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ObjectivesThere is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants.MethodsCRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL).ResultsSixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and 1 had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL).ConclusionsThere was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary.Trial registration number NCT02019602; Results.

In 2002, the Japan Pancreas Society (JPS) was the first in the world to propose diagnostic criteria for autoimmune pancreatitis (AIP). Since the concept of AIP has changed with the accumulation of AIP cases, the Research Committee of Intractable Pancreatic Diseases (RCIPD) provided by the Ministry of Health, Labour and Welfare of Japan and the JPS issued revised clinical diagnostic criteria of AIP in 2006. The Asan Medical Center of Korea also proposed diagnostic criteria for AIP in 2006. However, there are subtle but clinically challenging differences between the Japanese and Korean criteria. This inconsistency makes it difficult to compare data in studies from different centers and elucidate the characteristics of AIP. To reach a consensus on AIP, the RCIPD and the Korean Society of Pancreatobiliary Diseases established the following Asian criteria for the diagnosis of AIP: I-1. Imaging studies of pancreatic parenchyma show a diffuse/segmental/focally enlarged gland, occasionally with a mass and/or a hypoattenuation rim. I-2. Imaging studies of pancreaticobiliary ducts show diffuse/segmental/focal pancreatic ductal narrowing, often with stenosis of the bile duct. (Both I-1 and I-2 are required for diagnosis). II. Elevated level of serum IgG or IgG4, and detection of autoantibodies. III. Common lymphoplasmacytic infiltration and fibrosis, with abundant IgG4-positive cell infiltration. AIP should be diagnosed when criterion I and one of the other two criteria are satisfied, or when histology shows the presence of lymphoplasmacytic sclerosing pancreatitis in the resected pancreas. A diagnostic trial of steroid therapy can be applied carefully by expert pancreatologists only in patients fulfilling criterion I alone with negative diagnostic work-up results for pancreatobiliary cancer.

Mechanisms of Disease: Intravenous Immune Globulin — How Does It Work? The author reviews the many proposed mechanisms by which intravenous immune globulin may exert its antiinflammatory and autoimmunity-inhibiting clinical effects. No single mechanism can explain its activity in diseases with diverse pathophysiological pathways. In an era in which new biologics are being introduced to target inflammation and autoimmunity, some older treatments persist. Immune globulin–replacement therapy has been a lifesaving treatment for patients with antibody deficiency. When immune globulin replacement was introduced in the 1950s for the treatment of primary immunodeficiency diseases, it was administered subcutaneously or by intramuscular injection; subsequently, preparations suitable for intravenous use were developed, and these have undergone progressive changes in composition, particularly the elimination of sugars and normalization of the salt content and osmolarity. As a result, reactions have become much less frequent. Intravenous immune globulin is prepared from . . .

Background Revised clinical criteria for autoimmune pancreatitis (AIP) have been proposed by the Research Committee of Intractable Disease of the Pancreas and the Japan Pancreas Society. These criteria require distinguishing AIP from neoplastic lesions. However, this can be difficult, and patients often undergo surgery on the basis of suspected pancreatic cancer (PC). Methods AIP was diagnosed in 25 patients at the Aichi Cancer Center Hospital (ACCH) according to the revised AIP criteria. In each patient, endoscopic ultrasonography (EUS) was used to describe the conventional pancreatic parenchymal and ductal features of chronic pancreatitis (Sahai criteria), and other abnormal features, namely, diffuse hypoechoic areas (DHAs), diffuse enlargement (DE), focal hypoechoic areas (FHAs), focal enlargement, bile duct wall thickening (BWT), lymphadenopathy, and peripancreatic hypoechoic margins (PHMs). We compared these features between 25 patients with AIP and 30 patients with pancreatic cancer resected at ACCH. Results Few conventional EUS features of chronic pancreatitis (CP) were seen in patients with AIP (mean, 2.0 features). Frequencies of DHA, DE, BWT, and PHM were significantly higher in AIP than in PC. DHAs, DE, and FHAs resolved after steroid treatment. Conclusions Novel EUS features of AIP are useful in distinguishing AIP from PC and for following the effects of steroid therapy.

ObjectivesThe prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases who are frequently treated with disease modifying therapies remains poorly understood. This meta-analysis aims to assess the prevalence and clinical outcomes of COVID-19 in autoimmune diseases.MethodsElectronic databases were searched for observational and case–controlled studies. We sorted medications into glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic or targeted synthetic DMARDs (b/tsDMARDs), which was also divided into monotherapy and b/tsDMARDs–csDMARDs combination therapy.ResultsWe analysed 62 observational studies with a total of 319 025 patients with autoimmune diseases. The prevalence of COVID-19 was 0.011 (95% CI: 0.005 to 0.025). Meta-analysis of seven case–controlled studies demonstrated that the risk of COVID-19 in autoimmune diseases was significantly higher than in control patients (OR: 2.19, 95% CI: 1.05 to 4.58, p=0.038). Meta-regression analysis showed glucocorticoids were significantly associated with the risk of COVID-19. For clinical outcomes, we assessed 65 studies with 2766 patients with autoimmune diseases diagnosed with COVID-19. The rates of hospitalisation and mortality were 0.35 (95% CI: 0.23 to 0.50) and 0.066 (95% CI: 0.036 to 0.12), respectively. Glucocorticoids, csDMARDs and b/tsDMARDs–csDMARDs combination therapy increased the risk of these outcomes, whereas b/tsDMARDs monotherapy, particularly antitumour necrosis factor agents, were associated with a lower risk of hospitalisation and death.ConclusionsOur meta-analysis demonstrated that patients with autoimmune diseases had an increased risk of COVID-19, primarily attributed to glucocorticoid use. b/tsDMARDs monotherapy was associated with a lower risk of severe COVID-19 suggesting its safety in the COVID-19 pandemic.

We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant ( P  < 1.28 × 10 −11 ) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases. An analysis of 3,757 Sardinian genomes identifies 122 association signals for 459 immune cell traits at 69 loci. Some variants are associated with autoimmune disorders.

Sphingosine 1-phosphate (S1P) is an important circulating lipid mediator that is derived from the metabolism of cell membranes. Its diverse homeostatic roles, particularly in immunology and vascular biology, can go awry in numerous diseases, including multiple sclerosis, cardiovascular diseases, and fibrosis. The centrality of S1P signaling has led to the development of several drugs, including two approved for treatment of multiple sclerosis. In a Review, Cartier and Hla discuss the current understanding of how one mediator can carry out so many signaling roles in different tissues, how these become dysregulated in disease, and efforts in drug development to target S1P signaling. Science , this issue p. eaar5551 Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein–coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Tumor necrosis factor alpha (TNF-α) was initially recognized as a factor that causes the necrosis of tumors, but it has been recently identified to have additional important functions as a pathological component of autoimmune diseases. TNF-α binds to two different receptors, which initiate signal transduction pathways. These pathways lead to various cellular responses, including cell survival, differentiation, and proliferation. However, the inappropriate or excessive activation of TNF-α signaling is associated with chronic inflammation and can eventually lead to the development of pathological complications such as autoimmune diseases. Understanding of the TNF-α signaling mechanism has been expanded and applied for the treatment of immune diseases, which has resulted in the development of effective therapeutic tools, including TNF-α inhibitors. Currently, clinically approved TNF-α inhibitors have shown noticeable potency in a variety of autoimmune diseases, and novel TNF-α signaling inhibitors are being clinically evaluated. In this review, we briefly introduce the impact of TNF-α signaling on autoimmune diseases and its inhibitors, which are used as therapeutic agents against autoimmune diseases.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare autoimmune disease, which is characterized by the immune system attacking astrocytes in the central nervous system, resulting in inflammation and damage to the nervous system. We reported a 41-year-old female patient with only drowsiness for 3 months, who was, otherwise, healthy with no other signs of meningoencephalitis or myelitis. There were no obvious abnormalities in her neurological and ophthalmic tests. Brain magnetic resonance imaging (MRI) plain scan + enhancement with the gadolinium contrast agent revealed patchy hypointensity on T1-weighted imaging, hyperintensity on T2-weighted imaging, hyperintensity on T2-weighted fluid-attenuated inversion recovery in the left basal ganglia, corona radiata, and local septum pellucida, with no enhancement in the enhanced lesions. Cerebrospinal fluid (CSF) revealed white blood cell count of 5.00 × 106/L, CSF protein of 828.53 mg/L, and glucose of 2.83 mmol/L. Aquaporin-4 (AQP4) antibody, N-methyl-D-aspartate receptor (NMDAR) antibody and GFAP antibody were all positive, whereas the remaining autoimmune encephalitis antibody tests were negative. Oncology screening [including head, chest, and whole-abdomen (involving the pelvic cavity) CT and tumor markers] did not reveal any obvious evidence of tumor presence. The patient received systemic treatment with high-dose intravenous injection of steroids combined with immunosuppressive agents, and the clinical and imaging features of the patients improved. To the best of our knowledge, reports on overlapping positivity of AQP4 antibody and NMDAR antibody in patients with GFAP astrocytopathy were still very rare. We hope to supplement the existing literature on this topic, review the relevant literature, and strive to increase the understanding toward GFAP astrocytopathy with overlapping autoimmune syndrome so as to enable early diagnosis and early treatment and to improve the clinical outcome of patients.

ObjectivesTo describe patients with autoimmune inflammatory rheumatic diseases (AIRD) who had COVID-19 disease; to compare patients who required hospital admission with those who did not and assess risk factors for hospital admission related to COVID-19.MethodsAn observational longitudinal study was conducted during the pandemic peak of severe acute respiratory syndrome coronavirus 2 (1 March 2020 to 24 April). All patients attended at the rheumatology outpatient clinic of a tertiary hospital in Madrid, Spain with a medical diagnosis of AIRD and with symptomatic COVID-19 were included. The main outcome was hospital admission related to COVID-19. The covariates were sociodemographic, clinical and treatments. We ran a multivariable logistic regression model to assess risk factors for the hospital admission.ResultsThe study population included 123 patients with AIRD and COVID-19. Of these, 54 patients required hospital admission related to COVID-19. The mean age on admission was 69.7 (15.7) years, and the median time from onset of symptoms to hospital admission was 5 (3–10) days. The median length of stay was 9 (6–14) days. A total of 12 patients died (22%) during admission. Compared with outpatients, the factors independently associated with hospital admission were older age (OR: 1.08; p=0.00) and autoimmune systemic condition (vs chronic inflammatory arthritis) (OR: 3.55; p=0.01). No statistically significant findings for exposure to disease-modifying antirheumatic drugs were found in the final model.ConclusionOur results suggest that age and having a systemic autoimmune condition increased the risk of hospital admission, whereas disease-modifying antirheumatic drugs were not associated with hospital admission.