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Introduction: Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19+ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE). Methods: The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries. Planned Outcomes: The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue. Trial Registration: NCT04540497. [ABSTRACT FROM AUTHOR]

Sjögren’s syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren’s syndrome were undertaken, including the quantitation of the frequency of selected cell–cell interactions in the disease milieu. Quantitative analyses of CD4+ T cell subsets and of CD8+ T cells in the labial salivary glands from untreated patients with primary Sjögren’s syndrome revealed that activated CD8+ cytotoxic T cells (CD8+CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8+ T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren’s syndrome is primarily driven by CD8+CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells. [ABSTRACT FROM AUTHOR]

Introduction: Giant cell arteritis (GCA) requires treatment with high-dose, long-term glucocorticoids (GCs), and tocilizumab is often used early in the treatment paradigm. Weight gain, which is associated with morbidity and mortality, is a major concern for patients, though the factors that contribute to changes in body mass index (BMI) throughout the treatment of GCA are poorly understood. Methods: We analyzed GCA patients enrolled in the GiACTA (Tocilizumab in Giant Cell Arteritis) trial. We used univariable and multivariable mixed-effects modeling to examine the association between changes in BMI and cumulative GC dose, disease status at baseline (newly diagnosed versus relapsing), randomization to tocilizumab, and disease flares. Results: A total of 250 patients were included (75% females, mean age 69 years). The mean ± SD BMI change over 52 weeks was 1.18 ± 1.98 kg/m2. On multivariable analysis, cumulative prednisone dose at 52 weeks was independently associated with BMI increase (β = 0.94 kg/m2 for 0–1 g exposure; β = 1.40 kg/m2 for ≥ 4 g exposure; p for trend < 0.001). Relapsing disease at baseline (β = − 0.42 kg/m2 compared to those with newly diagnosed disease; p = 0.002) and flares over 52 weeks in newly diagnosed patients (β = − 0.18 kg/m2 per flare; p = 0.03) were independently associated with lower BMI increase. Conclusions: Cumulative prednisone exposure is associated with increased BMI in GCA patients. In those with newly diagnosed disease, effective disease control regardless of the treatment used also contributes to BMI increase. Modest weight gain may be an indicator of adequate treatment response. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4+ T cells have also been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years. [ABSTRACT FROM AUTHOR]

Introduction: The safety profile of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) is well established. TCZ was approved to treat giant cell arteritis (GCA) in 2017 in the USA and Europe, and its safety profile in patients with GCA continues to be defined. The objective of this analysis was to examine incidence rates (IRs) of adverse events of special interest (AESI) occurring during the TCZ clinical development program and in healthcare claims data in patients with GCA or RA.Methods: TCZ-naïve patients with GCA or RA were identified in the MarketScan administrative healthcare claims database. TCZ-treated patients with GCA from the GiACTA trial and TCZ-treated patients with RA from pooled clinical trial data were analyzed. The IRs of AESI (AESI IRs) were calculated for all cohorts. In the claims cohorts, risks of AESI were estimated using Poisson regression.Results: TCZ-naïve claims cohorts comprised 4804 patients with GCA [mean (standard deviation) age 73.4 (9.8) years; follow-up 3.9 (3.1) years] and 15,164 patients with RA [age 60.3 (8.2) years; follow-up, 4.5 (2.8) years]. TCZ-treated clinical trial cohorts comprised 149 patients with GCA [age 69.5 (8.4) years; exposure approx. 138 patient-years (PY)] and 7647 with RA [age 52 (12.6) years; exposure approx. 22,394 PY]. The IRs of infections, stroke, malignancies, myocardial infarction, and gastrointestinal perforations in the GCA claims cohort exceeded those in the RA claims cohort; the risk of AESI (adjusted for age and glucocorticoid use) was higher in patients with GCA than in those with RA. Similar patterns to the claims cohorts in terms of the AESI IRs were observed in clinical trial cohorts, although the number of events was limited in the GCA trial cohort.Conclusion: Higher IRs of AESI were observed in patients with GCA versus those with RA in both TCZ-naïve and -treated cohorts. Differences in underlying disease, age, and glucocorticoid use may influence AESI incidence, irrespective of intervention.Funding: This study was funded by F. Hoffmann-La Roche Ltd and Genentech, Inc. Article processing charges were funded by F. Hoffmann-La Roche Ltd.Plain Language Summary: Plain language summary is available for this article. [ABSTRACT FROM AUTHOR]

Lymphomas that occur in the setting of IgG4-related disease (IgG4-RD) are uncommon. Most reported cases derive from Asia and are MALT lymphomas occurring in orbital IgG4-RD. The spectrum of lymphomas among IgG4-RD patients in the Western world remains poorly defined. The aim of this study was to report our experience with lymphomas occurring in IgG4-RD. Eight cases were identified from the pathology and consultation files. The median age was 61 years (range 22-68) at IgG4-RD diagnosis and 63.5 years (range 33-79) at lymphoma diagnosis, with a M:F ratio of 4:4. The diagnosis of lymphoma and IgG4-RD was concurrent in three cases and asynchronous in five (interval 4.3-16.4 years). Concurrent cases included a MALT lymphoma and a diffuse large B cell lymphoma (DLBCL) occurring with IgG4-related sialadenitis and a follicular lymphoma occurring with orbital IgG4-RD. Asynchronous cases included a lymphoplasmacytic lymphoma with large cell transformation and intervening IgG4-related pancreatitis, a MALT lymphoma after lacrimal IgG4-RD, two DLBCLs after multiorgan IgG4-RD, and a DLBCL after IgG4-related sialadenitis. Our findings suggest that lymphomas in IgG4-RD are more varied in location and type than the experience reported from Asia to date. Pathologists should be aware of the potential for lymphoma to develop in patients with IgG4-RD and should have a high degree of suspicion when lymphadenopathy or extranodal masses persist despite appropriate therapy for IgG4-RD. The co-occurrence of IgG4-RD and lymphoma that is reported here and previously suggests a possible etiologic association. [ABSTRACT FROM AUTHOR]

Dominant social theories have rarely placed migration at the center of our understanding of society and social change. Classical theories in the Western tradition have been more preoccupied with the impact of economic and political revolutions on social change, stratification and class conflict, and have paid far less attention to other important aspects of society. Contemporary theories have expanded the theoretical gaze to include a much wider set of issues, from racial and gender divisions to warfare and the environment. In an era of globalization, we argue that such a marginalization of the migrant, and the failure to better integrate both internal and external migration into a more nuanced interpretation of social change, is a significant shortcoming. By examining some of the key elements linked to such human movement in Europe, North America and China -- in the light of five recent studies in this field -- we argue that migration is a vital factor in changing the world as we know it and consequently a central concern for social theory. This is a review essay on: Richard Alba and Nancy Foner. Strangers No More: Immigration and the Challenges of Integration in North America and Western Europe. Princeton: Princeton University Press, 2015. Louis DeSipio and Rodolfo de la Garza. US Immigration in the Twenty-First Century: Making Americans, Remaking America. Boulder, CO: Westview Press, 2015. Adrian Favell. Immigration, Integration and Mobility: New Agendas in Migration Studies. Colchester: ECPR Press, 2015. Zhongshan Yue. Social Integration of Rural-Urban Migrants in China: Current Status, Determinants and Consequences. Singapore: World Scientific Publishers, 2015. Robyn R Iredale and Fei Guo. Handbook of Chinese Migration: Identity and Wellbeing. Cheltenham: Edward Elgar Publishing, 2015. [ABSTRACT FROM AUTHOR]

We report the sonochemical synthesis of MOF (metal organic framework) nanoparticles of 30-200 nm in size and electrospraying of those particles on electrospun nanofibers to process a MOF-attached nanofibrous membrane. This membrane displayed significant selectivity towards CO and capacity of adsorbing with 4000-5000 ppm difference from a mixed gas flow of 1% CO and 99% N. Applying ultrasonic waves during the MOF synthesis offered rapid dispersion and formation of crystalline MOF nanoparticles in room temperature. The MOF nanoparticles of 100-200 nm in size displayed higher surface area and adsorption capacity comparing to that of 30-60 nm in size. Nanofibrous membrane was produced by electrospinning of MOF blended PAN solution followed by electrospraying of additional MOF nanoparticles. This yielded uniform MOF deposition on nanofibers, occurred due to electrostatic attraction between highly charged nanoparticles and conductive nanofibers. A test bench for real-time CO adsorption at room temperature was built with non-dispersive Infrared (NDIR) CO sensors. Comparative tests were performed on the membrane to investigate its enhanced adsorption capacity. Three layers of the as-produced membranes displayed CO adsorption for approximately 2 h. Thermogravimetric analysis (TGA) of the membrane showed the thermal stability of the MOF and PAN up to 290 and 425 °C, respectively. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD) is an immune-mediated disease driven by interactions on several levels between cells of the B and T lineages. A key driver of IgG4-RD is believed to be a novel CD4+ cytotoxic T lymphocyte that bears SLAM-F7 on its surface. This cell is presumed to be sustained by continuous antigen presentation by cells of the B cell lineage, particularly plasmablasts. Because IgG4-RD has been recognized for fewer than 15 years as a unified diagnostic entity, no controlled clinical trials or few prospective studies of any sort have been performed. Although progress in understanding disease pathophysiology will likely lead in due course to disease-specific therapies-undoubtedly with implications for other immune-mediated diseases-at this juncture, the management of IgG4-RD remains more an art than a science, driven largely by the published clinical experience of only a few centers of expertise. We identify here six common management dilemmas in IgG4-RD and describe our typical approach to the management of each one. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD) is a recently recognized entity that causes progressive fibrosis and formation of mass lesions. IgG4-RD can be diagnosed histologically by its hallmarks of storiform fibrosis, prominent lymphoplasmacytic infiltrate, and obliterative phlebitis, accompanied by the infiltration of excessive numbers of IgG4-positive plasma cells as well as elevations in serum IgG4 concentrations. A recent publication reported a case of IgG4-RD in the mastoid sinus, representing a new anatomic location for this disease. We report two additional cases of IgG4-RD occurring in the mastoid and causing clinical mastoiditis. The presenting symptoms were varied-tinnitus, hearing loss, and cranial nerve palsies. All three cases showed a dense lymphoplasmacytic infiltrate, storiform type fibrosis as well as elevated numbers of IgG4 positive plasma cells. The three patients responded to immunosuppressive therapy that included steroids and Rituximab. We further investigated 162 consecutive mastoiditis cases at our institution in order to determine the frequency of IgG4-RD as a previously unrecognized cause of mastoiditis. Within this latter cohort we identified nine cases of mastoiditis that had two of the histologic features of IgG4-RD, specifically storiform fibrosis and a dense lymphoplasmacytic infiltrate. Two of these cases showed >50 IgG4-positive plasma cells per high-power field with IgG4-IgG ratio of >40 %, thus fulfilling histological criteria for IgG4-RD. However, both were due to severe acute or chronic infection. In conclusion, we reaffirm IgG4 related mastoiditis as a distinct but uncommon cause of recurrent mastoiditis. The diagnosis of IgG4-related mastoiditis should be rendered with caution, and only after the exclusion of potential mimickers, particularly infection. [ABSTRACT FROM AUTHOR]

Objective: To characterise the delayed-type hypersensitivity (DTH) skin reaction to repeated challenges of keyhole limpet hemocyanin (KLH) and tuberculin purified protein derivative (PPD) in healthy volunteers, as a potential model to test T cell-targeted investigational agents. Subjects, treatment and methods: Forty-nine subjects received either KLH, PPD, or PBS repeat skin challenges, and clinical assessments including induration, erythema and Laser Doppler Imaging. Skin biopsies or suction blisters were taken after challenge to investigate the cellular infiltrate of the challenge site, the T cell activation status, as determined by LAG-3 expression, and, specifically for the blister, the concentrations of inflammatory cytokines. Point estimates, estimates of variation and corresponding 95 % confidence intervals were constructed for each type of challenge and timepoint. Results: The DTH response could be measured at 48 and 120 h post-KLH and PPD challenge with induration, erythema and Laser Doppler Imaging, with 48 h post-challenge demonstrating the peak of the response. PPD was well tolerated in subjects after multiple challenges, however, a significant number of KLH-treated subjects demonstrated an injection site reaction 6-7 days following the SC injection. PPD demonstrated a boost effect on the second challenge as measured by increased induration, where as this was not noted consistently for KLH. Compared to unchallenged and PBS control-injected skin, increased T cell numbers were detected in the challenge site by both the skin suction blister and biopsy technique, at either time point following KLH or PPD challenge. Use of the T cell activation marker LAG-3 demonstrated the activated phenotype of these cells. In skin blisters, higher numbers of LAG-3+ T cells were detected at 48 h post-challenge, whereas in the biopsies, similar numbers of LAG-3+ cells were observed at both 48 and 120 h. Analysis of blister T cell subpopulations revealed some differences in phenotypes between the time points and between the CD4 and CD8 T cells. Blister cytokine analysis revealed a pro-inflammatory dominated signature in PPD-challenged skin. Conclusions: In summary, our data support the use of a repeat KLH and PPD DTH challenge in clinical trials and that the clinical measures of induration and to a lesser extent erythema are appropriate to monitor the clinical DTH response. Both the blister and biopsy can be utilised to assess and quantify activated T cells and at the dose used, PPD was better tolerated than KLH and hence may be optimal for future studies. [ABSTRACT FROM AUTHOR]

Scleritis and uveitis are potentially blinding conditions that can be associated with systemic inflammatory diseases. Polymyalgia rheumatica (PMR) is a common rheumatic disorder of the elderly of uncertain etiology. Although there are a few published reports of scleritis and uveitis in PMR patients, the association of PMR to ocular inflammation has not been well established. The aim of this study is to report a series of PMR patients with scleritis and/or uveitis and review the prior published reports of this potential association. We retrospectively reviewed the medical charts of patients with PMR and scleritis or uveitis who were examined in the Ocular Immunology Service of Massachusetts Eye and Ear Infirmary. We also performed a systematic literature search (PubMed; January 1990 until January 2014) to identify earlier published reports. Seven PMR patients with ocular inflammatory disease (OID) were included in our study: two with scleritis, three with anterior uveitis, and two with panuveitis. The onset of PMR preceded the occurrence of OID in six patients, and in one patient uveitis developed 2 months prior to PMR. Five patients demonstrated a temporal association between flares of PMR and OID. In four patients, OID flares developed during tapering of systemic prednisone prescribed for PMR. Four of the five patients who had relapsing PMR had recurrent or persistent uveitis over the course of follow-up. PMR may be associated with both scleritis and uveitis and should be considered as a possible underlying cause of OID. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most frequent manifestations in the kidney—IgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4(+) T cells. Glucocorticoids are the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches. [ABSTRACT FROM AUTHOR]

lgG4-related disease (lgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of lgG4-RD and its most frequent manifestations in the kidney--lgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of lgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for lgG4. lgG4-related TIN bears the hallmark pathological findings of lgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to lgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of lgG4-RD, but the details of these roles remain unclear. The lgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4+ T cells. Glucocorticoids are the standard initial treatment for lgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches. [ABSTRACT FROM AUTHOR]