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Objective: new-onset refractory status epilepticus (NORSE) is defined as de novo refractory seizures occurring in previously healthy adults, without a clear underlying etiology. Due to refractory seizures and insufficient understanding of pathophysiology, management of these patients remains challenging and often leads to poor clinical outcomes. Various infectious and autoimmune mechanisms have been proposed but have not been validated and a large number of patients are thus labeled 'cryptogenic'. Moreover, histopathological findings have rarely been described in NORSE and are usually autopsy evaluations. In this paper, we describe the clinical correlates and histopathological findings in patients presenting with NORSE.Methods: A case series of five patients with NORSE who underwent neurosurgical intervention and had histopathological examination during their acute clinical course.Results: In all patients,status epileptics was refractory to treatment with antiseizure drugs (ASDs) and anesthetic agents. Autoimmune work-up revealed elevated titer of anti-GAD antibody in one patient but was unremarkable in others. Empiric use of immunomodulation therapy in three patients did not lead to cessation of status epilepticus (SE). Due to failure of prolonged medical management, three patients underwent palliative surgery for resection of epileptogenic tissue whereas the other two had diagnostic brain biopsy. Histopathology obtained during biopsy revealed evidence of vasculitis in one and necrotizing vasculopathy in another. The patient with anti-GAD antibodies had evidence of lymphocytic infiltration in limbic structures. The remaining two had nonspecific histopathological findings.Significance: Although our findings are limited by a small number of patients, it adds to the growing premise of NORSE being related to an underlying autoimmune process. Additional studies, especially with histopathological data are needed to better understand this devastating disorder. [ABSTRACT FROM AUTHOR]

• In this paper, a new erythrocyte agglutination methodology was established. • Objective, quantitative results can be obtained by automatic hematology analyzer. • It will greatly improve the sensitivity of antigen-antibody response detection. • New method can be used in the detection of some autoimmune diseases. The objective of this work was to explore the similarities and differences between the automatic hematology analyzer method and the traditional slide method in the detection of red blood cell (RBC) agglutination, and demonstrate that the automatic hematology analyzer is more intuitive and reliable for the detection of RBC agglutination. A further objective was to establish a new method to facilitate new ideas for clinical research. Type A serum was selected and diluted 1:2, 1:4, 1:8, 1:16, and 1:32, to react with the type B cells and the normal saline group was used as the control group. An RBC count was performed using an automatic hematology analyzer, after incubation in a warm bath for 30 min. The degree of agglutination on the glass slide was also recorded. A positive serum of antinuclear antibody (ANA) was collected and RBC agglutination between RBC-O and ANA positive serum was determined using the automatic hematology analyzer method. The relationship between the results from the automatic hematology analyzer and the agglutination strength using the glass slide method was determined. There was a significant difference between the serum of ANA positive patients and the normal control group (P < 0.05). A new method for detecting RBC agglutination using an automatic hematology analyzer has been established and is a valid tool for clinical research. [ABSTRACT FROM AUTHOR]

This paper represents the research results of echocardiographic study for early prediction of mortality. The classification task is solved by analyzing the echocardiographic data from medical information system. Echocardiographic data of 90000 hearts condition extracted directly from medical information system were analyzed. The considered echocardiographic studies were conducted for patients with CHF, CHD, hypertension, heart arrhythmia, valvular heart disease, autoimmune disease, congenital heart defect, cardiomyopathy, endocrine disease, heart failure, mixed connective tissue disease, cancer, aneurism. Using machine learning methods and neural networks it is possible to make an early prediction of mortality based on instrumental echocardiographic study. It can be offered to clinicians as support for accurate, reasonable saving clinical decisions with minimization risks for patient's health. The classification task mortality prediction is solved by machine learning methods with 97% ROC curve. The simple echocardiographic test results like FV Simpson, systolic volume, the valves condition, the condition of the ascending aorta and other echocardiographic data are used as predictors. Such a simple approach to solving critical tasks can make the method widely used in clinical practice. [ABSTRACT FROM AUTHOR]

Traditionally, autoimmune disease has been considered to be a case of false recognition; the immune system mistakenly identifies ‘self’ tissues as foreign, attacking them thus causing damage and malady. Accordingly, the history of autoimmunity is usually told as part ot the history of immunology, that is, of theories and experiments relating to the ability of the immune system to discriminate between self and nonself. This paper challenges this view, claiming that the emergence of the notion of autoimmunity in the 1950s must be considered as part of a long develolpment in thought about pathology throughout the twentieth century, namely the conceptualisaiton of disease as a reactive and self-destructive process. During the first part of the twentieth century this notion became one of the cornerstones of pathology and was increasingly employed for the explanation of the non-infections, slow-burning diseases. Thus, the category of chronic disease had been defined anew, now encompassing all those diseases characterised by a persistent inflammatory process. Inflammation, in turn, was conceived as double-eged physiological mechanism, which was usually the direct mediator of damage, of the essence of disease. The paper also shows how this kind of analysis could emable a unified historical discussion of autoimmunity and allergy, hitherto considered to have distinct conceptual origins. [Copyright &y& Elsevier]

Abstract Background To assess if hepatitis B vaccination in adults is causally associated with autoimmune diseases. Such causation has been claimed based mainly on case reports and uncontrolled studies, and a syndrome ‘Autoimmune/autoinflammatory Disorder Induced by Adjuvants’ (ASIA) has been claimed to be linked to immunization, particularly hepatitis B vaccination. Methods Review of peer-reviewed literature from January 1990 to March 2017 identifying controlled studies with documented incidence of autoimmune diseases occurring after hepatitis B vaccinations in adults. From 1297 studies identified, 259 were further assessed and 49 reviewed further; 19 relevant papers reporting 21 results are reviewed here, and 14 results included in a meta-analysis. Results Overall no association between hepatitis B vaccination and the onset of autoimmune diseases was seen. The overall odds ratio was 1.06, with 95% confidence limits of 0.93–1.21, with non-significant heterogeneity. Only one study showed a significant excess risk between hepatitis B immunisation and autoimmune disease. Conclusions Despite multiple case reports, there is no reliable scientific evidence of autoimmune diseases being caused by hepatitis B vaccinations. [ABSTRACT FROM AUTHOR]

Nuclear Factor Kappa-Β (NF-kB) is recognized as one of the main inflammatory pathways in the Autoimmune Disease (AD) Rheumatoid Arthritis (RA), which exhibits high levels of inflammatory cytokines such as IL-1, TNFa and IL-6 linked to bone erosion and disease progression. NF-kB is also the most studied pathophysiological mechanism in RA, however, over the last few decades, a more recently discovered Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL), also linked to NF-kB activation and bone erosion, has been the topic of interest for research in the area of AD management. As the non-discriminative long term suppression of the NF-kB pathway by pharmacological agents in the management of RA has been linked with a number of side effects and with the discovery of the RANKL mechanism, which may present a more targeted approach to the management of the AD, there has been renewed interest in research on the potential impact of nutritional interventions influencing the NF-kB pathway, RANKL as well as RA disease outcomes. Existing research highlights the potential utility of nutrients such as Omega 3 and Vitamin D, which may lower NF-kB activation in RA. There is, however, a gap in the knowledge of the effects of nutritional interventions on pathophysiological mechanisms contributing to RA and a more robust systematic analysis of whether nutrients or specific vitamins can have an effect on the NF-kB and RANKL main drivers of pathology in RA. Findings from this study suggest the potential of Vitamin D supplementation in lowering the levels of RANKL and related markers/cytokines such as Th17 cell levels, OPG/RANKL ratio and CXCL10 pathway, which may present as a viable nutrition intervention for the management of RA. The methodology of this review involved a Systematic Search of the Literature with a Critical Appraisal of papers. It incorporated three tranche searches of 1. review, 2. animal/in vitro and 3. intervention peer reviewed research published in the last 10 years, resulting in a total of 119 papers. Results provide an overview of the NF-kB pathway, a detailed mechanistic examination of the Receptor Activator of Nuclear Factor Kappa-Β Ligand (RANKL) which is linked to bone erosion, and finally a review of nutritional interventions relating to this mechanism of pathophysiology. The accepted papers were critically appraised using SIGN50 for human studies and the ARRIVE guidelines for animal studies; the narrative was and the extracted information coded into key themes. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic stem cell transplantation (AHSCT) is currently investigated as treatment for severe and refractory autoimmune diseases, such as multiple sclerosis (MS), systemic sclerosis (SSc), Crohn's disease (CD) and systemic lupus erythematosus. Randomized clinical trials in MS, SSc and CD have shown the efficacy of AHSCT to promote control of disease activity and progression, when compared to conventional treatment. The use of high dose immunosuppressive conditioning is essential to eliminate the autoimmune repertoire, and the re-infusion of autologous hematopoietic stem cells avoids long-term leucopenia by reconstitution of both immune and hematological systems. Recent studies showed that AHSCT is able to deplete the autoimmune compartment and further promote the formation of a new auto-tolerant immune repertoire, reducing the inflammatory milieu and leading to long-term clinical remission without any complementary post-graft treatment. Deep knowledge about the mechanisms of action related to AHSCT-induced remission is required for the management of possible post-AHSCT relapse and improvement of clinical protocols. This paper will review the mechanisms enrolled in the immune response resetting promoted by AHSCT in patients with autoimmune diseases. [ABSTRACT FROM AUTHOR]

The study of fundamental mechanisms of autoimmunity has been instrumental to clinical progress in the diagnosis and treatment of a range of immune-mediated inflammatory disorders. Dutch immunology has made major contributions to these developments, ranging from fundamental studies on immune cells, antibodies and cytokines to translational and clinical studies with targeted therapies in patients. In this paper we illustrate the progress made in our understanding of autoimmunity and the translational implications for human disease management by focusing on three areas: the autoantibody response in rheumatoid arthritis (RA), T-B cell interactions in Sjögren's syndrome (SS), and cytokine targeting in spondylarthritis (SpA). [ABSTRACT FROM AUTHOR]

Abstract: Background: The potential for development of autoimmune diseases after vaccination with new vaccines containing novel adjuvants is a theoretical concern. Randomised, placebo-controlled trials are the best method for assessing a potential causal relationship between an adverse event and vaccination, but usually have a sample size too small to detect adverse events occurring in <1% of subjects. Incomplete case documentation may hamper definitive diagnoses, preventing accurate causality assessment. To date there are no guidelines for collection, documentation and monitoring of potential immune mediated disorders (pIMD) reported in the course of clinical trials with adjuvanted vaccines. Objective: This paper proposes a methodology for collection of pIMDs in clinical vaccine trials, with the objective of obtaining complete and reliable data using standardised methodology for its collection and analysis. Recommendations: The role of the study investigator in prospective, standardised safety data collection is key and can be facilitated by providing a pIMD list in study documents and disease-specific standard questionnaires to assist timely and thorough documentation. External expert review of histopathology samples or other specialised diagnostic data would increase diagnostic accuracy. Centralised case ascertainment using standard case definitions would identify true cases of interest. We propose collection of safety data for at least 6 months and up to one year after the last vaccine dose. Bio-banking as a platform for collecting samples from enrolled patients for future use (e.g., to measure biomarkers of diagnostic, prognostic or predictive utility) could eventually provide valuable information in cases where a pIMD is diagnosed during the study period. Conclusion: Standardised collection of safety data to allow appropriate analyses are optimal approaches for detecting rare events in clinical trials. Appropriate data analysis will then more reliably define potential causal relationships with vaccination. [Copyright &y& Elsevier]

Abstract: A 20-year-old female with a diagnosis of autoimmune encephalitis against N-methyl-d-aspartate receptor was found to have a 13mm teratoma in the left ovary. The tumor had undergone massive coagulative necrosis within a normal ovary, a previously unreported feature. Necrosis of a mature cystic teratoma is very rare in the absence of ovarian torsion. It is proposed that necrosis may have induced a massive liberation of neuronal antigens. The vast majority of the tumors associated with this newly described condition are ovarian teratomas containing neural tissues. In this paper, we review their different histopathological aspects that may explain the relative incidence of various tumor types associated to this form of encephalitis. Anti N-methyl-d-aspartate receptor encephalitis has now become the most frequent autoimmune disorder associated with ovarian teratoma. [Copyright &y& Elsevier]

Abstract: MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression at the post-transcriptional level. The function of miRNA is the control of protein production by targeting mRNAs for translational repression or degradation. MiRNAs play a critical role in many biological processes such as cellular proliferation and maturation, apoptosis, regulation of chronic inflammation and development of cancer. It has recently been discovered that miRNAs are differentially expressed in autoimmune diseases (AID) and miRNA regulation may impact in the development or prevention of AID. In this paper we review the importance of miRNAs in AID in particular in inflammatory bowel disease (IBD). IBD is an AID whose pathophysiology remains uncertain. It is generally hypothesized that IBD is caused by the enteric microflora in genetically predisposed patients with an immune dysregulation in the gastrointestinal tract. Knowing the typical miRNA pattern of IBD will improve our knowledge of the pathogenesis of this disease and will lead to future well-focused projects to study the regulatory function of such miRNAs. Furthermore, it is possible that some miRNAs are specific to IBD and could serve as biomarkers with clinical applications for the diagnosis or assessment of disease activity. [Copyright &y& Elsevier]

Abstract: Osteonecrosis is a serious condition involving bone destruction that frequently requires surgical treatment to rebuild the joint. While there is an abundance of literature documenting corticosteroid related osteonecrosis, there is no consensus as to the relative risk of osteonecrosis after administration of steroids via parenteral, oral, topical, inhaled and other routes. This risk is an important prognostic indicator because identification and conservative intervention can potentially reduce morbidity associated with aggressive surgical treatment of osteonecrosis. This paper provides insight into establishing guidelines related to the risk of developing osteonecrosis as a result of corticosteroid use. Case studies, retrospective studies and prospective studies in humans on different corticosteroids and varied dosages were assessed. Most cases of osteonecrosis are secondary to systemically administered corticosteroids and/or high dose daily therapy, particularly in patients with underlying comorbidities including connective tissue diseases, hyperlipidemia, or previous trauma. Previous case reports of osteonecrosis related to inhaled or topical use of steroids are complicated by the fact that in the great majority of cases, the patients are also treated with systemic steroids prior to the development of osteonecrosis. Based on the literature, a set of recommendations regarding the risk of osteonecrosis in patients on steroids was formulated. [Copyright &y& Elsevier]

During the past few years technological advance have been allowed the developing of techniques that help to the diagnosis of multiple diseases. In the case of the autoimmune diseases, immunological techniques are helpful since they allow the detection of multiple autoantibodies at the same time with small volumes of sample. Together with the development of the new techniques, sensitivity and specificity in the detection of the antibodies specificities' also have been increased, in such a way that the clinicians can count with tests that allow them to make early diagnoses with greater certainty and also to follow the course of the disease based on the variation of the antibodies presents in the patient's samples. It is important to emphasize that the new techniques of laboratory that are used for the support of the diagnosis of autoimmune diseases, no longer are exclusive for research laboratories but by their facility of standardization, quality control and reproducibility they can be used in clinical laboratory of medium and small sizes. In the present paper we describe those techniques with greater application in the clinical laboratory of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Abstract : Type I Interferon (IFN-α/β) therapy has altered the natural course of multiple sclerosis. In this paper we evaluate the possible molecular mechanisms involved in the in vitro effects of IFN-α/β on peripheral blood mononuclear cells from patients with clinically definite Relapsing-Remitting Multiple Sclerosis. The total RNA from IFN-α, IFN-β treated cells and untreated cells was extracted and amplified for CD86, CD28, CTLA-4, TNF-α, IFN-γ, CCL2, CCR5, IL-13, MMP-9, TIMP-1, CD25, TGF-β, IL-10 and the transcriptional factor Foxp3 by Reverse Transcription–Polymerase Chain Reaction and the CD4+CD25high subset was evaluated using flow cytometry. In general, there were no significant differences concerning the modulation of the genes studied in the response to IFN-α and IFN-β treatments, which suggest a similar mechanism of action for both interferons. However, we found a significant increment in IFN-γ expression after IFN-α but not after IFN-β treatments. The in vitro treatment of mononuclear cells from multiple sclerosis patients with both interferons significantly increased the CD25 mRNA. Furthermore, we observed a CD25/Foxp3 correlation and an increment of the CD4+CD25high subset, indicating that the induction of regulatory T cells could be a crucial mechanism involved in the type I interferon effects. [Copyright &y& Elsevier]

Abstract: Medical conditions with known etiology and typical peripartal/postpartal disease exacerbations are now, without exception, considered autoimmune in etiology. Postpartum psychiatric conditions, and especially postpartum depression, currently, however, are still not understood in their etiology. This paper suggests that the typical postpartum flare pattern, and other clinical characteristics, point towards an autoimmune etiology for (postpartum) depression. The high prevalence of (postpartum) depression led to its designation as a major public health problem. A better understanding of etiology and pathophysiology would greatly advance the, currently still inaccurate, diagnosis of the condition, and improve approaches towards prevention and treatment. [Copyright &y& Elsevier]

Abstract: We cloned the SLAM associated protein (SAP) gene in 1995. In 1998, it was discovered that the SAP gene was defective in patients with X-linked lymphoproliferative disease. Subsequently, details on the key role of life-long immune memory (vaccination) and of life-long autoantibody production in patients suffering from autoimmune disease have been revealed. In this paper, we discuss the dual nature of SAP in humans: its beneficial effect on life-long immune memory (vaccination) and its harmful effect on life-long autoantibody production. [Copyright &y& Elsevier]

Abstract: The pathogenesis of diffuse connective tissue diseases (DCTD) is still unknown and has been extensively studied regarding its autoimmunity aspects related to extracellular matrix (ECM) remodelling, with an emphasis on the collagens at the inflammatory site. The present paper describes the pulmonary architectural and repair/remodelling responses to injury after immunization of rabbits with human type V collagen. The animal model consisted of rabbits immunized with collagen mixed with Freund''s adjuvant and sacrificed 7, 15, 30, 75, and 120 days after the first of four doses of antigen. Pulmonary architecture remodelling response was evaluated by histology, morphometry, and the immunofluorescence method, according to compartments of reference (parenchyma and interstitium) and injury: 1—inflammation (polymorphonuclear and mononuclear cells); 2—repair (fibrosis) and 3—ECM remodelling (collagen system). The results showed an intense inflammatory involvement of the pulmonary vascular and bronchiolar parenchyma, characterized by increased wall thickness in small arteries, infiltrations by pseudoeosinophils, and mononuclear cells. Progressive remodelling of the pulmonary ECM was characterized by collagen deposition in the septal and bronchovascular interstitium, especially in rabbits sacrifices at 75 and 120 days. The ECM remodelling process was not reproduced when rabbits were inoculated with collagen types I and III. We conclude that the model reproduces morphologic changes similar to those observed in many DCTD, encouraging realization of other experiments to gain a better understanding of the pathogenesis of these diseases. [Copyright &y& Elsevier]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. We examined molecular events involved in the initiation of autoimmune response in MS. Recent studies in our laboratory have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS. This paper provides insights into the physiologic and pathologic role of autoreactive T-cells, and characterizes structurally and functionally the specific targets for new therapies of MS. [Copyright &y& Elsevier]

Recently, Fc receptors for immunoglobulins moved further into the focus of pure and applied research as a role in the induction and development of autoimmune diseases and allergies is becoming more probable. Indeed by connecting the humoral with the cellular immune response FcRs possess an important role in the immune system in which the initial, crucial step is the binding of an immunoglobulin to the cell bound receptor. Thereafter a variety of effector functions depending on the cell and the receptor is triggered. This key event could recently be visualised with the solution of the crystal structure of a human Fc receptor in complex with its native ligand the Fc fragment of IgG1. In this paper the reasons for a 1:1 stoichiometry between Fc receptor and Fc Fragment and the medical applications of potential inhibitors of complex formation are highlighted. [Copyright &y& Elsevier]

Background: Although previous studies have examined the impact of curcumin supplementation on cytokine levels in patients with autoimmune disorders, we were unable to find a systematic review of the effect of curcumin supplementation on inflammatory biomarkers such as CRP and ESR in patients with rheumatoid arthritis or ulcerative colitis; therefore we conducted this systematic review and meta-analysis.Methods: Relevant studies published from inception to December 2020 were systematically searched through the PubMed, SCOPUS, and google scholar databases. We conducted our systematic review and meta-analysis according to the 2020 PRISMA guidelines. The quality of the papers were assessed by using the Cochrane Collaboration's risk of bias tool. Included studies were randomized clinical trials on the effects of supplementation with curcumin or its derivative on inflammatory factors in patients with rheumatoid arthritis and ulcerative colitis. Pooled effect sizes were calculated using a random-effects model and reported as the weighted mean difference (WMD) and 95 % CI.Results: In all, six studies met the inclusion criteria for this study. Curcumin supplementation in doses of 250-1500 mg/day over 8-12 weeks was observed to be associated with decreases in CRP and ESR in adult patients with rheumatoid arthritis and ulcerative colitis in comparison with the control group (WMD: -0.42; 95 % CI: -0.59, -0.26, I2 = 94.3 %; WMD: -55.96; 95 % CI: -93.74, -18.17, I2 = 99.7 %, respectively). Significant findings were also observed based on subgroup analyses by the study sample size, duration, participants' age, curcumin dosage, and type of disease.Conclusions: Curcumin supplementation was associated with significant reductions in levels of CRP and ESR in patients with rheumatoid arthritis and ulcerative colitis. Earlier studies reported curcumin as a safe complementary therapy for several diseases. However, a handful of studies were found on the effect of curcumin on autoimmune diseases despite our comprehensive search. Further studies are therefore warranted in this area. [ABSTRACT FROM AUTHOR]

Abstract: Regulatory T cells (Tregs) are subsets of T cells that are specifically dedicated to controlling immune responses. It has been established that Tregs play a key role in regulating autoimmune disease, allergy, cancer, infectious disease, and in the induction of transplantation tolerance. The latest progress in the development, function, mechanism of action, and homeostasis of regulatory T cells, and their translation to the clinic were presented at the International Conference on Regulatory T Cells and Clinical Application in Human Diseases in Beijing on 25–27 October 2008 (China Tregs 2008). In this Special Issue of International Immunopharmacology, several papers submitted to the China Tregs 2008 will highlight some of the recent advances in the biology of regulatory T cells and current strategies to translate regulatory T cells into the clinic. [Copyright &y& Elsevier]

In this paper, we consider dynamics and bifurcations in two HIV models with cell-to-cell interaction. The difference between the two models lies in the inclusion or omission of the effect of involvement. Particular attention is focused on the effects due to the cell-to-cell transmission and the effect of the involvement. We investigate the local and global stability of equilibria of the two models and give a comparison. We derive the existence condition for Hopf bifurcation and prove no Bogdanov-Takens bifurcation in this system. In particular, we show that the system exhibits the recurrence phenomenon, yielding complex dynamical behavior. It is also shown that the effect of the involvement is the main cause of the periodic symptoms in HIV or malaria disease. Moreover, it is shown that the increase of cell-to-cell interaction may be the main factor causing Hopf bifurcation to disappear, and thus eliminating oscillation behavior. Finally, numerical simulations are present to demonstrate our theoretical results. [ABSTRACT FROM AUTHOR]

Autoimmune disorders are a spectrum of diseases caused by impaired self-tolerance of the immune system. Previous studies underscored the association between autoimmune disorders and lymphomas. However, only a few papers studied the exact mechanisms of this association. The effect of IL-2, IL-5, IL-6, IL-10 and TNF-α, contribution of NOTCH, FAS and MHC receptor families, the interplay of various immune cells, and the relation of immunosuppressive agents and development of autoimmune disorders are the proposed mechanisms for this association. Each individual autoimmune disorder associates with particular types of lymphomas and their common pathways are not necessarily similar to other pairs of autoimmune disorder-lymphomas. Thus, the lymphomas susceptibility in various autoimmune disorders could not be investigated through a single pathway. In this review, we demonstrate the association between each pair of autoimmune disorder-lymphoma and the underlying pathways. By clarifying these associations, follow-up plans could be made leading to early diagnosis of lymphomas. [ABSTRACT FROM AUTHOR]

Chronic myelomonocytic leukemia (CMML) is a clonal disorder that is associated with a wide range of systemic inflammatory and autoimmune diseases (SIADs). Approximately 20% of patients with CMML will have an associated SIAD and recognizing this association is critical to the evaluation, prognostication and management of patients with CMML. In this paper, we review the evidence supporting a causative link between these two entities as well as the direction of this relationship. We argue that the data favors CMML as the antecedent and causative disease state with a few notable exceptions. Better understanding of this relationship aids clinicians in the education of their patients and in determining the optimal management approach at the bedside. It is important to recognize opportunities to harmonize the treatments of these disease processes, which may enhance the effectiveness of treatment while reducing the burden of adverse effects from redundant therapies. [ABSTRACT FROM AUTHOR]

Inhibition of the nuclear receptor Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a promising strategy for the treatment of autoimmune diseases. In this paper, we describe a series of allosteric, cysteine-dependent, inverse agonists of RORγt. Site-directed mutagenesis and molecular dynamics simulations are supportive of a mechanism of action through specific binding to Cys476 on alpha helix 11 of the ligand binding domain (LBD). Representative compounds in the series selectively inhibit RORγt, potently suppress interleukin-17A (IL-17A) production by human CD4+ T cells, and inhibit T helper 17 (Th17) differentiation from human naïve CD4+ T cells. The advanced compound 13 is orally bioavailable and active at a dose of 3 mg/kg in a murine collagen-induced model of rheumatoid arthritis. Collectively, these data are supportive of the development of compound 13 in autoimmune diseases. [ABSTRACT FROM AUTHOR]