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Background Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations. Methods In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels and severe viral infection outcomes. Results In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the USA with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (Area under the curve (AUC) = 0.73, P  = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including Coronavirus Disease 2019 (COVID-19), viral hepatitis and HIV [correlation coefficients: −0.79 (P  = 4e-2), −0.94 (P  = 6e-3) and −0.96 (P  = 8e-2), respectively]. Conclusions This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens. [ABSTRACT FROM AUTHOR]

Introduction: Paraneoplastic neurological syndromes (PNS) can worsen with immune checkpoint inhibitor (ICI) cancer immunotherapy., Case Report: A 66-year-old female with paraneoplastic Lambert-Eaton Myasthenic Syndrome (LEMS), which led to the diagnosis of metastatic neuroendocrine carcinoma, was treated with intravenous immune globulin (IVIg) (with minimal response), chemotherapy, and radiation, resulting in neurological improvement. However, sclerodermatous changes developed after a year. Due to cancer progression, dual ICI therapy was initiated, and the patient remained stable for eight months until the progression of both LEMS and cancer, ultimately leading to death., Discussion: This case highlights the challenges of managing pre-existing PNS during ICI therapy, emphasizing the need for a multidisciplinary approach and the consideration of unusual clinical presentations in therapeutic decision-making., Competing Interests: Declaration of competing interest None., (Published by Elsevier B.V.)

Objectives: The objectives of this study were to assess the prevalence and incidence of multimorbidity and its association with the SLICC/ACR damage index (SDI) among patients with SLE., Methods: Using prevalent and incident population-based cohorts of patients with SLE and their matched comparators, we assessed 57 chronic conditions. Chronic conditions were categorized as SDI-related or SDI-unrelated. Multimorbidity was defined as the presence of two or more chronic conditions. The prevalence of multimorbidity for both cohorts was compared using logistic regression. Cox models were used to examine the development of multimorbidity after SLE incidence., Results: The prevalent cohort included 449 patients with established SLE on 1 January 2015. They were three times more likely to have multimorbidity compared with non-SLE comparators [odds ratio (OR) 2.98, 95% CI 2.18-4.11]. The incident cohort included 270 patients with new-onset SLE. At SLE incidence, patients with SLE were more likely to have multimorbidity than comparators (OR 2.27, 95% CI 1.59-3.27). After incidence, the risk of developing multimorbidity was 2-fold higher among patients with SLE than among comparators [hazard ratio (HR) 2.11, 95% CI 1.59-2.80]. The development of multimorbidity was higher in patients with SLE based on SDI-related conditions (HR 2.91, 95% CI 2.17-3.88) than on SDI-unrelated conditions (HR 1.73, 95% CI, 1.32-2.26)., Conclusion: Patients with SLE had a higher burden of multimorbidity, even before the onset of the disease. The risk disparity continued after SLE classification and was also seen in a prevalent SLE cohort. Multimorbidity was driven both by SDI-related and unrelated conditions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: We aimed to characterize presentation and care pathways of patients with systemic lupus erythematosus (SLE), and delays in access to SLE-specialized care., Methods: We included patients with incident SLE from the Lupus Midwest Network registry. Time from the first medical encounter for SLE clinical manifestation to access to SLE-specialized care, physician diagnosis, and treatment was estimated. Delays were defined as ≥6 months to access specialized care. We compared SLE manifestations, disease activity, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage indexes (SDI) between patients with and without delays. Logistic regression models assessed associations with delays., Results: The study included 373 patients with SLE. The median time to access SLE-specialized care was 1.1 (95% confidence interval [CI] 0.9-1.5) months, time to diagnosis was 30.6 (95% CI 18.9-48.1) months, and time to treatment initiation was 4.7 (95% CI 3.9-8.4) months. Approximately 25% of patients (93 out of 373) experienced delays accessing specialized care, which were associated with fewer SLE manifestations at first SLE-related encounter (fewer than two SLE domains; 92% vs 72%, P < 0.001). Patients with mucocutaneous or musculoskeletal manifestations were less likely to experience delays, whereas hematologic (odds ratio [OR] 1.71, 95% CI 1.03-2.84) or antiphospholipid antibodies domains (OR 6.05, 95% CI 2.46-14.88) were associated with delays. Delays were associated with damage at first access to SLE-specialized care (SDI ≥1; 30% vs 7%, P < 0.001)., Conclusion: Patients follow a heterogeneous pathway to receive care. One-fourth of patients experienced delays accessing SLE-specialized care, which was associated with disease-related damage. Fewer manifestations, hematologic manifestations, or antiphospholipid antibodies were associated with delays., (© 2024 American College of Rheumatology.)

Introduction: The longitudinal responses towards multiple doses of COVID-19 mRNA vaccines in patients with systemic autoimmune diseases remain incompletely understood. While observational studies suggested the safety of COVID-19 mRNA vaccines in rheumatic disease patients, laboratory evidence is lacking., Methods: Here we evaluated seroreactivity, clinical manifestions, and multiple disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases., Results: Most patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Patients with systemic lupus erythematosus (SLE) or psoriatic arthritis (PsA) remained without significant flares post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I interferon (IFN) signature genes were highly variable but did not show consistent or significant increases. Frequency of double negative 2 (DN2) B cells remained largely stable., Discussion: Our data provide experimental evidences indicating the efficacy and safety of repeated COVID-19 mRNA vaccination in rheumatic disease patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 An, Figueroa-Parra, Zhou, Li, Jaquith, McCarthy-Fruin, Sletten, Warrington, Weyand, Crowson, Chumsri, Knutson, Sanchez-Rodriguez, Thanarajasingam, Duarte-García and Zeng.)

Background: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs., Methods: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment., Results: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04)., Conclusion: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749)., Competing Interests: Competing interests: The authors declare that they have no competing interests. MES-A has received consulting fees in the past 12 months from Pfizer, Eli Lilly and Bristol Myers Squibb, all unrelated to this study. IO funded by NYU SPORE P50CA225450. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers R01 AR077607, P30 AR070253, and P30 AR072577), the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. JAS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health. PG consulting for 4D Pharma, Aadi Bioscience, Astellas, Asieris Pharmaceuticals, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, Genentech, Gilead Sciences, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, PureTech, QED Therapeutics, Regeneron, Roche, Seattle Genetics, Silverback Therapeutics, Strata Oncology, UroGen Pharma; and has received institutional research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm Group, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, QED Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Systemic lupus erythematosus (SLE) is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study sought to identify optimal immune mediators informing an empirically refined flare risk index (FRI) reflecting altered immunity prior to clinical disease flare., Methods: Thirty-seven SLE-associated plasma mediators were evaluated by microfluidic immunoassay in 46 samples obtained in SLE patients with an imminent clinical disease flare (preflare) and 53 samples obtained in SLE patients without a flare over a corresponding period (pre-nonflare). SLE patients were selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting the American College of Rheumatology 1997 revised criteria for SLE or the Systemic Lupus International Collaborating Clinics 2012 revised criteria for SLE). Autoantibody specificities, hybrid SLE Disease Activity Index (hSLEDAI) scores, clinical features, and medication usage were also compared at preflare (mean ± SD 111 ± 47 days prior to flare) versus pre-nonflare (99 ± 21 days prior to nonflare) time points. Variable importance was determined by random forest analysis with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI., Results: Preflare versus pre-nonflare differences were not associated with demographics, autoantibody specificities, hSLEDAI scores, clinical features, nor medication usage. Forward selection and backward elimination of mediators ranked by variable importance resulted in 17 plasma mediator candidates differentiating preflare from pre-nonflare visits. A final combination of 11 mediators best informed a newly refined FRI, which achieved a maximum sensitivity of 97% and maximum specificity of 98% after applying decision curve analysis to define low, medium, and high FRI scores., Conclusion: We verified altered immune mediators associated with imminent disease flare, and a subset of these mediators improved the FRI to identify SLE patients at risk of imminent flare. This molecularly informed, proactive management approach could be critical in prospective clinical trials and the clinical management of lupus., (© 2022 American College of Rheumatology.)

This patient's nonadherence to treatment and lack of precautionary steps exacerbated this condition.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancer. Immune checkpoint inhibitors may cause a wide-range of autoimmune toxicities referred to as immune-related adverse events (irAEs). There is a paucity of data regarding the presentations and outcomes of patients receiving ICIs who seek care in an emergency department (ED). We performed a retrospective review of patients receiving an ICI who presented to a tertiary care ED between May 1, 2017, and April 30, 2018. Data including ED chief complaint, diagnosis, treatment, and disposition were collected along with baseline characteristics and diagnosis at the time of outpatient oncology follow-up. We report descriptive statistics summarizing the characteristics of the cohort. There were 98 ED visits identified among 67 unique patients. Immune-related adverse events were diagnosed in 16 (16.3%) cases. The most common chief complaints within the irAE group were gastrointestinal symptoms 10 (62.5%). Among the 16 confirmed irAE cases, the most common irAE diagnosed was colitis 9 (56.3%). Two (12.5%) patients with irAEs received corticosteroids during their stay in the ED, and 10 (62.5%) patients with irAEs required hospital admission. Emergency medicine providers documented consideration of an irAE in the differential diagnosis in 14.3% of all ED visits and in 43.8% of visits in which an irAE was ultimately diagnosed. Emergency providers should be familiar with ICIs given their expanding use and potential adverse effects to improve early recognition and patient outcomes in ED settings., (© 2021 THE AUTHORS.)

Objective: The objective of this study was to describe differences in the clinical course of patients with rheumatoid arthritis (RA) who are antinuclear antibody (ANA)-positive compared with those who are ANA-negative., Methods: This was a retrospective population-based cohort study of residents in Olmsted County, Minnesota, who first fulfilled 1987 American College of Rheumatology criteria for RA in 2009-2014. Data were collected on first documentation of joint swelling. Data on rheumatoid factor or anti-cyclic citrullinated peptide antibody testing and the ANA level were also collected. Comparisons between groups were performed by using χ 2 and rank sum tests., Results: In this cohort, 64% of patients were tested for ANA within ±90 days of RA criteria fulfillment. In the161 patients with ANA testing, 25% were ANA-positive. Patients who were ANA-positive were younger, female, and less likely to be current smokers. ANA positivity did not differ between patients with RA who were seropositive and seronegative. In seropositive patients who were ANA-positive, there was an increased time to fulfillment of RA criteria, increased time to treatment with disease-modifying antirheumatic drugs (DMARDs), and increased likelihood of being treated with hydroxychloroquine as opposed to methotrexate. Other outcomes, including disease activity and mortality, did not differ significantly between groups., Conclusion: In patients with RA, important differences exist between those who are ANA-positive and ANA-negative in terms of time to fulfillment of RA criteria and time to DMARD initiation as well as choice of initial pharmacotherapy. These findings could indicate a difference in clinical presentation or perception of patients with RA who are ANA-positive. Further research is needed to study the long-term outcomes of patients with RA who are ANA-positive., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To determine the clinical and serologic similarities and differences between inflammatory arthritis induced by immune checkpoint inhibitors (IA-irAE) and rheumatoid arthritis (RA)., Methods: In this retrospective cross-sectional comparative study, 20 patients with IA-irAE were age and sex matched to 40 seropositive and 40 seronegative RA patients. Electronic medical records were reviewed from diagnosis of inflammatory arthritis through May 2019. Arthritis characteristics, treatment, and relevant laboratory and serologic studies were captured., Results: Clinically, IA-irAE differed from seropositive and seronegative RA with respect to disease duration (4.18 versus 11.59 and 13.3 months, respectively, p = 0.005 (IA-irAE vs seropositive RA), p = 0.002 (IA-irAE vs seronegative RA)), polyarticular joint involvement at presentation (75% versus 97.5% and 100%, p = 0.013, p = 0.003), absence of erosive changes (5.9% vs 43.6% and 53.8%, p = 0.005, p = 0.001), mean prednisone dose (24.7 mg versus 16.53 mg and 15.68 mg, p = 0.008, p = 0.005), and use of methotrexate (5.0% versus 85.0% and 70.0%, p < 0.0001, p < 0.0001). Serologically, IA-irAE closely resembled seronegative RA. ANA positivity was seen in a minority of patients and did not differ significantly between all groups; however, the ANA staining pattern (speckled) was similar between IA-irAE and seronegative RA (100% versus 75%, respectively) and was not commonly observed in seropositive RA (18.2%)., Conclusion: IA-irAE is a new subset of IA that resembles seronegative RA immunologically. Our findings suggest that further study of IA-irAE might provide a window into underlying pathogenic mechanisms of early-stage seronegative RA. Key Points • Comprehensive comparison of clinical features between inflammatory arthritis irAE (IA-irAE) and regular rheumatoid arthritis indicates IA-irAE as a new subset of inflammatory arthritis. • IA-irAE resembles seronegative RA immunologically, suggesting that study of IA-irAE may provide a window into underlying pathogenic mechanisms of early-stage seronegative RA.

Mechanisms of immune checkpoints and their role in autoimmunity are discussed in the context of immune checkpoint inhibitor (ICI) therapy for cancer. The updated clinical spectrum of immune-related adverse events (irAEs), with an in-depth discussion of rheumatic irAEs, is presented. The relationship between ICI-induced loss of self-tolerance in cancer and the implications for understanding of irAEs, rheumatic irAEs in particular, is overviewed., Competing Interests: Disclosure Dr. Thanarajasingam is supported by the “Catalyst” award for Advancing in Academics Program, funded by the Department of Medicine, Mayo Clinic, Rochester, MN., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Longitudinally extensive transverse myelitis (LETM) accompanying systemic lupus erythematosus (SLE) is often due to coexisting aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder but has not been associated with myelin oligodendrocyte glycoprotein-IgG (MOG-IgG)., Objective and Methods: Case report at an academic medical center., Results: A 32-year-old woman developed severe transverse myelitis (paraplegia) shortly after SLE onset in the post-partum period. Magnetic resonance imaging (MRI) revealed an LETM, cerebrospinal fluid showed marked inflammation, and testing for infections was negative. Serum live-cell-based assay for MOG-IgG was positive but aquaporin-4-IgG was negative., Conclusion: In patients with SLE and LETM, MOG-IgG testing should be considered, in addition to AQP4-IgG.

Objective: Type I interferon (IFN) is important to systemic lupus erythematosus (SLE) pathogenesis, but it is not clear how chronic elevations in IFN alter immune function. We compared cytokine responses after whole blood stimulation with Toll-like receptor (TLR) agonists in high- and low-IFN SLE patient subgroups., Methods: SLE patients and nonautoimmune controls were recruited, and SLE patients were categorized as either high or low IFN. Whole blood was dispensed into tubes coated with lipopolysaccharide (LPS), oligonucleotides with cytosine-guanine repeats, Resiquimod, IFN-α, and IFN-α + LPS. Cytokine production in patient sera and after whole blood TLR stimulation was measured by multiplex assay, and type I IFN was assessed using a functional assay., Results: Circulating plasmacytoid dendritic cell numbers were specifically reduced in high-IFN SLE patients and not in low-IFN SLE patients. In serum, we observed that the correlations between cytokines in serum differed to a much greater degree between the high- and low-IFN groups ( P < 0.0001) than the absolute cytokine levels differed between these same groups. In stimulated conditions, the high-IFN patients had less cytokine production in response to TLR ligation than the low-IFN SLE patients. LPS produced the most diverse response, and a number of interactions between type I IFN and LPS were observed., Conclusion: We find striking differences in resting and stimulated cytokine patterns in high- vs. low-IFN SLE patients, which supports the biological importance of these patient subsets. These data could inform personalized treatment approaches and the pathogenesis of SLE flare following infection., (© 2019 The Authors. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To describe the prevalence, clinical presentation, and management of rheumatic immune-related adverse effects (Rh-irAEs) from immune checkpoint inhibitor (ICI) therapy., Methods: From a database of all patients who received any ICI at the Mayo Clinic Rochester, Minnesota campus between January 1, 2011 and March 1, 2018, we retrospectively identified those with Rh-irAEs, using diagnostic codes, search terms, and manual chart review., Results: Of the 1,293 patients who received any ICI, Rh-irAEs were clinically diagnosed in 43. Eighteen patients with Rh-irAEs who received ICI therapy elsewhere were also analyzed. Clinical syndromes included inflammatory arthritis (n = 34 [prevalence 2%]), myopathy (n = 10), and other rheumatic syndromes (n = 17). Inflammatory arthritis was most commonly polyarticular, and glucocorticoid treatment was required in 26 patients (76%). The mean ± SD duration of treatment was 18 ± 18 weeks. Five patients (15%) also received disease-modifying antirheumatic drugs, and ICI therapy had to be discontinued in 3 patients (9%). Myopathy was treated with glucocorticoids in all cases (mean ± SD treatment duration 15 ± 17 weeks) and led to 2 deaths and permanent ICI discontinuation in 9 patients (90%). Other syndromes included connective tissue diseases, vasculitis, polymyalgia rheumatica-like syndrome, and flare of preexisting rheumatic disease. Most (71%) were treated with immunosuppression, with 12% requiring ICI discontinuation., Conclusion: This study represents the largest cohort of patients with Rh-irAEs reported to date. Most patients received long courses of immunosuppressive treatment, although discontinuation of ICI therapy was required in only a minority., (© 2019, American College of Rheumatology.)

Objective: To determine the risk of rheumatic disease flare and adverse effects in patients with preexisting rheumatic disease who were receiving immune checkpoint inhibitor (ICI) therapy., Methods: A retrospective medical record review was performed to identify all patients who received ICI therapy at Mayo Clinic in Rochester, Minnesota between 2011 and 2016 (~700 patients). Those with a preexisting rheumatic disease were identified using specific diagnostic codes., Results: Sixteen patients were identified (81% female, median age 68.5 years). The most common rheumatic diseases were rheumatoid arthritis (n = 5), polymyalgia rheumatica (n = 5), Sjögren's syndrome (n = 2), and systemic lupus erythematosus (n = 2). Seven patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatic disease at the time of initiation of the ICI. The primary malignancies were melanoma (n = 10), pulmonary (n = 4), or hematologic (n = 2). In most cases, ICIs were offered only after failure of several other therapies. Immune-related adverse effects (IRAEs) occurred in 6 patients, and all were treated successfully with glucocorticoids and discontinuation of the ICI therapy. There were no significant differences in time from cancer diagnosis to immunotherapy, duration of immunotherapy, age, or sex between the patients with and those without IRAEs., Conclusion: To our knowledge, this represents the largest single-center cohort of patients with rheumatic diseases who were exposed to modern cancer immunotherapy. Only a minority of these patients experienced a flare of their preexisting rheumatic disease or any other IRAE., (© 2017, American College of Rheumatology.)

Objective: We describe a 38-year-old woman who presented with a history of inflammatory arthritis, rash, and daily fevers. She was noted to have chronic parvovirus infection with persistently detectable viral titers and a novel mutation in the ELANE gene. ELANE encodes neutrophil elastase, a neutrophil serine protease with important antimicrobial effects, and is found as part of neutrophil extracellular trap (NET) complexes. Pathogenic ELANE mutations have been identified in forms of hereditary neutropenia. However, our patient never had neutropenia. Because of the striking clinical scenario, we investigated this mutation functionally., Methods: NET formation by neutrophils was assessed by scanning electron microscopy. Neutrophil activation and neutrophil elastase production were evaluated by flow cytometry and fluorescent substrate-based functional assay, respectively. A multiplex assay was used to quantitate neutrophil inflammatory cytokine production. PyMOL software was used to generate 3-dimensional models of mutant elastase., Results: Activated neutrophils from the patient demonstrated a significantly decreased ability to form NETs on scanning electron microscopy, as well as quantitative defects in neutrophil activation and neutrophil elastase activity. The patient's neutrophils showed altered levels of interleukin-12 (IL-12) and IL-8, which are key cytokines for antiviral immunity and neutrophil chemotaxis. Three-dimensional mapping revealed that the mutation could alter protein folding and surface charge distribution, potentially perturbing protein trafficking. Thus, the mutation could affect neutrophil function by decreasing NETosis and altering key antiviral activities of neutrophils., Conclusion: This is the first report of a human pathogenic ELANE mutation associated with a defect in NETosis and a distinct syndrome of recurrent viral infection and chronic inflammation., (© 2017, American College of Rheumatology.)

Immune checkpoint inhibitors are approved for select cancer treatment and have shown survival benefit in patients with advanced melanoma. Adverse events, including immune-related adverse events, are common and potentially life-threatening. We describe cases of 2 patients with scleroderma (patient 1 had diffuse scleroderma, and patient 2 had limited scleroderma) that developed while they were receiving pembrolizumab therapy for metastatic melanoma. Prompt recognition and treatment of immune-related adverse events may improve tolerance to immune checkpoint inhibitors and contribute to an understanding of the manifesting autoimmune disease., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Malignant cells may subvert and escape endogenous host immune surveillance by up-regulation of immune inhibitory signals known as immune checkpoints. These checkpoints are important therapeutic targets, and antibodies that block checkpoint signaling have shown remarkable efficacy in some solid tumors as well as in some refractory hematologic malignancies. In hematologic cancers, the mechanism of these checkpoints is complex, as the tumor and immune system are one and the same. In this review, we evaluate the biology of checkpoint inhibition, review the current data on its efficacy in lymphoid tumors, and explore uncertainties in the field, including those involving the precise mechanisms of action, the appropriate timing of therapy, and the differences in response rate between lymphoid tumor types., (© 2016 Federation of European Biochemical Societies.)

Introduction: Lupus nephritis (LN) is a significant contributor to morbidity and mortality in systemic lupus erythematosus (SLE). Current therapies for LN are limited by significant toxicities and high rates of relapse. A clear and present need exists for the development of effective, targeted and well-tolerated treatment strategies for LN., Areas Covered: In this review, the authors examine sirukumab , a monoclonal antibody with high affinity for IL-6, as a novel agent with potential for use in the treatment of SLE and LN in particular. Their review focuses on the available data on the use of sirukumab in patients. Data from Phase I trials would indicate that sirukumab is generally safe and well tolerated. This review also reports the dose-dependent decreases in absolute neutrophil count and platelet count. To date, data for sirukumab in the treatment of SLE and LN are limited, but preliminary data suggest improvement in patient-reported outcomes, and transient improvement in clinical parameters., Expert Opinion: Considering scientific literature regarding IL-6 and the IL-6 receptor antagonist tocilizumab, one could extrapolate that sirukumab has the potential to treat LN by acting acutely and locally at the site of renal injury, as well as chronically by modulating the abnormal B- and T-cell subsets observed in SLE patients. However, the clinical efficacy of sirukumab in SLE and LN, in particular, remains to be seen in Phase III trials, and efficacy data in both the induction and maintenance phases of LN treatment will be of interest.

Background: Evidence-based practice in education requires high-quality evidence, and many in the medical education community have called for an improvement in the methodological quality of education research., Objective: Our aim was to use a valid measure of medical education research quality to highlight the methodological quality of research publications and provide an overview of the recent internal medicine (IM) residency literature., Methods: We searched MEDLINE and PreMEDLINE to identify English-language articles published in the United States and Canada between January 1, 2010, and December 31, 2011, focusing on IM residency education. Study quality was assessed using the Medical Education Research Study Quality Instrument (MERSQI), which has demonstrated reliability and validity. Qualitative articles were excluded. Articles were ranked by quality score, and the top 25% were examined for common themes, and 2 articles within each theme were selected for in-depth presentation., Results: The search identified 731 abstracts of which 223 articles met our inclusion criteria. The mean (±SD) MERSQI score of the 223 studies included in the review was 11.07 (±2.48). Quality scores were highest for data analysis (2.70) and lowest for study design (1.41) and validity (1.29). The themes identified included resident well-being, duty hours and resident workload, career decisions and gender, simulation medicine, and patient-centered outcomes., Conclusions: Our review provides an overview of the IM medical education literature for 2010-2011, highlighting 5 themes of interest to the medical education community. Study design and validity are 2 areas where improvements in methodological quality are needed, and authors should consider these when designing research protocols.

Relapsing polychondritis (RP) is an inflammatory disease of the cartilaginous tissue primarily affecting the cartilaginous structures of the ear, nose, joints, and the respiratory system. Cardiovascular complications of RP are associated with high morbidity and mortality and occur most commonly as valvular disease. Pericarditis is a less common complication, occurring in 4% of patients with RP and has not previously been described at presentation. We describe a case of relapsing polychondritis with acute pericarditis at presentation.

Objective: To examine the effect of census caps and unit-based admissions on resident workload, conference attendance, duty hour compliance, and patient safety., Participants and Methods: We implemented a census cap of 14 patients on 6 Mayo Clinic internal medicine resident hospital services and a unit-based admissions process in which patients and care teams were consolidated within hospital units. All 280 residents and 15,926 patient admissions to resident and nonresident services 1 year before the intervention (September 1, 2006, through August 31, 2007) and 1 year after the intervention (May 1, 2008, through April 30, 2009) were included. Residents' workload, conference attendance, and duty hours were tracked electronically. Patient safety variables including Rapid Response Team and cardiopulmonary resuscitation events, intensive care unit transfers, Patient Safety Indicators, and 30-day readmissions were compared preintervention and postintervention., Results: After the intervention, residents' mean (SE) ratings of workload appropriateness improved (3.10 [0.08] vs 3.87 [0.08] on a 5-point scale; P<.001), as did conference attendance (1523 [56. 8%] vs 1700 [63.5%] conferences attended; P<.001). Duty hour violations for working more than 30 consecutive hours and not having 10 hours off between duty periods decreased from 77 of 9490 possible violations (0.81%) to 27 (0.28%) and from 70 (0.74%) to 14 (0.15%) violations, respectively (both, P<.001). Thirty-day readmissions to resident services decreased (1010 [18.14%] vs 682 [15. 37%]; P<.001). All other patient safety measures remained unchanged. After adjustment for illness severity, there were no significant differences in patient outcomes between resident and nonresident services., Conclusion: Census caps and unit-based admissions were associated with improvements in resident workload, conference attendance, duty hour compliance, and readmission rates while patient outcomes were maintained., (Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Diabetic mastopathy is an uncommon, benign disease of the breast that can occur in women with diabetes and clinically mimic breast cancer. We describe a patient with long-standing type 1 diabetes who presented with a palpable breast mass with negative imaging findings on mammography, ultrasonography, and breast MRI. Surgical biopsy and histopathology confirmed diabetic mastopathy. We use this case to highlight the recognition, radiographic features, pathology, and management of this benign breast condition and emphasize that, in diabetic patients, the differential diagnosis of a new breast mass should include diabetic mastopathy.

Oncolytic virotherapy can be achieved in two ways: (1) by exploiting an innate ability of certain viruses to selectively replicate in tumor tissues, and (2) by using viruses to deliver toxic or immunostimulatory genes to tumors. Vesicular stomatitis virus (VSV) selectively replicates in tumors lacking adequate type I interferon response. The efficacy of oncolytic virotherapy using VSV against B16 melanomas in C57BL/6 mice is dependent on CD8(+) T and natural killer cells. Because immunotherapies that prime specific CD8(+) T cells against melanocyte/melanoma antigens can generate significant therapeutic responses, we hypothesized that engineering VSV to express the potent T cell costimulatory molecule CD40 ligand (VSV-CD40L) would enhance virotherapy with concomitant priming of melanoma-specific T cells. However, we observed no difference in antitumor efficacy between the parental VSV-GFP and VSV-CD40L. In contrast, intratumoral injection of a replication-defective adenovirus expressing CD40L (Ad-CD40L) consistently produced significantly greater therapy than either replication-competent VSV-GFP or VSV-CD40L. The Ad-CD40L-mediated tumor regressions were associated with specific T cell responses against tumor-associated antigens (TAAs), which took several days to develop, whereas VSV-CD40L rapidly induced high levels of T cell activation without specificity for TAAs. These data suggest that the high levels of VSV-associated immunogenicity distracted immune responses away from priming of tumor-specific T cells, even in the presence of potent costimulatory signals. In contrast, a replication-defective Ad-CD40L allowed significant priming of T cells directed against TAAs. These observations suggest that an efficiently primed antitumor T cell response can produce similar, if not better, therapy against an established melanoma compared with intratumoral injection of a replication-competent oncolytic virus.

Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non-CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy.

Strategies that generate tumor Ag-specific effector cells do not necessarily cure established tumors. We hypothesized that the relative efficiency with which tumor-specific effector cells reach the tumor is critical for therapy. We demonstrate in this study that activated T cells respond to the chemokine CCL3, both in vitro and in vivo, and we further demonstrate that expression of CCL3 within tumors increases the effector T cell infiltrate in those tumors. Importantly, we show that adenoviral gene transfer to cause expression of CCL3 within B16ova tumors in vivo increases the efficacy of adoptive transfer of tumor-specific effector OT1 T cells. We additionally demonstrate that such therapies result in endogenous immune responses to tumor Ags that are capable of protecting animals against subsequent tumor challenge. Strategies that modify the "visibility" of tumors have the potential to significantly enhance the efficacy of both vaccine and adoptive transfer therapies currently in development.

Summary Diverse immunotherapy approaches have achieved success in controlling individual aspects of immune responses in animal models. Transfer of such immunotherapies to clinical trials has obtained some success in patients, with clinical responses observed or effective antigen specific immune responses achieved, but has had limited impact on patient survival. Key elements required to generate de novo cell-mediated antitumour immune responses in vivo include recruitment of antigen-presenting cells to the tumour site, loading these cells with antigen, and their migration and maturation to full antigen-presenting function. In addition, it is essential for antigen-specific T cells to locate the tumour to mediate cytotoxicity, emphasizing the need for local inflammation to target effector cell recruitment. We review those therapies that involve the tumour site as a target and source of antigen for the initiation of immune responses, and discuss strategies to generate and co-ordinate an optimal cell-mediated immune response to control tumours locally.

Allelic loss of the chromosome 19q arm is a frequent event in human diffuse gliomas, suggesting that it contains a tumor suppressor gene. Recent deletion mapping studies have broadly implicated a 1.6-Mb interval between D19S241E and D19S596, with a limited subset of tumors, suggesting that the region may be as narrow as 150 kb. Focusing on this smaller interval, we have used cDNA selection, exon amplification, and genomic sequencing to identify three novel transcripts (EHD2, GLTSCR1, and GLTSCR2) and to map two known genes (SEPW1 and CRX). A partial transcript map of 19 transcripts and two EST markers has been constructed for the 1.6-Mb interval D19S241E-D19S596. Ten of these transcripts, including the 5 mapped to the 150-kb deletion interval, have been examined for alterations in a panel of gliomas with allelic loss of 19q. Tumor-specific alterations have not been identified in the transcripts examined thus far. Collectively, these data should facilitate subsequent efforts to identify and characterize the remaining transcripts in the 1.6-Mb interval., (Copyright 2000 Academic Press.)