Predictors of Thirty-Day Hospital Readmissions in Systemic Lupus Erythematosus in the United States: A Nationwide Study.

OBJECTIVE: To evaluate independent risk factors for readmission and to determine the major reasons for readmission in a nationally representative sample of patients with systemic lupus erythematosus (SLE). METHODS: We used the Nationwide Readmissions Database to identify adults with SLE who were discharged from hospital to home during January-November of 2016 and 2017. Thirty-day all-cause readmissions were identified. A multivariable adjusted survey-specific logistic regression model was used to identify factors associated with readmission. RESULTS: A total of 132,400 hospitalized adults with SLE were discharged home during the study period; 88.3% were female, with a median age of 51.0 years (interquartile range 38.7-61.9 years). Of these, 18,973 individuals (14.3%) were readmitted within 30 days of discharge from their index hospitalization. In multivariable analyses, the factors associated with the highest odds for readmission were autoimmune hemolytic anemia (odds ratio [OR] 1.86 [95% confidence interval (95% CI) 1.51-2.29]), glomerular disease (OR 1.27 [95% CI 1.19-1.36]), pericarditis (OR 1.35 [95% CI 1.14-1.60]), heart failure (OR 1.34 [95% CI 1.24-1.44]), age 18-30 years (OR 1.28 [95% CI 1.17-1.41] versus age ≥​65 years), and Medicare (OR 1.20 [95% CI 1.13-1.28]) and Medicaid insurance (OR 1.26 [95% CI 1.18-1.34]). Sepsis (7.6%), SLE (7.4%), heart failure (3.5%), and pneumonia (3.2%) were among the most common causes for readmission. CONCLUSION: In this nationally representative study of SLE readmissions, the strongest risk factors for 30-day readmission were younger age, SLE-related manifestations, and public insurance. These results identify patient groups with SLE that would benefit from postdischarge interventions designed to reduce hospitalizations and improve health outcomes.

Allergic Aspects of IgG4-Related Disease: Implications for Pathogenesis and Therapy.

IgG4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease frequently associated with allergy. The pathogenesis of IgG4-RD is poorly understood, and effective therapies are limited. However, IgG4-RD appears to involve some of the same pathogenic mechanisms observed in allergic disease, such as T helper 2 (Th2) and regulatory T cell (Treg) activation, IgG4 and IgE hypersecretion, and blood/tissue eosinophilia. In addition, IgG4-RD tissue fibrosis appears to involve activation of basophils and mast cells and their release of alarmins and cytokines. In this article, we review allergy-like features of IgG4-RD and highlight targeted therapies for allergy that have potential in treating patients with IgG4-RD.

Hemophagocytic lymphohistiocytosis: An update on pathogenesis, diagnosis, and therapy.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic triggers. Sustained, aberrant activation of cytotoxic CD8+ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.

Immunologic adverse events from immune checkpoint therapy.

The growth of cancer immunotherapy has led to an urgent need for a multispecialty approach to treating patients with advanced malignancies. Checkpoint inhibitor therapies cause a wide range of toxicities termed immune-related adverse events (irAEs) that can affect any organ system. Similar to the anti-tumor responses induced by these medications, irAEs represent an interruption of self-tolerance that results in T cell-driven cytotoxicity, the exact mechanisms of which are likely heterogeneous. This review describes the various immunologic pathways that may lead to irAEs along with the diverse clinical manifestations seen in clinical practice. Treatment based on the severity and specific organ involvement will also be discussed, along with an overview of current guidelines and potential challenges that arise with immunosuppressive medications.

Demographic, Clinical, and Immunologic Correlates among a Cohort of 50 Cocaine Users Demonstrating Antineutrophil Cytoplasmic Antibodies.

OBJECTIVE: Cocaine/levamisole-associated autoimmunity syndrome (CLAAS) is a poorly understood form of drug-induced autoimmunity. Our goals were to better characterize the spectrum of clinical and immunologic features of CLAAS, to identify demographic risk factors, and to generate new hypotheses regarding pathogenesis. METHODS: CLAAS subjects were identified between 2001 and 2015 at the University of Washington Medical Center, Harborview Medical Center, and affiliated clinics in Seattle, Washington, USA. Demographic, clinical, and immunologic variables were collected and correlated using contingency and logistic regression analyses. We used similar analyses to compare CLAAS subjects with all individuals exhibiting antineutrophil cytoplasmic antibodies (ANCA+) or cocaine use (Cocaine+) in an associated deidentified clinical data repository. RESULTS: We identified 50 CLAAS subjects. Compared to all Cocaine+ individuals (n = 2740), CLAAS subjects were more likely to be female and less likely to self-identify as black/African American. CLAAS subjects showed several ANCA patterns, including anti-MPO (myeloperoxidase)/anti-PR3 (proteinase 3) dual reactivity, a finding that appears to be specific to CLAAS. Hematologic, renal, and skin abnormalities were most frequently reported, including neutropenia and skin purpura. Finally, we observed strong, independent associations between the cytoplasmic ANCA (C-ANCA) pattern and mortality. CONCLUSION: We identify sex and race as important risk modifiers in the developing CLAAS among cocaine users. The development of C-ANCA was associated with increased mortality. Moreover, we confirm the enriched presence of anti-MPO/anti-PR3 dual reactivity in CLAAS, further supporting the diagnostic utility of this feature.

Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity.

Objective: Exposure to illicit cocaine and its frequent adulterant, levamisole, is associated with ANCAs targeting neutrophil elastase (NE), neutropenia and vasculitic/thrombotic skin purpura. The mechanisms of cocaine/levamisole-associated autoimmunity (CLAA) are unknown. The aim of this study was to assess the ability of cocaine and levamisole to induce the release of neutrophil extracellular traps (NETs), a potential source of autoantigen and tissue injury. Methods: We performed quantitative and qualitative assessment of NET formation in neutrophils from healthy donors exposed to either drug in vitro . In addition, IgG from sera of individuals with CLAA (CLAA-IgG) was assessed for its ability to enhance formation of, and to bind to, drug-induced NETs. Results: Both cocaine and levamisole could induce formation of NETs enriched in NE and, potentially, inflammatory mitochondrial DNA. Both drugs could also augment simultaneous release of B cell-activating factor belonging to the TNF family (BAFF). CLAA-IgG, but not IgG from healthy individuals, could potentiate drug-induced NETosis. Furthermore, CLAA-IgG, but not ANCA + control IgG, bound to drug-induced NETs in a pattern consistent with NE targeting. Conclusion: Both cocaine and levamisole may contribute to the development of ANCAs by inducing release of potentially inflammatory NETs in association with NE autoantigen and BAFF. Enhancement of drug-induced NET release by CLAA-IgG provides a potential mechanism linking vasculitis/pupuric skin disease to acute drug exposure in patients with CLAA. Further study of this under-recognized form of autoimmunity will be likely to provide mechanistic insight into ANCA-associated vasculitis and other diseases associated with NETosis.

Altered IgG autoantibody levels and CD4(+) T cell subsets in lupus-prone Nba2 mice lacking the nuclear progesterone receptor.

Important interactions between female reproduction and autoimmunity are suggested by the female-predominance of systemic lupus erythematosus (SLE) and other autoimmune diseases and the amelioration of certain autoimmune diseases during pregnancy. Sexually dimorphic risk of developing SLE involves modulation of genetic risk by environmental factors, sex hormones and non-hormonal factors encoded on the sex chromosomes. In some lupus models, estrogen, via estrogen receptor alpha (ER-α), enhances production of highly pathogenic IgG2a/c autoantibodies (autoAbs). Some studies indicate that treatment with progesterone, a chief female reproductive steroid, can suppress IgG2a/2c autoAb production. Little is known about how endogenous progesterone impacts lupus autoimmunity. To investigate this, we introduced a disruptive progesterone receptor (PR) gene mutation into lupus-prone mice and tracked the development of spontaneous IgG autoAbs. Here, we present evidence that PR can suppress the emergence of class-switched IgG2c autoAbs, suggesting that PR and ER-α counter-regulate a critical step in lupus autoimmunity. PR's control of IgG2c autoAb production correlates with alterations in the relative abundance of splenic T follicular helper (TFH) cells and non-TFH CD4(+) T cells, especially regulatory T cells (TREGS). Surprisingly, PR also appears to help to maintain sexually dimorphic abundance of splenic leukocytes, a feature common to many mouse models of SLE. Together our results identify a novel molecular link between female reproduction and lupus autoimmunity. Further investigation into the immunomodulatory functions of PR promises to inform reproductive health care in women and offers mechanistic insight into important immunologic phenomena of pregnancy.

Interdisciplinary exchange of ideas: progestagens for autoimmunity, biologics for pregnancy complications.

In recent years, there has been a growing interest in the role of immune, alloimmune and autoimmune processes in the pathogenesis of spontaneous preterm birth and recurrent pregnancy loss. The association between an inflammatory response and preterm labor has been established. Indeed, many women suffering from preterm labor have elevated inflammatory markers such as tumor necrosis factor alpha, interleukin 6 and matrix metaloproeinase 8. The role of immune processes in the pathogenesis of recurrent pregnancy loss has also been widely researched. Progesterone induces many physiologic effects necessary for healthy pregnancy, and progestagens supplementation has been used as an approach to prevent preterm labor and recurrent pregnancy loss. Progestagens also have potent anti-inflammatory and immunomodulatory actions. Because preterm labor and recurrent pregnancy loss are associated with abnormal inflammation, progestagens may maintain healthy pregnancy through both endocrine and immunologic actions. These immunologic actions, such as suppression of Th1- and Th17-related responses, enhancement of regulatory T cell (Tregs) activity and suppression of inflammation, may also be involved in pregnancy-induced remission of certain autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). Accordingly, there is growing interest in the potential therapeutic role of progestagens in the treatment of MS and RA. In this review, we suggest that biologic autoimmune modulators, especially those which affect immune pathways similar to progestagens, may provide more potent and specific effects, and hence better results than progestagens, in preventing preterm labor and recurrent pregnancy loss.

Modulation of autoimmune rheumatic diseases by oestrogen and progesterone.

Sexual dimorphism is evident in the risk and expression of several human autoimmune diseases. Differences in disease manifestations observed between sexes are likely to involve immunomodulation by sex steroids, nonhormonal factors encoded by genes on the X and Y chromosomes, and immunological phenomena unique to pregnancy. In systemic lupus erythematosus (SLE), and perhaps other autoantibody-mediated diseases, oestrogen seems to increase the risk of disease in genetically predisposed women by targeting key immune pathways, including the type 1 interferon (IFN) response, differentiation of CD4(+) T helper cells and survival of autoreactive B cells. By contrast, progesterone seems to reduce the risk of SLE by counteracting the effects of oestrogen on some of these same pathways, which suggests that the balance between oestrogen and progesterone can determine disease expression. In this Review we focus on the roles of the sex steroid hormones oestrogen and progesterone in modulating the risk and expression of SLE and rheumatoid arthritis. Intensive research in this area promises to identify novel therapeutic strategies and improve understanding of the immunological requirements and complications of pregnancy, and is expected to define the mechanisms behind sexual dimorphism in autoimmunity, immunity and other aspects of human health--a newly announced directive of the NIH.

The intracellular progesterone receptor regulates CD4+ T cells and T cell-dependent antibody responses.

Pg has distinct immunomodulatory properties involved in poorly understood immune phenomena, including maternal tolerance of the fetus, increased risk of certain infections during pregnancy or after Pg birth control, and pregnancy-associated remission of autoimmune disease. Several potential mechanisms have been identified, including alteration of Th1 and Treg activity, but the precise cellular and molecular targets of Pg immunomodulation in vivo remain obscure, partly because Pg can signal through several different receptor types. One such receptor, the iPR, encoded by the pgr gene, is essential for reproduction in female mice and is expressed in the thymus and CD4(+) T cells. We hypothesized that iPR regulates CD4(+) T cell activity and adaptive immune responses in vivo. With the use of iPR KO mice, we demonstrate that iPR specifically suppresses TD antibody responses, primarily by dampening CD4(+) Teff activity, likely via transcriptional repression of the IFN-γ gene and modulation of other programs regulating CD4(+) T cells. Our results highlight a novel mechanism linking the endocrine and immune systems, and they offer insight into important but poorly understood phenomena in women's health and autoimmunity.

Progesterone and autoimmune disease.

Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg's immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations.

Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice.

OBJECTIVE: While estrogen treatment exacerbates disease in models of systemic lupus erythematosus (SLE), the effects of progesterone are unclear. This study was undertaken to assess the effects of continuous progesterone treatment on autoantibody production and spontaneous glomerulonephritis (GN) in a mouse model of SLE. METHODS: Female (NZBxNZW)F1 (NZB/NZW) mice were treated with vehicle, 2 mg of depot medroxyprogesterone acetate (DMPA), or 10 mg of DMPA every 6 weeks. Survival, proteinuria, and serum anti-double-stranded DNA (anti-dsDNA) levels were monitored. At 39 weeks of age, kidneys were analyzed for abnormalities and glomerular accumulation of IgG subclasses and C3. Spleen leukocyte subsets were also analyzed. RESULTS: DMPA treatment reduced mortality in a dose-dependent manner in association with reduced proteinuria and glomerular damage. High-dose DMPA treatment resulted in a reduction of total serum IgG and IgG2a anti-dsDNA antibody levels, whereas IgG1 anti-dsDNA antibody levels were modestly increased. High-dose DMPA reduced glomerular accumulation of IgG1, IgG2a, IgG3, and complement, while low-dose DMPA decreased glomerular IgG2a and IgG3 levels compared with vehicle treatment. CONCLUSION: Our findings indicate that treatment of premorbid female NZB/NZW mice with DMPA reduces mortality and attenuates spontaneous GN, likely through multiple mechanisms, including altered ratios of protective Th2-related IgG antibodies versus nephritogenic Th1-related IgG autoantibodies. Thus, estrogen and progesterone may have disparate effects on lupus autoimmunity, lending new significance to observed hormonal imbalances in patients with SLE. These data also suggest that treatment of SLE patients with DMPA may have therapeutic benefit.

Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells.

Use of the progesterone (Pg) birth control depot medroxyprogesterone acetate (DMPA) increases a woman's risk for sexually transmitted infection with HIV or HSV-2 via unknown mechanisms. Plasmacytoid dendritic cells (pDCs) are circulating and tissue-resident sentinels capable of making large quantities of IFN-alpha upon recognizing viruses through TLRs 7 and 9. In this study, we show that Pg inhibits TLR9-induced IFN-alpha production by human and mouse pDCs and that DMPA impairs TLR9- and virus-induced IFN-alpha production by pDCs in mice, providing a potential explanation for how DMPA impairs innate antiviral immunity in women. Pg failed to inhibit the Mda-5 pathway of IFN-alpha induction in dendritic cells, suggesting that Pg regulates select antiviral DC programs. This may occur through selective blockade of IFN regulatory factor-7 activation, a novel steroid action. Thus, through inhibition of TLR-mediated IFN-alpha production by pDCs, Pg may regulate antiviral immunity.

Regulation of dendritic cells by female sex steroids: relevance to immunity and autoimmunity.

Dendritic cells (DCs) are critical mediators of adaptive immunity, tolerance and autoimmunity. The human immune system exhibits sexual dimorphism, which is most evident in the female predominance of autoimmune diseases such as systemic lupus erythematosus (SLE). Female sex steroids are strongly implicated in mediating immune sexual dimorphism, in part because estrogen accentuates disease in several models of lupus autoimmunity. In contrast, progesterone may prevent disease development. While much investigation has focused on the effects of estrogen and progesterone on lymphocyte functions, far less attention has been paid to the effects of these hormones on DCs. Current evidence now indicates estrogen can activate DCs, while in contrast, progesterone inhibits DC functions. Thus, we hypothesize that the opposite effects these two hormones have on lupus autoimmunity reflect opposing effects on DC functions. Thus, through direct actions on DCs, female sex steroids may influence autoimmunity, immunity and tolerance.