not detected under these conditions. Polyfunctional CD8 T cells homed to the bone marrow microenvironment of protected mice and preferentially expanded only when restimulated ex vivo with both Id peptide and MOPC315 cells. Protective activity was abrogated by depletion of either CD4 or CD8 lymphocytes.ConclusionThese results demonstrate that Id-HSB +poly (I:C) vaccine protects against MOPC315 growth by priming Id-specific CD4 Th cells that confer protection against tumor but are not directly cytotoxic. These data indicate that activation of CD8 CTL against MOPC315-associated antigens not present in the vaccine is one of the major mechanisms of tumor immunity.

26The JAK2V617F point mutation has been implicated in the pathogenesis of the vast majority of 27 myeloproliferative neoplasms (MPNs), but translocations involving JAK2 have increasingly been 28 identified in a subset of patients with JAK2V617F-negative MPNs. Here we present a case of a patient 29 diagnosed with JAK2V617F-negative polycythemia vera (PV) that transformed to MPN-blast phase 30 (MPN-BP). Cytogenetic and FISH analysis revealed a novel translocation of t(1;9)(p36;p24.1) and a 31 PEX14-JAK2 gene fusion, as a result of the translocation, was identified. The t(1;9)(p36;p24.1) has not 32 been previously described and represents a new addition to the list of known translocations involving 33 JAK2 that have been identified in hematologic malignancies. Although the prognostic and treatment 34 implications of JAK2 translocations in MPNs is not yet clear, positive outcomes have been described in 35 early case reports of the use of JAK inhibitors in these patients. Further research into the role of JAK2 36 translocations in the pathogenesis and outcomes of hematologic malignancies is warranted. 53the MPNs, but have also been identified in de novo leukemias of both myeloid and lymphoid lineages 54 (Table 2). 56Here we describe a case of a patient with JAK2V617F-negative PV who was found to have a novel JAK2 57 translocation, not previously described. We also provide a review of the known JAK2 translocations 58 associated with PV and other MPNs.59 4 60 Case Report 61 A 52 year old woman initially presented in 2008 with symptoms of headaches, dizziness, fatigue, 62 shortness of breath and numbness and tingling of the hands and feet and was found to have a 63 hematocrit (HCT) of 61% with normal white blood count (WBC) and platelet (PLT) count. The bone 64 marrow biopsy showed a hypercellular marrow (95%) with increased megakaryocytes in clusters, 65 without reticulin staining. The patient was found to meet World Health Organization's (WHO) diagnostic 66 criteria for JAK2V617F mutation negative PV and was initiated on treatment with aspirin and therapeutic 67 phlebotomy, to maintain the Hct <42%.68 69 A year later, the patient developed leukocytosis with a WBC 30 x10 9 /L and thrombocytosis with a PLT 70 count of 600,000/L. She was started on hydroxyurea at a dose of 500 mg daily, with subsequent 71 improvement in leukocytosis and thrombocytosis, but developed treatment emergent anemia. Repeat 72bone marrow biopsy and aspirate at that time showed a hypercellular marrow (100%) with trilineage 73 hematopoiesis, marked granulocytic hyperplasia, increased immature forms, with markedly increased 74 eosinophils (31%) and 7% blasts. Peripheral blood flow cytometry showed a small CD33+ and CD34+ 75 myeloblast population (1.4%). 77Several months following initiation of hydroxyurea, the patient developed constitutional symptoms. The 78WBC was found to be elevated to 72x 10 9 /L and peripheral blasts were 21%, consistent with 157 158 Translocations at 9p24.1 and the resultant gene fusion products have been identified ...