Muskardin, Theresa Wampler

Abstract 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.

AbstractA 17‐year‐old Caucasian boy presented with progressive left‐sided weakness, transient slurred speech, and skin lesions characterized by 3‐5 mm, pink, asymptomatic papules with white atrophic centers on his central abdomen, back, and lower extremities. Skin biopsy confirmed the diagnosis of malignant atrophic papulosis, a rare vasculopathy that leads to the occlusion of small‐ and medium‐sized arteries. He was treated with cyclophosphamide, eculizumab, treprostinil, pentoxifylline, heparin, and acetylsalicylic acid. Despite the aggressive immunosuppression, humanized monoclonal antibodies, and antiplatelet therapy, he died two months after presentation. We report this case to highlight diagnostic features, as well as to highlight the importance of early diagnosis and treatment.

ObjectiveOur aim was to identify cytokines and chemokines in patients with adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) that predict changes in disease activity.MethodsMultiplexed immunoassays (Meso Scale Discovery) enabled simultaneous measurement of interferon (IFN)‐regulated chemokines and other pro‐ and anti‐inflammatory cytokines specific to differentiation of specific T‐cell and innate pathways. Cytokine scores were computed for IFNCK (IP‐10, MCP‐1), Th1 (IFNɣ, TNFα, and IL2), Th2 (IL4, IL10, IL12, and IL 13), Th17 (IL6, IL17, IL1β), macrophage (MIP‐1α, MIP‐1β, IL8), and regulatory (IL10, TNFα) factors. Spearman correlation and mixed models were used to examine whether cytokines at a previous visit predict change in disease activity at the next visit.ResultsThe study included 36 patients (16 DM and 20 JDM) with at least two visits (87 patient intervals between two visits). Mean age (SD) at inclusion was 56.9 (18.4) years for DM and 10.8 (6.6) years in JDM, 67% of patients were female, 89% Caucasian. The mean (SD) physician global, muscle and extra‐muscular disease activity Visual Analog Scale scores at inclusion were 41 (26), 36 (30), and 34 (21) mm, respectively. The change in IFN score from one visit to the next was associated with the change in physician global (P = 0.010) and extramuscular (P < 0.001) disease activity scores. Preliminary results revealed significant correlations of previous IFNCK score and IL‐6 with subsequent disease activity measures, but after adjustment for multiple visits per patient, these associations did not reach statistical significance.ConclusionThere is a potential relationship between IFNCK and other cytokine scores seen in adult and juvenile DM with future disease states.

ObjectiveWe 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.MethodsNET 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.ResultsActivated 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.ConclusionThis 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.

BACKGROUND. Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1–blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS. Six mutation-positive DIRA patients (children, ages 3–6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS. Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION. Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION. ClinicalTrials.gov NCT01801449. FUNDING. NIH, NIAMS, and NIAID.

Febrile infection‐related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin‐1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super‐refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939–945

ObjectiveTo evaluate the incidence and prevalence of juvenile idiopathic arthritis (JIA) in Olmsted County, Minnesota in 1994–2013 and trends in juvenile rheumatoid arthritis (JRA) in 1960–2013.MethodsCases of arthritis in 1994–2013 were identified by diagnosis code with medical chart review to confirm diagnosis separately for JIA and JRA. Overall incidence rates with 95% confidence intervals (95% CIs) were age and sex adjusted to the 2010 US white population. Comparisons were made with an earlier (1960–1993) cohort from this same population.ResultsSeventy‐one incident cases of JIA in 1994–2013 were identified, with an overall age‐ and sex‐adjusted incidence rate of 10.3 per 100,000 (95% CI 7.9–12.7). Forty‐two (59%) were female, with an incidence of 12.4 per 100,000 (95% CI 8.6–16.2), as compared to 8.3 per 100,000 (95% CI 5.2–11.3) in males. The most common subtype was oligoarthritis (63%). The mean ± SD age at diagnosis was 8.2 ± 5.3 years. The prevalence of JIA on January 1, 2000 and January 1, 2010 was 51.0 per 100,000 (95% CI 25.2–76.8) and 57.6 per 100,000 (95% CI 31.0–94.5), respectively. When the annual incidence of JRA was compared over time from 1960 to 2013, there was no significant change in incidence overall; however, the incidence decreased among females (P = 0.003). A cyclic pattern of incidence was observed, with peaks approximately every 10 years. Similar to the findings with regard to incidence, prevalence did not change overall, but decreased among females (P = 0.048). There were 4 deaths in the cohort of JRA patients diagnosed in 1960–2013; the standardized mortality ratio was 1.50 (95% CI 0.41–3.83).ConclusionIncidence of juvenile arthritis overall in Olmsted County, Minnesota has not changed significantly in the past 53 years. A consistent cyclic pattern was noted.