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Patients with immune-mediated inflammatory diseases (IMIDs) receiving B cell-depleting therapy (BCDT) are among the most vulnerable to severe COVID-19, as well as the most likely to suboptimally respond to SARS-CoV-2 vaccines. However, little is known about the frequency or severity of breakthrough infection in this population. We retrospectively analyzed a large group of vaccinated IMID patients undergoing BCDT in order to identify breakthrough COVID-19 infections and assess their outcomes.In this retrospective cohort study, the pharmacy records and COVID-19 registry at the Cleveland Clinic were searched using specific International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes to identify IMIDs patients who 1) received treatment with BCDT, 2) were vaccinated against SARS-CoV-2, and 3) experienced breakthrough infections. Each electronic medical record was reviewed to extract clinical data and outcomes. Univariate and multivariable logistic/proportional odds regression models were used to examine the risk factors for severe outcomes.Of 1,696 IMID patients receiving BCDT, 74 developed breakthrough COVID-19 prior to December 16, 2021. Outcomes were severe, with 29 patients hospitalized (39.2%), 11 patients requiring critical care (14.9%), and 6 deaths (8.1%). Outpatient anti-SARS-CoV-2 monoclonal antibodies were used to treat 21 patients, with 1 hospitalization and no deaths. A comparator analysis examining 1,437 unvaccinated IMID patients receiving BCDT over the same time period identified 57 COVID-19 cases (4.0%), with 28 requiring hospitalization (49.1%), including 7 deaths (12.3%).IMID patients receiving BCDT regardless of vaccine status appear to be vulnerable to infection with SARS-CoV-2, and use of BCDT is frequently associated with severe outcomes. Outpatient use of anti-SARS-CoV-2 monoclonal antibody therapy appears to be associated with enhanced clinical outcomes.

Contact allergy can manifest in a variety of ways clinically. Systemic contact allergy may occasionally present with pain in muscles and joints. Fibromyalgia is a chronic rheumatic disease characterized by pain and with virtually unknown aetiology.The aim of this study was to investigate the contact allergy rates to the sensitizers in a baseline series and compare with corresponding rates in dermatitis patients and the general population.Patch testing with the Swedish baseline series was performed in 120 individuals with fibromyalgia. Fisher's exact test was used for pair-wise comparisons of contact allergy rates between the fibromyalgia group and two control groups, dermatitis patients and individuals in the general population.Contact allergy was significantly more common in the fibromyalgia group compared to the general population concerning nickel and the fragrance markers Myroxolon pereirae and fragrance mix I. There were fewer allergic reactions to preservatives in the fibromyalgia group compared with the dermatitis group.Myroxolon pereirae and fragrance mix I represent besides fragrance allergy also allergy to flavouring substances which indicate that oral exposure to flavouring substances and hygiene products might be important for sensitization and possibly elicitation of systemic contact allergy symptoms in fibromyalgia individuals.

Previous work identified three subgroups of children with ASD based upon co-occurring conditions (COCs) diagnosed during the first 5 years of life. This work examines prenatal risk factors, given by maternal medical claims, for each of the three subgroups: children with a High-Prevalence of COCs, children with mainly developmental delay and seizures (DD/Seizure COCs), and children with a Low-Prevalence of COCs. While some risk factors are shared by all three subgroups, the majority of the factors identified for each subgroup were unique; infections, anti-inflammatory and other complex medications were associated with the High-Prevalence COCs group; immune deregulatory conditions such as asthma and joint disorders were associated with the DD/Seizure COCs group; and overall pregnancy complications were associated with the Low-Prevalence COCs group. Thus, we have found that the previously identified subgroups of children with ASD have distinct associated prenatal risk factors. As such, this work supports subgrouping children with ASD based upon COCs, which may provide a framework for elucidating some of the heterogeneity associated with ASD.

The prognosis in systemic lupus erythematosus (SLE) has improved due to better treatment and care, but cardiovascular disease (CVD) still remains an important clinical problem, since the risk of CVD in SLE is much higher than among controls. Atherosclerosis is the main cause of CVD in the general population, and in SLE, increased atherosclerosis, especially the prevalence of atherosclerotic plaques, has been demonstrated. Atherosclerosis is an inflammatory condition, where immunity plays an important role. Interestingly, oxidized low-density lipoprotein, defective clearance of dead cells, and inflammation, with a pro-inflammatory T-cell profile are characteristics of both atherosclerosis and SLE. In addition to atherosclerosis as an underlying cause of CVD in SLE, there are also other non-mutually exclusive mechanisms, and the most important of these are antiphospholipid antibodies (aPL) leading to the antiphospholipid antibody syndrome with both arterial and venous thrombosis. aPL can cause direct pro-inflammatory and prothrombotic effects on endothelial and other cells and also interfere with the coagulation, for example, by inhibiting annexin A5 from its antithrombotic and protective effects. Antibodies against phosphorylcholine (anti-PC) and other small lipid-related epitopes, sometimes called natural antibodies, are negatively associated with CVD and atherosclerosis in SLE. Taken together, a combination of traditional risk factors such as hypertension and dyslipidemia, and nontraditional ones, especially aPL, inflammation, and low anti-PC are implicated in the increased risk of CVD in SLE. Close monitoring of both traditional risk factors and nontraditional ones, including treatment of disease manifestations, not lest renal disease in SLE, is warranted.

Rituximab (RTX), a chimeric monoclonal antibody targeting CD20-positive cells, is a valuable treatment option for malignant and benign immune-related disorders. The rationale of targeting the CD20 antigen relies on depletion of both healthy and autoreactive/malignant CD20-espressing cells, but normal B-cell reconstitution is expected within months after treatment. Nevertheless, a number of recent studies have documented prolonged B-cell deficiency associated with new-onset hypogammaglobulinemia in patients receiving RTX. Awareness of post-RTX hypogammaglobulinemia has become wider among clinicians, with a growing number of reports about the increased incidence, especially in children. Although these patients were previously regarded as affected by secondary/iatrogenic immunodeficiency, atypical clinical and immunological manifestations (e.g., severe or opportunistic infections; prolonged B-cell aplasia) raise concerns of delayed manifestations of genetic immunological disorders that have been unveiled by B-cell perturbation. As more patients with undiagnosed primary immune deficiency receiving RTX have been identified, it remains the challenge in discerning those that might display a higher risk of persistent RTX-associated hypogammaglobulinemia and need a tailored immunology follow-up. In this review, we summarize the principal evidence regarding post-RTX hypogammaglobulinemia and provide a guideline for identifying patients at higher risk of RTX-associated hypogammaglobulinemia that could harbor an inborn error of immunity.

Systemic lupus erythematosus (SLE) patients have more pregnancy complications than healthy patients. Data regarding pregnancy outcomes in women with undifferentiated connective tissue disease (UCTD) are more limited, and existing studies are concentrated in Italy and predominantly in patients with a new diagnosis. Our objective was to compare pregnancy outcomes for UCTD and SLE patients with established disease.Between 2008 and 2017, patients with UCTD and SLE at an academic medical center were recruited to a prospective pregnancy registry. UCTD was defined as a positive autoantibody plus connective tissue disease symptoms not meeting criteria for another rheumatic diagnosis. SLE was defined by American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria or by physician diagnosis. Data were collected throughout pregnancy and postpartum. Comparator groups included UCTD, low-activity SLE, and high-activity SLE.A total of 150 SLE and 51 UCTD pregnancies were analyzed. Disease activity was low in most patients, although more patients with SLE had severe activity during pregnancy (12% versus 2%; P = 0.05). The frequencies of prematurity and preeclampsia were significantly lower in UCTD than in high-activity SLE patients (preterm 17% versus 45% [P = 0.004] and preeclampsia 6% versus 34% [P = 0.0008]), although similar to low-activity SLE patients. More infants who were small for gestational age were born to SLE than UCTD patients (33% versus 7% [P = 0.0005]), regardless of disease activity level.Pregnancies in women with UCTD managed by a rheumatologist have a high rate of pregnancy success and fewer risks than those in women with active SLE.

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Carvacrol (CAR) showed various pharmacological and therapeutic effects in different disorders. In the current article, the experimental and clinical effects of CAR on respiratory, allergic, and immunologic disorders are described. Various databases, including PubMed, Science Direct, and Scopus, were searched regarding the effects of CAR on respiratory and allergic disorders until the end of October 2021. CAR showed the relaxant effect, with various possible mechanisms suggesting the bronchodilatory effect in obstructive pulmonary diseases. The preventive effects of CAR on experimental animal models of respiratory diseases were shown through mechanisms such as antioxidant, immunomodulatory, and anti-inflammatory. CAR also showed therapeutic potential on lung cancer, lung infections, and allergic and immunologic disorders. Clinical studies also revealed therapeutic effects of CAR on asthma, sulfur-mustard-induced lug disorders, and some other allergic and immunologic diseases. Pharmacological and therapeutic effects of CAR indicate possible remedy effects of this agent in the treatment of respiratory, allergic, and immunologic diseases.

Electronic health records (EHRs) represent powerful tools to study rare diseases. Our objective was to develop and validate EHR algorithms to identify systemic lupus erythematosus (SLE) births across centers.We developed algorithms in a training set using an EHR with over 3 million subjects and validated the algorithms at 2 other centers. Subjects at all 3 centers were selected using ≥1 code for SLE International Classification of Diseases, Ninth Revision (ICD-9) or SLE International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Clinical Modification (ICD-10-CM) and ≥1 ICD-9 or ICD-10-CM delivery code. A subject was a case if diagnosed with SLE by a rheumatologist and had a birth documented. We tested algorithms using SLE ICD-9 or ICD-10-CM codes, antimalarial use, a positive antinuclear antibody ≥1:160, and ever checked double-stranded DNA or complement, using both rule-based and machine learning methods. Positive predictive values (PPVs) and sensitivities were calculated. We assessed the impact of case definition, coding provider, and subject race on algorithm performance.Algorithms performed similarly across all 3 centers. Increasing the number of SLE codes, adding clinical data, and having a rheumatologist use the SLE code all increased the likelihood of identifying true SLE patients. All the algorithms had higher PPVs in African American versus White SLE births. Using machine learning methods, the total number of SLE codes and an SLE code from a rheumatologist were the most important variables in the model for SLE case status.We developed and validated algorithms that use multiple types of data to identify SLE births in the EHR. Algorithms performed better in African American mothers than in White mothers.

Abnormal central pain processing is a leading cause of pain in fibromyalgia (FM) and is perceptually characterized with the psychophysical measure of temporal summation of pain (TSP). TSP is the perception of increasingly greater pain in response to repetitive or tonic noxious stimuli. Previous neuroimaging studies have used static (i.e., summary) measures to examine the functional magnetic resonance imaging (fMRI) correlates of TSP in FM. However, functional brain activity rapidly and dynamically reorganizes over time, and, similarly, TSP is a temporally evolving process. This study was undertaken to demonstrate how a complete understanding of the neural circuitry supporting TSP in FM thus requires a dynamic measure that evolves over time.We utilized novel methods for analyzing dynamic functional brain connectivity in patients with FM in order to examine how TSP-associated fluctuations are linked to the dynamic functional reconfiguration of the brain. In 84 FM patients and age- and sex-matched healthy controls, we collected high-temporal-resolution fMRI data during a resting state and during a state in which sustained cuff pressure pain was applied to the leg.FM patients experienced greater TSP than healthy controls (mean ± SD TSP score 17.93 ± 19.24 in FM patients versus 9.47 ± 14.06 in healthy controls; P = 0.028), but TSP scores varied substantially between patients. In the brain, the presence versus absence of TSP in patients with FM was marked by more sustained enmeshment between sensorimotor and salience networks during the pain period. Furthermore, dynamic enmeshment was noted solely in FM patients with high TSP, as interactions with all other brain networks were dampened during the pain period.This study elucidates the dynamic brain processes underlying facilitated central pain processing in FM. Our findings will enable future investigation of dynamic symptoms in FM.

Lupus anticoagulant hypoprothrombinemia síndrome (LAHPS) is a rare entity. A 54-year-old woman diagnosed with systemic lupus erythematosus (SLE) present in August 2020 with cerebellar haemorrhage, coagulation factor II deficiency was found. After increasing corticosteroid dose and adjustment of immunosuppressive therapy FII levels increased. She has no presented new haemorrhagic events.

OBJECTIVE Elevated interleukin 10 (IL10) in SLE patients has B-cell promoting effects, contributing to autoantibody production and tissue damage. We aimed to characterize upregulated IL10+ B-cell subsets and dysregulated IL10 expression in SLE B cells for new therapeutic options. METHODS Proportions of Th10 and IL10+ B-cell subsets in PBMCs were assessed using flow cytometry. The IL10-3'UTR dual-luciferase vector was constructed and co-transfected with siRNA, miRNA mimics or inhibitors into RAJI cell line. Transcript levels were quantified using Taqman assays. RESULTS Culture conditions that induced IL10+ Breg in healthy controls (HC) resulted in expansion of IL10+ DN2 (IgD- CD27- CD21- CD11c+ ) B-cells in SLE PBMCs. Proportions of IL10+ DN2, but not those of IL10- DN2, correlated with disease activity, levels of antibodies to dsDNA, and associated with high levels or seropositivity of anti-Smith and anti-cardiolipin IgG in SLE patients from two cohorts of mainly African Americans and Asians, respectively. Proportions of Th10 (CD45RA- CXCR5- CXCR3+ PD1hi CD4+ ) cells correlated with IL10+ DN2 frequencies, ANA titers and proteinuria levels in SLE patients. Screening predicted IL10 3'UTR-targeting miRNAs in SLE B cells identified miR-17-5p and miR-20a-5p with their levels inversely correlated with IL10 and transcription factor E2F2. In RAJI cells, knockdown of E2F2 expression resulted in increased levels of miR-17-5p and miR-20a-5p and decreased IL10 mRNA and protein levels, and overexpression and inhibition of miR-17-5p down-regulated and up-regulated IL10 mRNA levels respectively; suggesting regulation of IL10 expression by E2F2-miR-17-5p loop. CONCLUSION IL10 promotes extrafollicular autoimmune responses in active SLE patients, which might be dampened by targeting the E2F2-miR-17-5p circuitry.

To describe the baseline characteristics of patients with positivity for antiphospholipid antibodies (aPLs) who were enrolled in an international registry, the Antiphospholipid Syndrome (APS) Alliance for Clinical Trials and International Networking (APS ACTION) clinical database and repository, overall and by clinical and laboratory subtypes.The APS ACTION registry includes adults who persistently had positivity for aPLs. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS only, obstetric APS only, and both thrombotic APS/obstetric APS). We assessed baseline characteristics of patients tested for the presence of three aPLs (lupus anticoagulant [LAC] test, anticardiolipin antibody [aCL], and anti-βThe 804 aPL-positive patients assessed in the present study had a mean age of 45 ± 13 years, were 74% female, and 68% White; additionally, 36% had other systemic autoimmune diseases. Of these 804 aPL-positive patients, 80% were classified as having APS (with 55% having thrombotic APS, 9% obstetric APS, and 15% thrombotic APS/obstetric APS). In the overall cohort, 71% had vascular thrombosis, 50% with a history of pregnancy had obstetric morbidity, and 56% had experienced at least one non-criteria manifestation. Among those with three aPLs tested (n = 660), 42% were triple aPL-positive. While single-, double-, and triple aPL-positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup, which consisted of aCLs or anti-βOur study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter international cohort. Within single aPL positivity, LAC may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.

Non-white people are more likely to develop systemic lupus erythematosus (SLE), yet are underrepresented in SLE clinical trials. The efficacy and safety of drugs may be influenced by ancestry, and ancestrally diverse study populations are necessary to optimize treatments across the full spectrum of patients. However, barriers to entry into clinical trials are amplified in non-white populations. To address these issues, a conference was held in Bethesda, Maryland from October 15th -16th , 2019 entitled "Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers." Participants included people with lupus, lupus physicians, lupus clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups, and United States government representatives (the Office of Minority Health, Centers for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration). For all of these groups, the organizers purposefully included people of non-white ancestry. Decreased participation of non-white SLE patients in clinical research was evaluated through historical, societal, experiential, and pragmatic perspectives, and several interventional programs to increase non-white patient participation in SLE and non-SLE research were described and discussed. The presentations and discussions highlighted the need for changes at the societal, institutional, research team, referring physician, and patient education levels to achieve equitable ancestral representation in SLE clinical studies.

Background Most patients with methotrexate‐associated lymphoproliferative disorder (MTX‐LPD) show diffuse large B‐cell lymphoma (DLBCL) or classic Hodgkin lymphoma (CHL) types. Patients with MTX‐LPD often have spontaneous remission after MTX discontinuation, but chemotherapeutic intervention is frequently required in patients with CHL‐type MTX‐LPD. In this study, we examined whether programmed cell death‐ligand 1 (PD‐L1) expression levels were associated with the prognosis of MTX‐LPD after MTX discontinuation. Methods A total of 72 Japanese patients diagnosed with MTX‐LPD were clinicopathologically analyzed, and immunohistochemical staining of PD‐L1 was performed in 20 DLBCL‐type and 24 CHL‐type MTX‐LPD cases to compare with the clinical course. Results PD‐L1 was expressed in 5.0% (1/20) of patients with DLBCL‐type MTX‐LPD, whereas it was expressed in 66.7% (16/24) of the patients with CHL‐type MTX‐LPD in more than 51% of tumor cells. Most CHL‐type MTX‐LPD patients with high PD‐L1 expression required chemotherapy owing to exacerbations or relapses after MTX discontinuation. However, no significant differences in clinicopathologic findings at diagnosis were observed between PD‐L1 high‐ and low‐expression CHL‐type MTX‐LPD. Conclusion PD‐L1 expression was significantly higher in patients with CHL‐type than DLBCL‐type MTX‐LPD, suggesting the need for chemotherapy in addition to MTX discontinuation in CHL‐type MTX‐LPD patients to achieve complete remission. No association was observed between PD‐L1 expression levels and clinical findings at diagnosis, suggesting that PD‐L1 expression in tumor cells influences the pathogenesis of CHL‐type MTX‐LPD after MTX discontinuation., Patients with classic Hodgkin lymphoma (CHL)‐type methotrexate‐associated lymphoproliferative disorder (MTX‐LPD) with high programmed cell death‐ligand 1 (PD‐L1) expression tended to have exacerbations and relapses after MTX discontinuation. Our study suggests that the PD‐1/PD‐L1 pathway may be involved in refractoriness to MTX discontinuation in CHL‐type MTX‐LPD.

How Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (DLBCL) occasionally occurs following chronic inflammation remains to be elucidated. The case of a 57‐year‐old man who developed pulmonary EBV‐positive DLBCL from underlying silicosis lesions is presented. Immunohistochemical examination of the resected silicosis lesions showed predominant helper T cells and M1/M2 macrophages, with a lack of B cells, regulatory T cells, and resident memory T cells. Two years later, EBV‐positive DLBCL emerged unexpectedly from the silicosis. The imbalance of the immune cells in the microenvironment, at least in part, may help explain how chronic inflammation contributes to EBV‐positive DLBCL., The underlying silicosis lesions showed predominant Th cells and M1/M2 macrophages, with a lack of B cells, Treg cells, and TRM cells. The imbalance of the immune cells in the microenvironment, at least in part, may help to explain how chronic inflammation contributes to EBV‐positive diffuse large B‐cell lymphoma.

Aims It is unknown whether Epstein-Barr virus (EBV) infection can occur in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, also known as double-hit or triple-hit lymphoma (DHL/THL). Methods and results Here we report 16 cases of EBV+ DHL/THL from screening 846 cases of DHL/THL and obtaining additional EBV+ cases through multi-institutional collaboration: 8 MYC/BCL2 DHL, 6 MYC/BCL6 DHL, and 2 THL. There were 8 men and 8 women with a median age of 65 years (range, 32-86). Two patients had a history of follicular lymphoma and one had AIDS. Nine of 14 patients had an International Prognostic Index of ≥3. Half of the cases showed high-grade/Burkitt-like morphology and the other half diffuse large B-cell lymphoma morphology. By immunohistochemistry, the lymphoma cells were positive for MYC (n=14/16), BCL2 (n=12/16), BCL6 (n=14/16), CD10 (n=13/16), and MUM1 (n=6/14). By Hans algorithm, 13 cases were classified as GCB and 3 as non-GCB. The lymphomas frequently showed an EBV latency type I with a median EBV-encoded small RNAs of 80% positive cells (range, 20-100%). After a median follow-up of 36.3 months (range, 2.0-41.6), 7 patients died with a median survival of 15.4 months (range, 3.4-47.3) after diagnosis of EBV+ DHL/THL. Five of 6 patients with MYC/BCL6 DHL were alive including 4 in complete remission. In contrast, only 4/10 patients with MYC/BCL2 DHL or THL were alive including 2 in complete remission. The median survival in patients with MYC/BCL6 DHL was unreached and was 21.6 months in patients with MYC/BCL2 DHL or THL. Conclusions EBV infection in DHL/THL is rare (~1.5%). Cases of EBV+ DHL/THL are largely similar to their EBV-negative counterparts clinicopathologically. Our findings expand the spectrum of EBV+ B-cell lymphomas currently recognized in the WHO classification and suggest differences between EBV+ MYC/BCL2 and MYC/BCL6 DHL that may have therapeutic implications.

BACKGROUND: Asthma is one of the leading causes of school absenteeism. Schools can play an important role in coordinating asthma care. The purpose of this study was to assess the implementation of asthma-related school health policies and practices across states and how they have changed over time. METHODS: Data were analyzed from 36 states that conducted School Health Profiles surveys during 2008 to 2018. Trends in 6 topics were analyzed by logistic regression and JointPoint trend test. RESULTS: Trends in efforts to identify and track students with asthma and improve students’ and parents’ knowledge about asthma were stable or increased. Interest among lead health education teachers in receiving professional development on asthma trended downward in 35 of 36 states. CONCLUSIONS: Stable to upward trends suggest that a majority of schools have maintained or improved their efforts to identify and track students with asthma and increase the knowledge of students and parents about asthma. However, further improvement is needed in referral of students with asthma to health care professionals and encouraging asthma-related professional development of lead health education teachers.

Although it is not recognized as essential to test for antiphospholipid antibody (aPL) in stroke of unknown cause, aPL-related stroke may account for a considerable number of cryptogenic strokes. We aimed to assess the current status and diagnostic value of aPL testing in cryptogenic stroke patients.Consecutive patients admitted with acute ischemic stroke were examined to confirm the factors associated with performing aPL testing and with positive aPL test results in real-world practice. Cryptogenic stroke patients were separately examined in the same manner. The antibody profiles of cryptogenic stroke patients with aPL positivity were compared by age.Among 2947 patients, 606 (20.6%) were tested for aPLs and 129 (21.3%) were positive. Physicians tended to perform aPL testing in patients aged50 years and in cryptogenic stroke patients. Cryptogenic stroke was a strong predictor of positive aPL results (adjusted odds ratio 3.70, 95% confidence interval 2.38-5.76). However, aPL positivity did not differ by age in stroke patients. Among 283 cryptogenic stroke patients, 136 (48.1%) were tested for aPLs and 56 (41.2%) were positive. aPL tests were performed predominantly in patients aged50 years rather than in older patients, even among cryptogenic stroke patients. The two age groups had similar positivity rates of40% (50 years: 43.2%; ≥50 years: 40.4%; p = 0.92) and their antibody profiles were similar.A significant number of patients with cryptogenic stroke had positive aPL results regardless of age. aPL testing may offer additional diagnostic opportunities in cryptogenic stroke patients, and thus may reduce the incidence of cryptogenic stroke.

Introduction Graft‐versus‐host disease (GVHD) is frequent and fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT) and characteristically involves skin, gut, and liver. Macrophages promote tissue regeneration and mediate immunomodulation. Macrophages are divided into two different phenotypes, classically activated M1 (pro‐inflammatory or immune‐reactive macrophages) and alternatively activated M2 (anti‐inflammatory or immune‐suppressive macrophages). The anti‐inflammatory effect of M2 macrophage led us to test its effect in the pathophysiology of GVHD. Methods GVHD was induced in lethally irradiated BALB/c mice. M2 macrophages derived from donor bone marrow (BM) were administered intravenously, while controls received donor BM‐mononuclear cells and splenocytes. Animals were monitored for clinical GVHD and analyzed. Results We confirmed that administering donor BM‐derived M2 macrophages attenuated GVHD severity and prolonged survival after HSCT. Moreover, donor BM‐derived M2 macrophages significantly suppressed donor T cell proliferation by cell‐to‐cell contact in vitro. Conclusions We showed the protective effects of donor‐derived M2 macrophages on GVHD and improved survival in a model of HSCT. Our data suggest that donor‐derived M2 macrophages offer the potential for cell‐based therapy to treat GVHD., Adoptive transferred M2 macrophages prolong the survival of GVHD mice.

BACKGROUND In Canada, the deferral for men who have sex with men (MSM) has been progressively reduced from a permanent deferral for MSM since 1977, to 5 years, 1 year, and, most recently, 3 months. We estimated human immunodeficiency virus (HIV) residual risk and compliance with the MSM time deferral after each change. METHODS Four anonymous online compliance surveys were carried out before and after each change. HIV incidence and prevalence were monitored from 2010 to 2021. Residual risk was estimated using the incidence-window period model. RESULTS Human immunodeficiency virus prevalence, incidence, and residual risk did not change with incrementally shorter MSM deferrals. The residual risk per million donations post 3-month deferral was 0.05 (0.001-0.371). Men with temporally remote MSM history became eligible and, therefore, compliant as the deferral periods decreased (Cochran-Armitage p value =

Down syndrome-associated arthritis (DA) is underrecognized, and current therapies used for juvenile idiopathic arthritis (JIA) appear to be poorly tolerated and less effective in patients with DA. The objective of this study was to characterize clinical manifestations and therapeutic preferences in DA compared to JIA, using the new Childhood Arthritis and Rheumatology Research Alliance (nCARRA) registry.In a case-control study, between July 2015 and March 2019, patients with a diagnosis of JIA and Down syndrome (DS) were identified and matched by age, sex, and JIA subtype to patients who have JIA without DS. Collected data included demographic characteristics, disease characteristics, laboratory results, treatment exposure, and outcome measures.A total of 36 children with DA and 165 with JIA were identified. Most patients presented with polyarticular rheumatoid factor-negative disease. At entry into the nCARRA registry, there were minimal differences between the groups, and at the last visit there were significant differences (P0.05) for multiple outcome measures. Patients with DA and those with JIA had similar therapeutic exposure to disease-modifying antirheumatic drugs (DMARDs) and biologics, but those with DA had more DMARD-related adverse events (93% versus 25%) and biologic therapy ineffectiveness (60% versus 17%).There was little difference between patients with DA and those with JIA at baseline, and similar therapy was implemented for those in the nCARRA registry; however, at the last visit, the patients with DA had greater disease burden. Additionally, there were more DMARD-related adverse events and biologic ineffectiveness for those patients with DA. More research is needed to determine differences in pathophysiology and optimal therapeutic approaches.

CD49d, the α4 chain of the VLA-4 integrin, is a negative prognosticator in chronic lymphocytic leukemia (CLL) with a key role in CLL cell-microenvironment interactions mainly occurring via its ligands VCAM-1 and fibronectin. In the present study, we focused on EMILIN-1 (Elastin-MIcrofibriL-INterfacer-1), an alternative VLA-4 ligand whose role has been so far reported only in non-hematological settings, by investigating: i) the distribution of EMILIN-1 in CLL-involved tissues; ii) the capability of EMILIN-1 to operate, via its globular C1q (gC1q) domain, as additional adhesion ligand in CLL; iii) the functional meaning of EMILIN-1 gC1q/VLA-4 interactions in CLL. EMILIN-1 is widely present in the CLL-involved areas of bone marrow biopsies (BMBs) without difference between CD49d negative and positive cases, displaying at least three different expression patterns: "fibrillar", "dot-like" and "mixed". The lack in CLL-BMB of neutrophil elastase, whose proteolytic activity degrades EMILIN-1 and impairs EMILIN-1 function, suggests full functional EMILIN-1 in CLL independently of its expression pattern. Functionally, EMILIN-1 gC1q domain promotes adhesion of CLL cells through specific interaction with VLA-4, and releases pro-survival signals for CLL cells, as demonstrated by enhanced ERK and AKT phosphorylation and impairment of in-vitro-induced apoptosis. EMILIN-1/VLA-4 interaction can efficiently contribute to the maintenance of the neoplastic clone in CLL. This article is protected by copyright. All rights reserved.

Sclerodermatous graft-versus-host disease (GVHD) is one of the many clinicopathological variants of chronic GVHD. One of the rarest forms of this variant is GVHD-associated angiomatosis (GVHD-AA). We describe the case of a 62-year-old male with sclerodermatous GVHD who presented, in consecutive years, two different lesions that showed characteristics of GVHD-AA. The first lesion fitted perfectly with the previously known features of this rare entity. However, the second lesion, was more interesting as the angiomatoid lesion was surrounded by newly appeared adipocytes, something not previously described. The appearance of this peculiar adipose tissue may be explained as related to an important dermal atrophy, as a concomitant appearance of a lipomatous nevus and GVHD-AA or finally, as mature adipose tissue related to a previous inflammatory process, that is lipomatous metaplasia. Both lesions were diagnosed as GVHD-AA, and the second one was considered to be associated with dermal lipomatous metaplasia. We also considered that hypoxia could be related to both lesions. In the present report we review previously published cases of GVHD-AA and discuss the different hypothesis that could explain the appearance of metaplasia associated to the second lesion. This article is protected by copyright. All rights reserved.

Suicidal ideation is approximately three times more prevalent in gay men than heterosexual men with research tending to focus on causation rather than protective factors. This exploratory study examined how gay men perceived suicidal ideation among members of their own community, and whether the support of gay friends was perceived as protective. Twenty-three Australian gay men (aged between 18 and 65) participated in the study, with qualitative data obtained through the method of story completion. Constructionist thematic analysis highlighted ways in which a fictitious gay male protagonist with suicidal thoughts was viewed as reluctant to reveal these thoughts. However, when the character did, he was seen to benefit from the compassionate involvement of his gay friend. Additionally, the gay protagonist was perceived as experiencing stressors that heightened his community's minority status. Practically, the findings indicated that gay friends could play an important role in assisting their peers recover from suicidal ideation.

Chronic-lymphocytic-leukemia (CLL) is the most prevalent leukemia in developed countries, caused by monoclonal proliferation of CD5+ B-cells and accumulation of mature-appearing-neoplastic lymphocytes in blood, bone marrow, and secondary lymphoid organs. Oral manifestations of CLL are infrequent and rarely reported in literature. We report a new case of a 67-year old man who presented with the complaints of tooth mobility and gingival swelling. Extra-oral examination was remarkable for cutaneous pallor and bilateral cervical lymphadenopathy involving the submandibular, and deep cervical lymph nodes on both sides of the neck. Complete blood count revealed normal red blood cell count (4.25 × 106/μl), normal platelet count (136 × 103/μl) and increased white blood cell count (25.3 × 103/μl). Differential white blood cell count showed marked lymphocytosis (88%), and blood film revealed the presence of leukocytosis, with small mature-looking lymphocytes, and mild thrombocytopenia. A flow cytometry immune-phenotyping revealed that 55% of peripheral blood cells were monoclonal B-lymphocytes expressing CD19, CD20, CD23, CD200, CD22, CD5, CD38, CD11c, sIgD and Kappa light chain confirming the diagnosis of CLL. Oral healthcare professionals should consider systemic causes, such as CLL, in the differential diagnosis of generalized tooth mobility and gingival swelling, particularly in patients with associated symptoms such as lymphadenopathy, fever, weight loss, and general fatigue.

Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with-and most likely a driver of-gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high-grade MYC-associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS-010759. Mechanistically, IACS-010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC-overexpressing cells. In line with these findings, the BCL2-inhibitory compound venetoclax synergized with IACS-010759 against double-hit lymphoma (DHL), a high-grade malignancy with concurrent activation of MYC and BCL2. In BCL2-negative lymphoma cells, instead, killing by IACS-010759 was potentiated by the Mcl-1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3-mimetic drugs provides a novel therapeutic principle against aggressive, MYC-associated DLBCL variants.

Residual limb pain (RLP) and phantom limb pain (PLP) profoundly affect the lives of many individuals who have undergone lower- or upper-extremity amputation. Despite the considerable impact of RLP/PLP on quality of life in persons with amputation, there have been few attempts to evaluate the efficacy of percutaneous interventions in the treatment of RLP and/or PLP. This narrative review evaluates the effectiveness of percutaneous treatments for RLP and/or PLP in patients after lower-extremity amputation. Peripheral nerve stimulation, alcohol neurolysis, conventional thermal radiofrequency ablation, perineural corticosteroid injection, botulinum toxin injection, and etanercept injection were associated with varying success rates. Wide confidence intervals and small treatment cohorts impede assessments of overall success. High-quality studies of nonsurgical, percutaneous treatments for RLP and/or PLP are lacking. Well-designed randomized controlled trials and large cohort studies with comparison groups using validated outcomes are needed to determine the effectiveness of nonsurgical interventions for the treatment of RLP and PLP.

BACKGROUND AND OBJECTIVES Pemphigus has been associated with physical and psychiatric comorbid diseases. This study aims to further investigate these associations in patients with pemphigus, and to analyze the relationships of comorbid conditions with sex and age, pemphigus disease area index score, diagnostic delay and cutaneous/mucous involvement. PATIENTS AND METHODS Patients with pemphigus were matched by age, gender and area of residence with eight controls each. The odds of comorbid conditions in patients vs. matched controls was determined using univariate conditional logistic regression models. Comorbid diseases significantly associated with the diagnosis of pemphigus at P

Diffuse large B‐cell lymphoma (DLBCL) is a clinically heterogeneous entity, in which the first‐line treatment currently consists of an immuno‐chemotherapy regimen (R‐CHOP). However, around 30% of patients will not respond or will relapse. Overexpression of c‐MYC or p53 is frequently found in DLBCL, but an association with prognosis remains controversial, as for other biomarkers previously linked with DLBCL aggressivity (CD5, CD23, or BCL2). The aim of this study was to explore the expression of these biomarkers and their correlation with outcome, clinical, or pathological features in a DLBCL cohort. Immunohistochemical (c‐MYC, p53, BCL2, CD5, and CD23), morphological (‘starry‐sky’ pattern [SSP]), targeted gene panel sequencing by next‐generation sequencing (NGS), and fluorescence in situ hybridisation analyses were performed on tissue microarray blocks for a retrospective cohort of 94 R‐CHOP‐treated de novo DLBCL. In univariate analyses, p53 overexpression (p53high) was associated with unfavourable outcome (p = 0.04) and with c‐MYC overexpression (p = 0.01), whereas c‐MYC overexpression was linked with an SSP (p = 0.004), but only tended towards an inferior prognosis (p = 0.06). Presence of a starry‐sky morphology was found to be correlated with better survival in p53high DLBCL (p = 0.03) and/or c‐MYC‐positive DLBCL (p = 0.002). Furthermore, NGS data revealed that these three variables were associated with somatic mutations (PIM1, TNFRSF14, FOXO1, and B2M) involved in B‐cell proliferation, survival, metabolism, and immune signalling. Taken together, these results show that the SSP pattern seems to be a protective factor in high‐risk DLBCL subgroups and highlight cell death as a built‐in failsafe mechanism to control tumour growth.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder. Lupus nephritis (LN) is one of the severe clinical implications in SLE, and this was relates to fibrosis in the kidney. As an important marker in the tumor necrosis factor (TNF) superfamily, TNF-like weak inducer of apoptosis (TWEAK) has been given much attention with respect to its role in regulating pro-inflammatory immune response. Fibroblast growth factor-inducible 14 (Fn14), the sole receptor for TWEAK, has been found expressed in different immune and non-immune cells. TWEAK binds to Fn14, and then regulates inflammatory components production via downstream signaling pathways. To date, dysregulated expression of TWEAK, Fn14 has been reported in SLE, LN patients, and in vivo, in vitro studies have discussed the significant role of TWEAK-Fn14 axis in SLE, LN pathogenesis, partly through mediating the fibrosis process. In this review, we will discuss the association of TWEAK-Fn14 axis in lupus. Understanding the relationship will better realize the potential for making TWEAK-Fn14 as a marker for the diseases, and will help to give many clues for targeting them in treatment of lupus in the future.

OBJECTIVE The literature provides some evidence of peripheral airways key role in the pathogenesis of asthma. However, the extent to which lung periphery including acinar zone contribute to asthma activity and control in pediatric population is unclear. Therefore, the aim of the study was to estimate peripheral airways involvement in children with asthma exacerbation and stable asthma simultaneously via different pulmonary function tests. METHODS Children with asthma exacerbation (n = 20) and stable asthma (n = 22) performed spirometry, body plethysmography, exhaled nitric oxide, impulse oscillometry (IOS), and multiple-breath washout (MBW). RESULTS Peripheral airway's function indexes were increased in children with asthma, particularly in group with asthma exacerbation when compared with stable asthma group. The prevalence of abnormal results was significantly higher in asthma exacerbation. All children with asthma exacerbation had conductive ventilation inhomogeneity; 76% had acinar ventilation inhomogeneity. According to IOS measurements, resistance and reactance were within normal range, but other IOS parameters were significantly higher in children with asthma exacerbation compared with stable asthma group. The 36% of children with acute asthma had air trapping. CONCLUSION Significant involvement of peripheral airways was observed in children with asthma, particularly in asthma exacerbation, which determine lung periphery as important additional target for therapy and provide new insights into pathophysiological process of pediatric asthma.

Despite the expanding clinical application of hydroxychloroquine in dermatology, the overall data on hydroxychloroquine use among dermatologists are limited. With retrospective review of the medical records of the 790 patients who were prescribed hydroxychloroquine, we classified the diagnoses into 12 disease categories, the lupus erythematosus group being the largest. The lupus erythematosus group had the longest prescription duration (median, 6.2 months), whereas the photodermatitis group had a significantly shorter prescription duration (median, 0.5 months). The overall good response rate was 77.1%. The photodermatitis group had the best response (88.7%), followed by the lupus panniculitis (85.1%) and lichen planus (84.4%). In conclusion, hydroxychloroquine has proven utility for various inflammatory skin diseases, including but not limited to cutaneous lupus erythematosus.

Few data exist on Epstein-Barr virus (EBV) prevalence across the full spectrum of lymphoma subtypes, particularly in sub-Saharan Africa. The objective of our study was to test the presence of EBV in a nationally representative sample of malignant lymphomas diagnosed in the Butaro Cancer Center of Excellence (BCCOE) in Rwanda. Of 102 Hodgkin (HL) and 378 non-Hodgkin lymphomas (NHL) diagnosed in BCCOE between 2012 and 2018, 52 HL and 207 NHL were successfully tested by EBV-encoding RNA in situ hybridization. EBV prevalence was 54% in HL, being detected in all classical HL subtypes: mixed-cellularity (n = 3/8), nodular-sclerosis (n = 7/17) and lymphocyte-rich (n = 2/3). EBV prevalence was 9% in NHL, being 10% among 158 B-cell NHL, 3% among 35 T-cell NHL and the single NK-cell NHL was EBV-positive. Among B-cell NHL, EBV was present in the majority of Burkitt (n = 8/13), and was also rarely detected in follicular (n = 1/4) and acute B-cell lymphoblastic (n = 1/45) lymphomas. Five of the 45 (11%) diffuse large B-cell lymphomas (DLBCLs) were EBV-positive, including three out of five plasmablastic lymphoma (PBL). Of 39 HL and 163 NHL of known human immunodeficiency virus (HIV) status, 2 (5%) and 14 (9%) were HIV-positive, respectively, of which only four were also EBV-positive (2 PBL, 2 HL). In summary, we report rare regional-level data on the association of EBV with classical HL, Burkitt and DLBCLs, and report sporadic detection in other subtypes possibly related to EBV. Such data inform the burden of disease caused by EBV and can help guide application of future advances in EBV-specific prevention and therapeutics.

Pulmonary complications post-hematopoietic stem cell transplantation (HSCT) such as diffuse alveolar hemorrhage (DAH) can occur in 2% to 14% of HSCT patients and have a mortality greater than 80%. Diffuse alveolar hemorrhage is considered to be an inflammatory response; therefore, HSCT patients are primarily treated with different types of systemic corticosteroids with varying dosages. Other treatments currently reported in the literature in conjunction with corticosteroids include aminocaproic acid, recombinant factor VIIa (rFVIIa), and etanercept. This review highlights appropriate frontline and adjunctive treatment options for HSCT patients with DAH and outcomes for each intervention. To perform the review, the PubMed database was searched from inception through March 19, 2021, to identify potential studies using the search terms DAH and HSCT, DAH and hematopoietic cell transplant (HCT), DAH and stem cell, lung injury and HSCT, and lung injury and HCT. When applicable, references from articles identified in the search were also reviewed for inclusion. Much of the data identified were limited to retrospective cohort studies and case series. Based on the data available, the treatment approach should consist of corticosteroid therapy with a suggested methylprednisolone dose of 250 mg daily followed by a 50% taper every 3 days. Intrapulmonary administration of rFVIIa and intravenous administration of aminocaproic acid could be considered as adjunctive agents in those patients who do not promptly respond to corticosteroid therapy. Due to a lack of data specific to HSCT patients who develop DAH and the risk of infectious complications, etanercept should be avoided. Future studies should be designed as randomized controlled trials and examine the use of adjunctive therapies in the upfront setting for HSCT patients with DAH.

Autophagy is a process which is highly conserved in eukaryotes to degrade or recycle cytoplasmic components through lysosomes to maintain cellular homeostasis. Recent studies have shown that autophagy also plays critical roles in cell apoptosis, inflammation, pathogen clearance, and so on under stressed conditions and thereby has been linked to a variety of human disorders. The skin is the largest organ of the body and serves as the first line of defense against environmental insult. Skin as a nutrient-poor environment requires recycling of limited resources via the autophagy machinery to maintain homeostasis. Therefore, dysregulation of autophagy has been linked to skin diseases. In this review, we describe the molecular machinery and regulation of autophagy, discuss its role in keratinocytes and skin barrier, skin immune cells, and immune-related skin diseases including autoimmune skin disorders, allergic skin diseases, infectious skin disorders, and antitumor immunity against skin tumor. Finally, we highlight the potential of autophagy as a therapeutic target for immune-related skin diseases, and delivery of autophagy-related molecules (such as inducers, inhibitors, or nucleic acid molecules) by virtue of physical materials (such as nanoparticles) or biological materials (such as peptides) to skin topically may obtain clinical benefits in immune-related skin diseases. Moreover, developing autophagy-related gene product-based biomarkers may be promising to diagnose immune-related skin diseases.

BACKGROUND As a consequence of the improved availability of combined antiretroviral therapy (cART) in resource-limited countries, an emergence of HIV drug resistance (HIVDR) has been observed. We assessed the prevalence and spectrum of HIVDR in patients with failure of second-line cART at two HIV clinics in central Ethiopia. METHODS HIV drug resistance was analysed in HIV-1-infected patients with virological failure of second-line cART using the geno2pheno application. RESULTS Among 714 patients receiving second-line cART, 44 (6.2%) fulfilled the criteria for treatment failure and 37 were eligible for study inclusion. Median age was 42 years [interquartile range (IQR): 20-45] and 62.2% were male. At initiation of first-line cART, 23 (62.2%) were WHO stage III, mean CD4 cell count was 170.6 (range: 16-496) cells/µL and median (IQR) HIV-1 viral load was 30 220 (7963-82 598) copies/mL. Most common second-line cART regimens at the time of failure were tenofovir disoproxil fumarate (TDF)-lamivudine (3TC)-ritonavir-boosted atazanavir (ATV/r) (19/37, 51.4%) and zidovudine (ZDV)-3TC-ATV/r (9/37, 24.3%). Genotypic HIV-1 resistance testing was successful in 35 (94.6%) participants. We found at least one resistance mutation in 80% of patients and 40% carried a protease inhibitor (PI)-associated mutation. Most common mutations were M184V (57.1%), Y188C (25.7%), M46I/L (25.7%) and V82A/M (25.7%). High-level resistance against the PI ATV (10/35, 28.6%) and lopinavir (LPV) (5/35, 14.3%) was reported. As expected, no resistance mutations conferring integrase inhibitor resistance were detected. CONCLUSIONS We found a high prevalence of resistance mutations, also against PIs (40%), as the national standard second-line cART components. Resistance testing before switching to second- or third-line cART is warranted.

BACKGROUND Previous studies on maternal folate status during pregnancy and child asthma risk yielded mixed results, and few considered maternal asthma history, a known risk factor of childhood asthma. This study examined whether the role of maternal folate in childhood asthma differs by maternal asthma history and whether there is an interaction between the two factors. METHODS This study included 1948 mother-child dyads from the Boston Birth Cohort. Childhood asthma was defined based on physician diagnosis documented in electronic medical records, and maternal asthma was based on standard questionnaire interview. Maternal plasma folate level within a few days of delivery was measured by chemiluminescent immunoassay. Logistic regression models were applied to examine individual and joint associations of maternal asthma history and plasma folate level with childhood asthma, adjusting for other covariables. RESULTS When stratified by maternal asthma history, an L-shaped relationship between maternal folate level and child asthma was observed in children born to mothers with asthma history (pinteraction = 0.03). The highest risk was found in children having maternal asthma history and low maternal folate level (odds ratio = 5.93; 95% confidence interval: 2.86-12.3) compared with children without maternal asthma history and with sufficient maternal folate levels. Sensitivity analyses using different definitions of asthma and stratified by major covariables yielded similar findings. CONCLUSION In this US prospective high-risk birth cohort, maternal asthma history and low folate level interactively increased the risk of child asthma. If further confirmed, optimizing maternal folate levels during pregnancy may mitigate child asthma risk in the setting of maternal asthma history.

OBJECTIVE We aimed to investigate the impact of applying the 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria for systemic lupus erythematosus (SLE) in a previously described cohort of women with undifferentiated connective tissue disease (UCTD). METHODS This study included 133 women with UCTD. At the time of inclusion into the study, none of the patients met any classification criteria for other defined systemic connective tissue disease. RESULTS When applying the 2019 EULAR/ACR classification criteria to the cohort, 22 patients (17%) fulfilled the classification criteria for SLE. Patients classified as having SLE had significantly higher frequencies of mucocutaneous manifestations (23% versus 5%; P = 0.007), arthritis (59% versus 17%; P < 0.001), isolated urine abnormalities (18% versus 1%; P < 0.001), and highly specific antibodies (50% versus 15%; P < 0.001) compared to the other patients with UCTD. At follow-up, these patients were statistically significantly more likely to also meet the 1997 ACR revised SLE criteria and the Systemic Lupus International Collaborating Clinics (SLICC) criteria (18.2% versus 1.8%; P < 0.001) compared to the other UCTD patients. Patients who were diagnosed as having SLE according to the ACR 1997 update of the SLE revised criteria and the SLICC criteria during the follow-up scored higher on outcome measures when classified as having SLE according to the new 2019 EULAR/ACR classification criteria when compared to the other patients with UCTD (mean ± SD score 8.3 ± 3.7 versus 4.5 ± 4; P < 0.05). CONCLUSION When applying the 2019 EULAR/ACR criteria for SLE in a cohort of patients with UCTD, we observed that in up to 17% of cases the original classification could be challenged. New implementation will help to identify earlier patients at higher risk of developing more severe CTD manifestations.

While systemic lupus erythematosus is often complicated by preeclampsia, it is difficult to differentiate between its exacerbation and preeclampsia. The soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio is unknown in systemic lupus erythematosus with preeclampsia before 20 weeks of gestation. Three nulliparous women with systemic lupus erythematosus developed preeclampsia at 13, 13, and 17 weeks of gestation with sFlt-1/PlGF ratios of 427, 865, and 525, respectively. Two patients terminated their pregnancies and delivered within 2 weeks, while one experienced intrauterine fetal death 4 weeks after the measurements. Their symptoms gradually improved, and all patients were discharged within 3 months. The sFlt-1/PlGF ratio may be used in the differential diagnosis of preeclampsia and systemic lupus erythematosus exacerbation before 20 weeks of gestation.

Asthma is the most common respiratory illness in Aboriginal and Torres Strait Islander Australians. From the Mater Mothers routinely collected perinatal data in Brisbane we have identified that 24% of Indigenous and 17% of non-Indigenous women have pregnancies complicated by asthma. Indigenous women with asthma are more likely to have poorer birth outcomes when compared to non-Indigenous women with asthma, with neonatal death being doubled in asthmatic Indigenous women. These data indicate that asthma management during pregnancy is an unmet need for Indigenous women and essential if we are to avoid these devastating outcomes for Indigenous families.

The frequency of CD20+ T cells was reported to be increased in several inflammatory conditions. We report that in patients with multiple sclerosis (MS), CD20+ T cells display a distinct proinflammatory phenotype with pathogenic properties. Anti-CD20 treatment virtually extinguished CD20+ T cells, which might explain its broad effectiveness. Dimethyl fumarate dampened activity of differentiated CD20+ T cells, whereas fingolimod reduced their abundance only as part of its overall T cell suppressive capacity. Natalizumab increased the frequency of CD20+ effector T cells. Widely used MS therapeutics affect this proinflammatory T cell subset with assumed pathogenic potential in a surprisingly differential manner. ANN NEUROL 2021 ANN NEUROL 2021;90:834-839.

The first line of treatment for pemphigus is systemic corticosteroids. When steroids alone do not result in remission, additional immunosuppressants are recommended. Twenty‐two patients with pemphigus vulugris were treated with steroids and other immunomodulators. However, they were refractory, and hence, methotrexate (MTX) was administered. The efficacy of MTX was assessed for 16 patients who were able to continue MTX therapy for 1 year. Steroid dose reduction was possible in 11 patients. One patient with severe infections had diabetes and was elderly. Our results suggested that MTX was useful as a steroid‐sparing agent in treating recalcitrant pemphigus, when an initial immunosuppressant treatment had failed. However, adverse effects should be closely monitored.

Purpose Some studies have indicated that using 500 mg/m2 rituximab combined with CHOP‐14 may be beneficial for elderly men but not women with diffuse large B‐cell lymphoma (DLBCL). The purpose of this study was to investigate the potential benefit of escalated doses of rituximab with CHOP‐21 as the first‐line treatment in male patients with DLBCL. Methods We performed a retrospective cohort study to analyze the survival benefit of rituximab 500 mg/m2 plus the CHOP‐21 regimen (Escalated‐R‐CHOP‐21) as the first‐line treatment compared with using rituximab 375 mg/m2 plus the CHOP‐21 regimen (Standard‐R‐CHOP‐21) in men with DLBCL. We used propensity score matching to maximize the balance of the observed covariables. The primary endpoints of this study were the progression‐free survival (PFS) rate and overall survival (OS) rate at 3 years. Results After a median follow‐up of 47 months (IQR 31–65), no significant difference in PFS and OS was found for men treated with Escalated‐R‐CHOP‐21 compared with Standard‐R‐CHOP‐21 [3‐year PFS: 69.7% versus 71.9%, p = 0.867; 3‐year OS: 83.0% versus 82.4%, p = 0.660]. After 1:1 propensity score matching, we found that the patients using Escalated‐R‐CHOP‐21 had statistically significant survival benefits relative to Standard‐R‐CHOP‐21 among the 96 matched elderly male patients for 3‐year PFS [75.5% (95% CI 62.8–88.2) versus 58.2% (95% CI 44.3–72.1); p = 0.019] and 3‐year OS [86.6% (95% CI 76.4–96.8) versus 65.8% (95% CI 52.1–79.5); p = 0.017]. However, no differences in survival were observed for younger male patients. Furthermore, the dose effect in PFS of Escalated‐R‐CHOP‐21 was more obvious for elderly male patients with no high‐risk extranodal sites (p = 0.005 and interaction p = 0.030). Conclusion Escalated‐R‐CHOP‐21 could be a safe and effective option for treating elderly male patients with DLBCL. This study provides new insight into optimizing the standard treatment regimen, which may have important therapeutic implications in elderly male patients with DLBCL., In this study, we investigated the potential benefit of rituximab 500 mg/m2 plus the CHOP‐21 regimen (Escalated‐R‐CHOP‐21) as the first‐line treatment compared with using rituximab 375 mg/m2 plus the CHOP‐21 regimen (Standard‐R‐CHOP‐21) in male patients with DLBCL. We found that only elderly men had statistically significant survival benefits from Escalated‐R‐CHOP‐21 than Standard‐R‐CHOP‐21 of 3‐year PFS [75.5% (95% CI 62.8–88.2) vs. 58.2% (95%CI 44.3–72.1); p = 0.019] and 3‐year OS [86.6% (95% CI 76.4–96.8) vs. 65.8.0% (95% CI 52.1–79.5); p = 0.017] without causing severe toxicity after propensity score matching.

Elevated Epstein-Barr virus (EBV) DNA load is common in lymphomas. However, it remains unclear whether the disparity in viral load and its prognostic value in lymphomas are correlated with Epstein-Barr encoding region (EBER) status. In this retrospective multicenter study, we collected the data of pretreatment whole blood EBV DNA (pre-EBV DNA) and EBER status and evaluated their disparity and prognostic values in lymphomas. A total of 454 lymphoma patients from December 2014 to August 2020 were retrospectively retrieved. Mann-Whitney U test, Kruskal-Wallis test and Bonferroni's adjustment were used to explore the disparity of EBV DNA and EBER status in lymphomas. Time-dependent receiver operating characteristic analysis and MaxStat analysis were used to determine optimal cutoff points of pre-EBV DNA load. Univariable and multivariable Cox proportional hazards models were established for the estimation of prognostic factors. The positive rate of EBV DNA in natural killer T-cell lymphoma (NKTL) patients was higher than that in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) patients, and the median positive pre-EBV copy number of NKTL was also higher than that of FL and DLBCL. EBV DNA could clearly distinguish the prognosis of DLBCL, NKTL, HL and peripheral T-cell lymphoma, and the integration of EBER status and EBV DNA could differentiate the prognosis of HL patients. Multivariable results revealed that pre-EBV DNA load had an effect on the prognosis of NKTL, FL and DLBCL. The status of pre-EBV DNA and EBER were disparate. Whole blood pre-EBV DNA predicted the prognosis of lymphomas, and the combination of EBV and EBER status could differentiate the prognosis of HL.

B-cell lymphoma of the central nervous system (CNS) is a rare malignancy with diffuse large B-cell lymphoma (DLBCL) variant being most common. Although DLBCL has a high propensity to relapse locally within the CNS, only a few cases of cutaneous metastasis have been described in the literature. We present a unique case of cutaneous metastasis of a primary DLBCL of the CNS in a 79-year-old man who was in clinical remission for four years until presenting with a lesion in the left adrenal gland and cutaneous nodules on the left flank. Skin biopsy specimen revealed a diffuse dermal infiltrate of atypical B-cell lymphocytes with expression of CD20, BCL-2, BCL-6, and MUM-1, suggestive of DLBCL. For differentiation between another primary or a recurrent process, immunoglobulin kappa (IgK) light chain gene rearrangement was performed and demonstrated that the DLBCL of the skin and CNS were of the same clonal origin. Restaging CT after initiating chemotherapy and daily ibrutinib showed complete resolution of the left adrenal mass and resolving cutaneous lesions. Our case demonstrates the rare, late cutaneous metastasis of DLBCL of the CNS and highlights the importance of genetic testing for the distinction between the primary and secondary lesions. This article is protected by copyright. All rights reserved.

Aim To assess the potential of interleukin-6 (IL-6) signaling blockade in the lung to treat SARS-CoV-2 infection via model-based simulation by exploring soluble IL-6 receptor (sIL-6R) sequestration by tocilizumab (TCZ) and IL-6 sequestration by siltuximab (SIL). Methods Literature values of IL-6, IL-6 antagonist SIL, sIL-6R, IL-6R antagonist TCZ, and their respective binding constants were used to develop a model to predict the impact of treatment on IL-6 signaling. Models were used to generate simulated bronchoalveolar lavage fluid (BALF) concentrations for normal subjects, subjects at risk of developing acute respiratory distress syndrome (ARDS), and subjects with ARDS under four conditions: without treatment, treatment with TCZ, treatment with SIL, and treatment with TCZ + SIL. Results With TCZ intervention, IL-6 levels are unaffected and sIL-6R is reduced somewhat below the Normal case. IL-6:sIL-6R complex only slightly decreased relative to the no-intervention case. With SIL intervention, sIL-6R levels are unaffected and IL-6 is greatly reduced below the Normal case. IL-6:sIL-6R complex is greatly decreased relative to the no-intervention case. With TCZ + SIL intervention, IL-6 and sIL-6R levels are reduced below the Normal case and achieve suppression equivalent to monotherapy results for their respective targets. IL-6:sIL-6R complex reduction is predicted to be greater than that achieved with monotherapy. This reflects sequestration of both components of the complex and the nonlinear binding equilibrium. Conclusion Co-administration of both IL-6 and IL-6R sequestering products such as SIL and TCZ may be necessary to effectively treat COVID-19 patients who have or are at risk of developing ARDS.

Few cases of natural sudden death presenting as an undiagnosed lymphoma have been reported in the literature, especially in adolescents. Herein we provide a report of sudden death caused by undiagnosed classic Hodgkin lymphoma (cHL). We describe an 18-year-old female who collapsed after several weeks of weight loss, decreased appetite, and dyspnea. At autopsy, a bulky mass arising in the mediastinum and neck compressed the esophagus and trachea, surrounded the great vessels, obliterated the pericardial sac, and infiltrated the myocardium. The lungs were collapsed and large pleural effusions were present. The tumor burden, which weighed at least 2710 g in aggregate, was entirely above the diaphragm. Microscopic examination of the masses showed features typical for nodular sclerosis cHL including large bands of sclerosis, numerous Hodgkin/Reed-Sternberg (HRS) cells, and an eosinophil-rich mixed inflammatory cell infiltrate. Immunohistochemical stains showed the HRS cells to be uniformly positive for CD30 and CD15 and negative for CD3, CD20, CD45, and PAX5. This case exemplifies a rare sudden natural death due to previously undiagnosed cHL in a young patient.

OBJECTIVE The clinical variability of systemic lupus erythematosus (SLE) caused by the unpredictability of flares contributes to patients experiencing a diminished sense of social support. Digital health interventions (DHIs) have the potential to improve patients' social support but have yet to be studied extensively in SLE. Our objective was to assess general and SLE-specific internet usage as well as specific suggestions for SLE-related digital resources and tools among patients with SLE at the Washington University Lupus Clinic. METHODS Fifty-six participants were recruited from the Washington University Lupus Clinic. Ten-minute structured interviews consisting of multiple choice and open-ended questions were conducted. A descriptive statistical analysis was conducted with the quantitative data, while the qualitative data were analyzed using an open coding approach. RESULTS Nearly all respondents indicated having access to the internet (98.2%). Eighty percent currently use the internet for their SLE. The qualitative data indicate that patients with SLE use the internet for understanding flares and changes in their symptoms and/or laboratory results, want an increased variety of SLE information online, have a desire to exchange personal experiences and knowledge of SLE with others, and desire increased diversity in the methods of delivering digital SLE information. CONCLUSION Our findings support the continued use of DHIs for patients with SLE. We believe that these findings will aid the future development of DHIs tailored to patients with SLE.

Polymyalgia rheumatica following immunization with Covid-19 mRNA vaccine: TRL-7 and TRL-9 as common link.