Prognostic value of automated assessment of interstitial lung disease on CT in systemic sclerosis.

OBJECTIVE: Stratifying the risk of death in SSc-related interstitial lung disease (SSc-ILD) is a challenging issue. The extent of lung fibrosis on high-resolution CT (HRCT) is often assessed by a visual semiquantitative method that lacks reliability. We aimed to assess the potential prognostic value of a deep-learning-based algorithm enabling automated quantification of ILD on HRCT in patients with SSc. METHODS: We correlated the extent of ILD with the occurrence of death during follow-up, and evaluated the additional value of ILD extent in predicting death based on a prognostic model including well-known risk factors in SSc. RESULTS: We included 318 patients with SSc, among whom 196 had ILD; the median follow-up was 94 months (interquartile range 73-111). The mortality rate was 1.6% at 2 years and 26.3% at 10 years. For each 1% increase in the baseline ILD extent (up to 30% of the lung), the risk of death at 10 years was increased by 4% (hazard ratio 1.04, 95% CI 1.01, 1.07, P = 0.004). We constructed a risk prediction model that showed good discrimination for 10-year mortality (c index 0.789). Adding the automated quantification of ILD significantly improved the model for 10-year survival prediction (P = 0.007). Its discrimination was only marginally improved, but it improved prediction of 2-year mortality (difference in time-dependent area under the curve 0.043, 95% CI 0.002, 0.084, P = 0.040). CONCLUSION: The deep-learning-based, computer-aided quantification of ILD extent on HRCT provides an effective tool for risk stratification in SSc. It might help identify patients at short-term risk of death.

Hydroxychloroquine levels in pregnancy and materno-fetal outcomes in Systemic Lupus Erythematosus patients.

OBJECTIVES: Data about hydroxychloroquine (HCQ) levels during pregnancy are sparse. We assessed HCQ whole blood levels at first trimester of pregnancy as a potential predictor of maternal and obstetric/fetal outcomes in patients with systemic lupus erythematosus (SLE). METHODS: We included pregnant SLE patients enrolled in the prospective GR2 study receiving HCQ, with at least one available first-trimester whole-blood HCQ assay. We evaluated several cut-offs for HCQ whole blood levels, including ≤200 ng/ml for severe non-adherence. Primary outcomes were maternal flares during the second and third trimesters of pregnancy, and adverse pregnancy outcomes (APOs: fetal/neonatal death, placental insufficiency with preterm delivery, and small-for-gestational-age neonates). RESULTS: We included 174 patients (median age: 32.1 years, IQR 28.8-35.2). Thirty (17.2%) patients had flares, 4 (2.3%) being severe. APOs occurred in 28 patients (16.1%). There were no significant differences in APOs by HCQ level for either those with subtherapeutic HCQ levels (≤500 ng/ml vs >500 ng/ml: 23.5% vs 14.3%, p = 0.19) or those with non-adherent HCQ levels (≤200 ng/ml vs >200 ng/ml: 20.0% vs 15.7%, p = 0.71). Similarly, the overall rate of maternal flares did not differ significantly by HCQ level cut-off, but patients with subtherapeutic (HCQ ≤500 ng/ml: 8.8% vs 0.7%, p = 0.02) and non-adherent HCQ levels (≤200 ng/ml: 13.3% vs 1.3%, p = 0.04) had significantly more severe flares. CONCLUSION: In this large prospective study of pregnant SLE patients, first-trimester subtherapeutic (≤500 ng/ml) and severe non-adherent (≤200 ng/ml) HCQ levels were associated with severe maternal flares, but not with APOs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02450396.

Clinical features and long-term outcomes of patients with systemic polyarteritis nodosa diagnosed since 2005: Data from 196 patients.

BACKGROUND: The landscape of polyarteritis nodosa (PAN) has substantially changed during the last decades. Recent data regarding causes, characteristics, and prognosis of systemic PAN in the modern era are lacking. METHODS: This retrospective study included patients with systemic PAN referred to the French Vasculitis Study Group between 2005 and 2019. Characteristics, associated conditions and outcomes were collected, and predictors of relapse and death were analyzed. RESULTS: 196 patients were included. Main clinical symptoms were constitutional (84%), neurological (59%), skin (58%) and musculoskeletal (58%) manifestations. Secondary PAN accounted for 55 (28%) patients, including myelodysplastic syndrome (9%), solid cancer (7%), lymphoma (4%) and autoinflammatory diseases (4%). No patient had active HBV infection. All treated patients (98.5%) received glucocorticoids (GCs), alone (41%) or in combination with immunosuppressants (59%), with remission achieved in 90%. Relapses were independently associated with age >65 years (HR 1.85; 95% CI1.12-3.08), gastrointestinal involvement (1.95; 95% CI1.09-3.52) and skin necrotic lesions (HR 1.95; 95%CI 1.24-3.05). One-, 5- and 10-year overall survival rates were 93%, 87% and 81%, respectively. In multivariate analyses, age >65 years (HR 2.80; 95%CI 1.23-6.37), necrotic purpura (HR 4.16; 95%CI 1.62-10.70), acute kidney injury (HR 4.89; 95% 1.71-13.99) and secondary PAN (HR 2.98; 95%CI 1.29-6.85) were independently associated with mortality. CONCLUSION: Landscape of PAN has changed during the last decades, with the disappearance of HBV-PAN and the emergence of secondary PAN. Relapse rate remains high, especially in aged patients with gastrointestinal and cutaneous necrosis, as well as mortality.

Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.

West Oakland's Experience in Building Community Power to Confront Environmental Injustice Through California's Assembly Bill 617.

We explored how air quality management processes associated with Assembly Bill 617 (AB 617) in West Oakland, California, represent a shift in power relationships between government agencies and communities toward the goal of addressing legacies of environmental injustice. We drew from a statewide assessment of community engagement in AB 617's first year, and an analysis of the West Oakland AB 617 process. The first comprised 2 statewide surveys (n = 102 and n = 106), 70 key informant interviews, observation of all AB 617 first-year sites, and analysis of related planning documents. The second comprised 2 rounds of interviews (n = 22 and n = 23, with a total of 19 individuals) and extensive participant observation. Several factors are necessary for pursuing environmental justice: (1) invest in community partnerships and collaborations, (2) honor community knowledge and data, (3) ensure that community constituents share power in environmental governance, and (4) adopt explicit racial justice frameworks. Although still a work in progress, AB 617 offers important lessons for community and policy organizations nationwide engaged in environmental justice. (Am J Public Health. 2022;112(2):262-270. https://doi.org/10.2105/AJPH.2021.306592).

Skewed peripheral B- and T-cell compartments in patients with ANCA-associated vasculitis.

OBJECTIVES: To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). RESULTS: GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21- B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P < 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P < 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). CONCLUSION: Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.

White blood count, D-dimers, and ferritin levels as predictive factors of pulmonary embolism suspected upon admission in noncritically ill COVID-19 patients: The French multicenter CLOTVID retrospective study.

BACKGROUND: A high prevalence of pulmonary embolism (PE) has been described during COVID-19. Our aim was to identify predictive factors of PE in non-ICU hospitalized COVID-19 patients. METHODS: Data and outcomes were collected upon admission during a French multicenter retrospective study, including patients hospitalized for COVID-19, with a CT pulmonary angiography (CTPA) performed in the emergency department for suspected PE. Predictive factors significantly associated with PE were identified through a multivariate regression model. RESULTS: A total of 88 patients (median [IQR] age of 68 years [60-78]) were analyzed. Based on CTPA, 47 (53.4%) patients were diagnosed with PE, and 41 were not. D-dimer ≥3000 ng/mL (OR 8.2 [95% CI] 1.3-74.2, sensitivity (Se) 0.84, specificity (Sp) 0.78, P = .03), white blood count (WBC) ≥12.0 G/L (29.5 [2.3-1221.2], Se 0.47, Sp 0.92, P = .02), and ferritin ≥480 µg/L (17.0 [1.7-553.3], Se 0.96, Sp 0.44, P = .03) were independently associated with the PE diagnosis. The presence of the double criterion D-dimer ≥3000 ng/mL and WBC ≥12.0 G/L was greatly associated with PE (OR 21.4 [4.0-397.9], P = .004). CONCLUSION: The white blood count, the D-dimer and ferritin levels could be used as an indication for CTPA to confirm PE on admission in non-ICU COVID-19 patients.

Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener's). Results of a single-center cohort study on 66 patients.

The aim of this study was to evaluate the efficacy and safety of rituximab (RTX) associated with glucocorticoid treatment based on disease severity, as a remission induction treatment for granulomatosis with polyangiitis (GPA) (Wegener's) and to analyze the results of long-term maintenance therapy with low doses of RTX in a routine time-based protocol. This single-center retrospective study used standardized data collection from all GPA patients receiving RTX between 2002 and 2013. The remission induction regimen consisted of RTX and glucocorticoids, adapted according to disease severity. Once remission was achieved, patients received RTX maintenance treatment (500 mg every 6 months) for 18 months. Sixty-six GPA patients received RTX for remission induction. After six months, a response had been achieved in 78.8% of these patients, with a moderate oral prednisone regimen (mean dose at baseline, 32.8 ± 23.4 mg/day). Subglottic stenosis increased the risk of treatment failure (OR = 31.2, P = 0.0104). RTX maintenance treatment was continued for 18 months in 92% of the GPA patients, who were followed for 34.2 ± 26.2 months (mean total cumulative RTX dose of 4.6 ± 1.7 g). The relapse rate was 11.2/100 patient-years. The relapses occur a mean of 13.5 ± 14.7 months after the last RTX infusion. Twenty-one severe adverse events were recorded; 13.6% patients had severe infections. We conclude that in this single-center cohort, RTX associated with glucocorticoid treatment adapted for disease severity appeared to induce remission effectively in GPA patients. Maintenance treatment with low doses of RTX in a routine time-based protocol was safe and associated with low rates of relapse on treatment.

High prevalence of infectious events in thrombotic thrombocytopenic purpura and genetic relationship with toll-like receptor 9 polymorphisms: experience of the French Thrombotic Microangiopathies Reference Center.

BACKGROUND: Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP. STUDY DESIGN AND METHODS: We recruited randomly and prospectively a cohort of 280 consecutive TTP patients during a 9-year period. Features of infection were systematically recorded. RESULTS: Features consistent with an infectious event were observed in 114 patients (41%) at time of TTP diagnosis. Infectious agents were documented in 34 cases and were mainly Gram-negative bacilli. At time of diagnosis infected patients more frequently had fever (p < 0.001). Infections at diagnosis did not impact prognosis and outcome. Thirty-six percent of patients experienced an infectious event during hospitalization, which resulted in more exacerbation of TTP (p = 0.02). Infections were not overrepresented during treatment in patients who received steroids and/or rituximab. Further genetic analysis of toll-like receptor (TLR)-9 functionally relevant polymorphisms revealed that TLR-9 +2848 G and TLR-9 +1174 A genotypes were more frequent in TTP patients than in controls (p = 0.04 and p = 0.026, respectively) and more particularly in patients negative for the Class II human leukocyte antigen system susceptibility allele DRB1*11 (p = 0.001 and p = 0.002, respectively). Haplotypes estimation showed that 1174A-2848G haplotype was significantly more frequent in TTP (p = 0.004), suggesting a primary role for this haplotype variation in conferring a predisposition for acquired TTP. CONCLUSION: Infections should be considered as an aggravating factor during the course of TTP. Particular polymorphisms in TLR-9 gene may represent risk factors for TTP.

Community-Engaged Research and the Use of Open Access ToxVal/ToxRef In Vivo Databases and New Approach Methodologies (NAM) to Address Human Health Risks From Environmental Contaminants.

BACKGROUND: The paper analyzes opportunities for integrating Open access resources (Abstract Sifter, US EPA and NTP Toxicity Value and Toxicity Reference [ToxVal/ToxRefDB]) and New Approach Methodologies (NAM) integration into Community Engaged Research (CEnR). METHODS: CompTox Chemicals Dashboard and Integrated Chemical Environment with in vivo ToxVal/ToxRef and NAMs (in vitro) databases are presented in three case studies to show how these resources could be used in Pilot Projects involving Community Engaged Research (CEnR) from the University of California, Davis, Environmental Health Sciences Center. RESULTS: Case #1 developed a novel assay methodology for testing pesticide toxicity. Case #2 involved detection of water contaminants from wildfire ash and Case #3 involved contaminants on Tribal Lands. Abstract Sifter/ToxVal/ToxRefDB regulatory data and NAMs could be used to screen/prioritize risks from exposure to metals, PAHs and PFAS from wildfire ash leached into water and to investigate activities of environmental toxins (e.g., pesticides) on Tribal lands. Open access NAMs and computational tools can apply to detection of sensitive biological activities in potential or known adverse outcome pathways to predict points of departure (POD) for comparison with regulatory values for hazard identification. Open access Systematic Empirical Evaluation of Models or biomonitoring exposures are available for human subpopulations and can be used to determine bioactivity (POD) to exposure ratio to facilitate mitigation. CONCLUSIONS: These resources help prioritize chemical toxicity and facilitate regulatory decisions and health protective policies that can aid stakeholders in deciding on needed research. Insights into exposure risks can aid environmental justice and health equity advocates.

A Changed Man: A Rare Case of Behcet's Disease Autoimmune Encephalitis.

Behcet's disease (BD) is characterized by recurrent oral ulcers with concomitant systemic multi-organ involvement, which may include neurological disease, ocular disease, vascular disease, genital ulcers, skin lesions, and arthritis. The clinical symptoms arise from vasculitis that involves small, medium, and large blood vessels. We present the case of a young male who presented with atypical Behcet's autoimmune encephalitis with recurrent oral ulcers, neurological manifestations, HLA-B51 positivity, abnormal EEG findings, and improvement following multiple plasma exchange treatments.

A Recurring Theme: A Rare Case of Pembrolizumab-induced Acute Interstitial Nephritis.

Pembrolizumab is utilized in the treatment of multiple different malignancies, including non-small cell lung cancer, head and neck squamous cell carcinoma, melanoma, renal cell carcinoma, endometrial cancer, and more. Pembrolizumab is an immune checkpoint inhibitor that inhibits the programmed cell death-1 (PD-1) signaling pathway. Despite its benefits in treating multiple cancers, there are many reported adverse effects of Pembrolizumab affecting various organ systems; rarely it can cause acute interstitial nephritis (AIN). We present the case of a 79-year-old male with metastatic retroperitoneal squamous cell carcinoma who was found to have recurrent acute interstitial nephritis after pembrolizumab therapy.

An uncommon combination: a case report of herpes simplex virus encephalitis induced takotsubo cardiomyopathy.

Background: Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy or broken-heart syndrome, is a non-ischemic cardiomyopathy that presents as a transient regional systolic dysfunction of the left ventricle with minimal increase in troponins. The pathogenesis of takotsubo cardiomyopathy is not well understood. Some possible theories include increased catecholamines causing sympathetic overdrive, microvascular dysfunction, coronary spasm, or inflammation. The association of herpes simplex virus (HSV) encephalitis with takotsubo cardiomyopathy has rarely been reported with only two cases being described in literature. Case Description: We present a patient that came in with altered mental status who was found to have herpes simplex virus 1 (HSV-1) encephalitis. During his hospital stay, the patient had developed shortness of breath on hospital day 3. The patient's troponin was found to be mildly elevated and echocardiogram revealed takotsubo cardiomyopathy with left ventricle ejection fraction (LVEF) of 20% and severe hypokinesis of all left ventricle segments except the basal segments. His echocardiogram nine months prior revealed a LVEF 60-65%. He was treated with intravenous (IV) acyclovir and repeat echocardiogram three weeks following hospitalization revealed resolution of his takotsubo cardiomyopathy. Conclusions: Physicians should keep HSV encephalitis induced takotsubo cardiomyopathy in their differential diagnosis when patients present with HSV encephalitis along with shortness of breath and pulmonary vascular congestion on imaging.

An Unexpected Lymphoma: A Rare Case of Primary Gastric Burkitt's Lymphoma.

Primary gastric Burkitt's lymphoma is an aggressive non-Hodgkin's lymphoma that has been rarely reported in the literature. The majority of primary gastric lymphomas are diffuse large B-cell lymphomas and mucosa-associated lymphoid tissue (MALT) lymphomas. Patients with primary gastric Burkitt's lymphoma can present with abdominal pain, hematemesis, melena, perforation, and obstruction. Diagnosis is made with a combination of clinical, radiological, and pathological findings. Treatment data are limited due to the limited cases reported. We present a case of a 47-year-old female who presented with diffuse abdominal pain, melena, and coffee-ground emesis that was diagnosed with primary gastric Burkitt's lymphoma following biopsies taken from a gastric ulcerated mass found on upper endoscopy.

Helper T cell immunity in humans with inherited CD4 deficiency.

CD4+ T cells are vital for host defense and immune regulation. However, the fundamental role of CD4 itself remains enigmatic. We report seven patients aged 5-61 years from five families of four ancestries with autosomal recessive CD4 deficiency and a range of infections, including recalcitrant warts and Whipple's disease. All patients are homozygous for rare deleterious CD4 variants impacting expression of the canonical CD4 isoform. A shorter expressed isoform that interacts with LCK, but not HLA class II, is affected by only one variant. All patients lack CD4+ T cells and have increased numbers of TCRαß+CD4-CD8- T cells, which phenotypically and transcriptionally resemble conventional Th cells. Finally, patient CD4-CD8- αß T cells exhibit intact responses to HLA class II-restricted antigens and promote B cell differentiation in vitro. Thus, compensatory development of Th cells enables patients with inherited CD4 deficiency to acquire effective cellular and humoral immunity against an unexpectedly large range of pathogens. Nevertheless, CD4 is indispensable for protective immunity against at least human papillomaviruses and Trophyrema whipplei.

Adult-onset asthma associated with periocular xanthogranuloma: new diagnostic and therapeutic approaches in a very rare systemic disease.

PURPOSE: To report some novel findings concerning the systemic manifestations and treatment of adult-onset asthma and periocular xanthogranuloma, a rare type of non-Langerhans histiocytosis that can lead to important visual dysfunction. METHODS: A retrospective case series of 2 patients was evaluated for orbital and systemic manifestations using fluorodeoxyglucose positron emission tomography/CT and/or orbital MRI. Histological specimens were reviewed in all patients. Oral prednisone was initiated at 1 mg/kg daily and gradually tapered to a minimum effective dose. Efficacy was assessed on the basis of an objective observation of decreased swelling. RESULTS: One patient displayed original uptake foci involving intrathoracic lymphadenopathies, the trajectory of the paraumbilical vein and perirectal fat. Low-dose prednisone was able to induce a durable response in the authors' patients. CONCLUSIONS: Fluorodeoxyglucose positron emission tomography/CT may be useful for the diagnostic workup and follow-up assessment of patients with adult-onset asthma and periocular xanthogranuloma. Oral corticosteroids can be used successfully as first-line treatment in such patients.