Treatment Of Several Autoimmune Diseases Research Articles

Optimal Weight-based Dosing of Intravenous Immunoglobulin (IVIG) among Overweight and Obese Patients

Background: Intravenous immunoglobulin (IVIG), as an expensive medication under a national shortage, has been widely used for the treatment of several autoimmune diseases and immunodeficiency syndromes. Although conducting studies on therapeutic indications of IVIG has increased significantly, a limited number of researches have investigated individualized dosing in terms of the drug, disease state, and some patient-specific factors like obesity. Objective: The objective of the review was to describe the impact of various weight-based dosing regimens on the pharmacokinetics parameters, efficacy, safety, and cost of IVIG and to choose the best dosing approach for obese patients. Methods and Results: Thirteen of the total 128 manuscripts collected, reviewed, and analyzed were found from Scopus, PubMed, and Google scholar. Discussion: The evidence suggests that obesity may have an impact on IVIG pharmacokinetics, safety, and efficacy. Conclusion: The logical approach is to initial the dose based on the ideal or adjusted body weight and then modify the maintenance dose according to the patient's clinical response.

The Metabolism and Disposition of Brepocitinib in Humans and Characterization of the Formation Mechanism of an Aminopyridine Metabolite.

<s><s></s></s> Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine kinase 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance and metabolic profiles were determined using accelerator mass spectrometry in six healthy male participants following a single oral 60 mg dose of 14C-brepocitinib (~300 nCi). The average mass balance recovery was 96.7% {plus minus} 6.3% with the majority of dose (88.0% {plus minus} 8.0%) recovered in urine and 8.7% {plus minus} 2.1% of the dose in recovered in feces. Absorption of brepocitinib was rapid, with maximal plasma concentrations of total radioactivity and brepocitinib achieved within 0.5 hours after dosing. Circulating radioactivity consisted primarily of brepocitinib (47.8%) and metabolite M1 (37.1%) derived from hydroxylation at the C5' position of the pyrazole ring. Fractional contributions to metabolism via cytochrome P450 (CYP) enzymes were determined to be 0.77 for CYP3A4/5 and 0.14 for CYP1A2 based on phenotyping studies in HLM. However, additional clinical studies are required to understand the potential contribution of CYP1A1. Approximately 83% of the dose was eliminated as N-methylpyrazolyl oxidative metabolites, with 52.1% of the dose excreted as M1 alone. Notably, M1 was not observed as a circulating metabolite in earlier metabolic profiling of human plasma from a multiple ascending study with unlabeled brepocitinib. Mechanistic studies revealed M1 was highly unstable in human plasma and phosphate buffer, undergoing chemical oxidation leading to loss of the 5-hydroxy-1-methylpyrazole moiety and formation of aminopyrimidine cleavage product M2. Time dependent inhibition and trapping studies with M1 yielded insights into the mechanism of this unusual and unexpected instability. Significance Statement This work describes the mass balance and metabolic profile of brepocitinib in human, a JAK1/TYK2 inhibitor being developed for treatment of autoimmune diseases.

Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study

Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production. In a placebo-controlled clinical study, these same endpoints were evaluated in healthy volunteers that were treated with a cumulative dose of 2400 mg HCQ over 5 days. In vitro, HCQ inhibited TLR responses with IC50s > 100 ng/mL and reaching 100% inhibition. In the clinical study, maximal HCQ plasma concentrations ranged from 75 to 200 ng/mL. No ex vivo HCQ effects were found on RIG-I-mediated cytokine release, but there was significant suppression of TLR7 responses and mild suppression of TLR3 and TLR9 responses. Moreover, HCQ treatment did not affect B cell and T cell proliferation. These investigations show that HCQ has clear immunosuppressive effects on human PBMCs, but the effective concentrations exceed the circulating HCQ concentrations under conventional clinical use. Of note, based on HCQ’s physicochemical properties, tissue drug concentrations may be higher, potentially resulting in significant local immunosuppression. This trial is registered in the International Clinical Trials Registry Platform (ICTRP) under study number NL8726.

Role of Vitamin D in Celiac Disease and Inflammatory Bowel Diseases

Vitamin D (VD) is a pro-hormone that has long been known as a key regulator of calcium homeostasis and bone health in both children and adults. In recent years, studies have shown that VD may exert many extra-skeletal functions, mainly through a relevant modulation of the innate and adaptive immune system. This has suggested that VD could play a fundamental role in conditioning development, clinical course, and treatment of several autoimmune disorders, including celiac disease (CD) and inflammatory bowel diseases (IBDs). The main aim of this review is to evaluate the relationships between VD, CD, and IBDs. Literature analysis showed a potential impact of VD on CD and IBDs can be reasonably assumed based on the well-documented in vitro and in vivo VD activities on the gastrointestinal tract and the immune system. The evidence that VD can preserve intestinal mucosa from chemical and immunological damage and that VD modulation of the immune system functions can contrast the mechanisms that lead to the intestinal modifications characteristic of gastrointestinal autoimmune diseases has suggested that VD could play a role in controlling both the development and the course of CD and IBDs. Administration of VD in already diagnosed CD and IBD cases has not always significantly modified disease course. However, despite these relevant problems, most of the experts recommend monitoring of VD levels in patients with CD and IBDs and administration of supplements in patients with hypovitaminosis.

Design of Novel IRAK4 Inhibitors Using Molecular Docking, Dynamics Simulation and 3D-QSAR Studies.

Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate and/or adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serine/threonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation. MyD88 gain-of-function mutations or overexpression of IRAK4 has been implicated in various types of malignancies such as Waldenström macroglobulinemia, B cell lymphoma, colorectal cancer, pancreatic ductal adenocarcinoma, breast cancer, etc. Moreover, over activation of IRAK4 is also associated with several autoimmune diseases. The significant role of IRAK4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. Nevertheless, there is still a need of selective inhibitors for the treatment of cancer and various autoimmune diseases. A great need for the same intrigued us to perform molecular modeling studies on 4,6-diaminonicotinamide derivatives as IRAK4 inhibitors. We performed molecular docking and dynamics simulation of 50 ns for one of the most active compounds of the dataset. We also carried out MM-PBSA binding free energy calculation to identify the active site residues, interactions of which are contributing to the total binding energy. The final 50 ns conformation of the most active compound was selected to perform dataset alignment in a 3D-QSAR study. Generated RF-CoMFA (q2 = 0.751, ONC = 4, r2 = 0.911) model revealed reasonable statistical results. Overall results of molecular dynamics simulation, MM-PBSA binding free energy calculation and RF-CoMFA model revealed important active site residues of IRAK4 and necessary structural properties of ligand to design more potent IRAK4 inhibitors. We designed few IRAK4 inhibitors based on these results, which possessed higher activity (predicted pIC50) than the most active compounds of the dataset selected for this study. Moreover, ADMET properties of these inhibitors revealed promising results and need to be validated using experimental studies.

Elaeocarpus sylvestris extract (ESE) inhibits inflammatory mediators and increases the efficacy of sulfasalazine in rheumatoid arthritis

BackgroundInterest in plant-based therapeutic products for treatment of several autoimmune diseases, including rheumatoid arthritis (RA), is increasing as current RA medications and treatments are either very expensive or ineffective. PurposeWe investigated the anti-inflammatory activity of Elaeocarpus sylvestris extract (ESE) and its therapeutic potential in collagen-induced arthritis (CIA) in the DBA/1 J mouse model and an in vitro model. MethodsIn the in vitro assay, the effects of ESE and a combination of ESE + sulfasalazine (SLZN) on nitric oxide and proinflammatory cytokine expression induced by lipopolysaccharide in RAW264.7 cells were confirmed. Furthermore, enzyme-linked immunosorbent assays and real-time polymerase chain reactions were used to measure levels of RA-related inflammatory cytokines and biomarkers in serum and knee joints to evaluate the changes caused by co-administration of ESE and SLZN in our mouse CIA model. Micro-CT scans of knee joints were analyzed for all groups. ResultsESE and the combination of ESE + SLZN downregulated the expression of lipopolysaccharide-induced nitric oxide and proinflammatory cytokines in RAW264.7 cells. Also, combined ESE and SLZN treatment improved arthritis score, edema volume, and proinflammatory cytokine serum levels compared with the CIA group. In addition, chemokine expression was downregulated compared with the CIA group. ConclusionThese findings suggest that coadministration of ESE and SLZN can improve the efficacy of arthritis treatment with reduced side effects.

Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells.

RORγt is an isoform of RORC, preferentially expressed in Th17 cells, that functions as a critical regulator of type 3 immunity. As murine Th17-driven inflammatory disease models were greatly diminished in RORC knock-out mice, this receptor was prioritised as an attractive therapeutic target for the treatment of several autoimmune diseases. Human genetic studies indicate a significant contributory role for RORC in several human disease conditions. Furthermore, genome-wide association studies (GWAS) report a significant association between inflammatory bowel disease (IBD) and the RORC regulatory variant rs4845604. To investigate if the rs4845604 variant may affect CD4+ T cell differentiation events, naïve CD4+ T cells were isolated from eighteen healthy subjects homozygous for the rs4845604 minor (A) or major (G) allele). Isolated cells from each subject were differentiated into distinct T cell lineages by culturing in either T cell maintenance medium or Th17 driving medium conditions for six days in the presence of an RORC inverse agonist (to prevent constitutive receptor activity) or an inactive diastereomer (control). Our proof of concept study indicated that genotype had no significant effect on the mean number of naïve CD4 T cells isolated, nor the frequency of Th1-like and Th17-like cells following six days of culture in any of the four culture conditions. Analysis of the derived RNA-seq count data identified genotype-driven transcriptional effects in each of the four culture conditions. Subsequent pathway enrichment analysis of these profiles reported perturbation of metabolic signalling networks, with the potential to affect the cellular detoxification response. This investigation reveals that rs4845604 genotype is associated with transcriptional effects in CD4+ T cells that may perturb immune and metabolic pathways. Most significantly, the rs4845604 GG, IBD risk associated, genotype may be associated with a differential detoxification response. This observation justifies further investigation in a larger cohort of both healthy and IBD-affected individuals.

Dimethyl fumarate inhibits antibody-induced platelet destruction in immune thrombocytopenia mouse

BackgroundImmune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. However, whether it ameliorates ITP is unclear. This study aims to evaluate whether DMF has a preventive effect on ITP in mice.MethodsDMF (30, 60 or 90 mg/kg body weight) was intraperitoneally injected into mice followed by injection of rat anti-mouse integrin GPIIb/CD41antibody to induce ITP. Peripheral blood was isolated to measure platelet count and spleen mononuclear cells were extracted to measure Th1 and Treg cells along with detecting the levels of IFN-γ, and TGFβ-1 in plasma and CD68 expression in spleen by immuohistochemical staining. Additionally, macrophage cell line RAW264.7 was cultured and treated with DMF followed by analysis of cell apoptosis and cycle, and the expression of FcγRI, FcγRIIb and FcγRIV mRNA.ResultsDMF significantly inhibited antiplatelet antibody-induced platelet destruction, decreased Th1 cells and the expression of T-bet and IFN-γ, upregulated Treg cells and the expression of Foxp3 and TGF-β1 as well as reduced CD68 expression in the spleen of ITP mouse. DMF-treated RAW264.7 cells showed S-phase arrest, increased apoptosis and downregulated expression of FcγRI and FcγRIV. Meanwhile, in vitro treatment of DMF also decreased the expression of cyclin D1 and E2, reduced Bcl-2 level and increased Bax expression and caspase-3 activation.ConclusionsIn conclusion, DMF prevents antibody-mediated platelet destruction in ITP mice possibly through promoting apoptosis, indicating that it might be used as a new approach for the treatment of ITP.

Homogeneous Immunoassay Using a Tri-Part Split-Luciferase for Rapid Quantification of Anti-TNF Therapeutic Antibodies.

Anti-TNF therapeutics bind and sequester tumor necrosis factor (TNF) to prevent downstream signaling and are clinically important in the treatment of several autoimmune diseases. Effective treatment with these drugs requires frequent therapeutic drug monitoring (TDM). Current analytical methods, including reporter gene assay (RGA), enzyme-linked immunosorbent assay (ELISA), and mobility shift assay (MSA), can be technically rigorous, slow, and expensive. These qualities prevent the implementation of point-of-care testing and ultimately limit the frequency and utility of monitoring. An assay simple enough to be performed in the clinic would enable increased TDM frequency, more accurate dosing, and improved patient outcomes. Toward this end, we developed a homogeneous immunoassay based on a tri-part split-luciferase system for "add-and-read" detection of anti-TNF therapeutics. In our platform, two small fragments of the split-luciferase, called β9 and β10, are each fused to a different interacting protein. The binding of each of these proteins to anti-TNF antibodies forces the split-luciferase components into proximity where they reform the active luciferase. We identified the fusion proteins, β9-protein A (β9-A) and β10-TNF, as promising binding pairs. We systematically adjusted assay conditions to optimize the signal/background (S/B) ratio, limit of detection (LOD), and percent recovery. The assay has a large dynamic range (0.5-32 μg/mL) and is sensitive enough to monitor both subtherapeutic and supratherapeutic serum concentrations of anti-TNF antibodies, as demonstrated in clinical samples.

Quantitative Mass Spectrometry Imaging to Study Drug Distribution in the Intestine Following Oral Dosing.

Local delivery to the lower gut to treat diseases of the colon has become a topic of special attention. Tissue exposure of locally acting agents is not represented by plasma concentrations. Therefore, reliable methods to measure tissue uptake at the primary site of action (e.g., epithelial layer or lamina propria) are vital. This work investigates the suitability of mass spectrometry imaging (MSI) in quantitatively visualizing intestinal transmural drug distribution. Tofacitinib (Tofa), a drug approved for the treatment of several autoimmune diseases, including ulcerative colitis, was selected as a tool compound for feasibility studies. One- and 7-h postdose sections of the ileum, proximal- and distal-colon from rats that received an oral solution of Tofa were subjected to matrix-assisted laser desorption ionization (MALDI)-MSI. A dilution series of individual concentrations sprayed over an entire tissue section allowed for tissue type-specific quantitation. At 1 h (systemic Tmax), the signal was highest in the ileum, whereas at 7 h, the signal was highest in the colon, when the unabsorbed fraction of the compound reached the colon. A combination of three-dimensional (3D) intensity plots and hematoxylin and eosin (H&E) stains showed a visually observable gradual decrease in Tofa concentration from the lumen toward the muscular layer of the proximal colon. The high luminal concentration of Tofa indicated that flushing of the intestines with saline does not result in complete removal of the drug material from the lumen. This could cause an overestimation of drug concentration in gut tissue homogenates by conventional liquid chromatography-mass spectrometry (LC-MS) methods. This study demonstrates the utility of MSI to differentiate between the lumen and intestinal wall layers and enables proper interpretation of tissue distribution data.

Measuring atropisomers of BMS-986142 using 2DLC as an enabling technology

BMS-986142 has been developed as an innovative Bruton’s tyrosine kinase inhibitor for treatment of several autoimmune diseases. The drug substance of BMS-986142 may contain three potential atropisomeric impurities due to its unique structural characteristics. Developing a single liquid chromatography (LC) method to separate all four highly structurally related atropisomers and other process impurities from each other turned out to be a daunting task. Two-dimensional LC (2DLC) was found to be an extremely powerful enabling technology for extracting purity information out of the complex sample impurity profile and facilitated process development before a final single dimension method was discovered. The off-the-shelf 2DLC instrument could be configured to allow injection of the targeted first dimension peak through either no-loss multiple heart-cutting fractions or as a large, single volume fraction with on-line dilution. Excellent precision (relative standard deviation of 0.3 %) and recovery (101.2 ± 0.2 %) was achieved for an atropisomer impurity at a 10 % monitoring level in the first configuration with sensitivity down to 0.2 % w/w. With the second instrument configuration, which eliminated the need for fraction recombination, similar figures of merit were maintained for the second dimension at the cost of losing the ability to collect and park multiple fractions.

The immunomodulatory effects of mesenchymal stromal cell-based therapy in human and animal models of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune inflammatory disease with no absolute cure. Although the exact etiopathogenesis of SLE is still enigmatic, it has been well demonstrated that a combination of genetic predisposition and environmental factors trigger a disturbance in immune responses and thereby participate in the development of this condition. Almost all available therapeutic strategies in SLE are primarily based on the administration of immunosuppressive drugs and are not curative. Mesenchymal stromal cells (MSCs) are a subset of non-hematopoietic adult stem cells that can be isolated from many adult tissues and are increasingly recognized as immune response modulating agents. MSC-mediated inhibition of immune responses is a complex mechanism that involves almost every aspect of the immune response. MSCs suppress the maturation of antigen-presenting cells (DC and MQ), proliferation of T cells (Th1, T17, and Th2), proliferation and immunoglobulin production of B cells, the cytotoxic activity of CTL and NK cells in addition to increasing regulatory cytokines (TGF-β and IL10), and decreasing inflammatory cytokines (IL17, INF-ϒ, TNF-α, and IL12) levels. MSCs have shown encouraging results in the treatment of several autoimmune diseases, in particular SLE. This report aims to review the beneficial and therapeutic properties of MSCs; it also focuses on the results of animal model studies, preclinical studies, and clinical trials of MSC therapy in SLE from the immunoregulatory aspect.

Vitamin D and psoriasis: an update for dermatologists and nutritionists.

Psoriasis is a common chronic immune-mediated inflammatory skin disease, now considered a systemic inflammatory process with several comorbidities. The skin produces vitamin D by the action of ultraviolet light. Vitamin D performs various immunomodulatory, anti-inflammatory, antioxidant and antifibrotic actions. The immunomodulatory effects of vitamin D offer opportunities to improve the treatment of several autoimmune diseases, such as psoriasis. In the literature, several significant associations are reported between low levels of vitamin D and psoriasis. Today, topical vitamin D represents an important therapeutic option due to its action on the proliferation and maturation of keratinocytes. The situation is different regarding the oral intake and integration of vitamin D in psoriasis patients. The use of vitamin D supplementation as an adjunctive treatment option in these patients is still discussed. This work aims to analyze the association between psoriasis and vitamin D levels according to dermatologists and nutritionists.

CXCR3 antagonist AMG487 inhibits glucocorticoid-induced tumor necrosis factor-receptor-related protein and inflammatory mediators in CD45 expressing cells in collagen-induced arthritis mouse model

Rheumatoid arthritis (RA) is an autoimmune disease classified by uncontrolled joint inflammation leading to the destruction of both cartilage and joints. Despite progress made in RA treatment in the past decade, new drugs with high efficacy and fewer long-term adverse effects are still needed; thus, safe anti-inflammatory therapies for RA are urgently needed. Previous results demonstrated that the CXCR3 antagonist is an extremely attractive therapeutic target for the treatment of several autoimmune diseases, suggesting that it might have an inhibitory effect on RA. In this study, we investigated the effect of AMG487, a selective CXCR3 antagonist, on collagen-induced arthritis (CIA) in mice and evaluated its potential therapeutic mechanism.Following induction of CIA, mice were treated with AMG487 (5 mg/kg, intraperitoneally), to investigate their protective effects against CIA. CD4, CD25, CCR6, IL-9, NF-κB, IL-6, IL-17A, IL-21, STAT6 and Foxp3 expressing GITR+ and CD45+ cells were measured in the spleen using flow cytometry to assess anti-inflammatory effects of AMG487. The mRNA and protein expression of GITR, CCR6, IL-9, and IL-21 were measured using quantitative real-time PCR and western blot analysis in knee tissue. AMG487 significantly alleviated joint inflammation by decreasing GITR+CD25+, GITR+CD45+, GITR+IL-9+, GITR+NF-κB+ CD45+CD4+, CD45+CCR6+, CD45+IL-6+ cells, CD45+IL-17A+, and CD45+IL-21+, and increasing GITR+Foxp3+ and GITR+STAT6+ cells. There was a significant decrease in mRNA and protein expression of GITR, CD4, CCR6, IL-6, IL-9, and IL-21 in knee tissue of CIA mice. This study demonstrates that AMG487 has a potential therapeutic effect on RA and could explore novel anti-inflammatory therapies for its treatment.

Pulmonary Adverse Events of Small Molecule Tyrosine Kinase Inhibitors: Meta-Analysis and Systematic Review

Background Small molecule tyrosine kinase inhibitors (smTKI) are signalling molecules, which modulate the cytokine receptor-mediated intracellular signal cascade, and is an effective treatment for several autoimmune diseases and malignancies. As smTKI are novel, long-term safety is uncertain. Commonly reported side effects include infections, typically pulmonary and herpes zoster. As published data mainly examines tofacitinib trials, the class effect of smTKI is unknown. Methods We performed a meta-analysis of all published trial data on the pulmonary adverse effects of smTKIs. EMBASE, MEDLINE, and CENTRAL databases were searched up to September 2018 for randomized controlled trials, observational studies, case reports, and post marketing surveillance, comparing any smTKI with placebo or another therapy, or as monotherapy at different doses. Primary outcomes comprised of any respiratory complications including upper and lower respiratory tract infections, influenza, opportunistic respiratory infections, pneumonia, interstitial pneumonitis, pulmonary embolism, and lung neoplasm. Findings We identified 2253 citations for screening, and selected 150 for full text review. Seventy-five studies were analyzed, including 49 RCTs, 16 observational studies, three case reports, and seven post-marketing surveillance studies, comprising 153,942 participants. Median duration of RCTs was 24 weeks. The overall risk of any pulmonary adverse event with smTKI is low across RCTs and observational studies. There was significantly increased risk of developing upper respiratory tract infections (URTI) (RD 0·03, 95% CI 0·02 to 0·04, p<0·00001, 36 trials, 16419 participants), pneumonia (RD 0·0032; 95% CI 0·0003 to 0·0060, p=0·03, 31 trials, 15001 participants) and influenza (RD 0·0078; 95% CI 0·0031, 0·0126; p=0·001, 5 trials, 16395 participants) after smTKI exposure. No significantly increased risk was found for other respiratory complications. Interpretation SmTKI increases risk of URTI, pneumonia and influenza compared with placebo or conventional agents. The risk of any pulmonary adverse event with smTKI is low. Funding Nil

1171 National Burden of Gastrointestinal Tuberculosis: Insights From the Nationwide Inpatient Sample

INTRODUCTION: Gastrointestinal tuberculosis (GI TB) is a rare and morbid extrapulmonary manifestation of TB. There is scant published data regarding the prevalence of GI TB. ThE aim of our study was to assess the overall burden of inpatient GI TB in the United States. We also looked at demographic characteristics, comorbidities and all-cause inpatient mortality among patients with GI TB. METHODS: All adults hospitalized with the diagnosis of either gastric TB or intestinal TB or both, during the years 2010 to 2014, were identified using the Nationwide Inpatient Sample (NIS). Patients with tuberculous associated peritonitis were also included. We studied racial, regional and gender-specific characteristics of these patients. Other demographic data such as risk factors and comorbidities were also identified. Outcomes of interest included inpatient mortality and length of stay. RESULTS: During the five-year study period, there were a total of 2,300 inpatient hospital admissions for GI TB. We observed a downward trend in the prevalence of GI TB in the US during this time (469 vs 340 vs 380 vs 329 vs 78; P = 0.56) (Figure 1). Patients affected were predominantly Hispanic (36.04% vs 53.99% vs 24.78% vs 30.17%; P = 0.002) in all four regions. Several other comorbidities and conditions were identified as enlisted in Table 1. The overall inpatient mortality (6.25% vs 1.20% vs 2.61% vs 3.24%; P = 0.206) and mean length of stay (18.11 vs 9.07 vs 10.56 vs 14.57 days; P = 0.001) were highest in the NE region as compared to MW, SO and WE regions. In addition, hospitalized patients with GI TB were less likely to be female in Northeastern (NE) states (30.91% vs 56.29% vs 51.64% vs 50.64%; P = 0.05) as compared to Midwest (MW), Southern (SO) and Western (WE) states. CONCLUSION: Since the introduction of antituberculous therapy, the global and national overall burden of GI TB has decreased significantly. It is, however, important to note that although rare, GI TB continue to affect high-risk patient populations such as immigrants, prisoners, HIV patients and patients who are immunocompromised from receiving various biologic agents for treatment of several autoimmune diseases. Our study shows that although prevalent, overall inpatient admissions associated with GI TB have been decreasing over the last few years; however they are associated with high mortality. Our study highlights continued prevalence of GI TB amongst inpatients in the US, and emphasizes the importance of clinical suspicion when evaluating high risk patients.

Immunosupressive means: study of assortment and consumption in Ukraine

Immunosuppressive drugs (immunosuppressants) are drugs of various pharmacological and chemical groups suppressing immunological reactions in the body. Immunosuppressants are prescribed for the treatment of severe autoimmune diseases and inhibition of the graft rejection reaction.Aim. To study the range and consumption of immunosuppressants on the pharmaceutical market ofUkraine for 2014-2016.Materials and methods. The calculation of immunosuppressants consumption was carried out according to DDDs/1000 inhabitants/day or DID.Results. During 2014-2016 immunosuppressants were represented on the market from 44 to 51 TN based on 14INN predominantly foreign manufacturers (90 %). The vast majority range of immunosuppressants on the market belonged to methotrexate (27-24 %) and cyclosporine (23-20 %). The drugs prices varied in a wide range, but increase every year. The total consumption of drugs was low and amounted to 0.23 DID (2014), 0.33 DID (2015), 0.30 DID (2016), respectively. Methotrexate preparations had the highest consumption volumes, which is associated with their relatively low cost, the availability of generic drugs, proven efficacy in rheumatic and oncological diseases.Conclusions. A sufficient assortment of immunosuppressive agents is presented on the Ukrainian pharmaceutical market. The volume indicators of immunosuppressants consumption are generally rather low, which may be caused by significant cost of this drugs group treatment.

Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes.

Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use. Naltrexone is a reversible competitive antagonist at μ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders. However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response. Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect. Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.

Efficacy of Adding Oral Simvastatin to Topical Therapy for Treatment of Psoriasis: The Vietnamese Experience.

BACKGROUND:Psoriasis, the prevalence of which ranges from 2% to 3% of the general population, has been recently recognised as not only a chronic inflammatory skin disorder but also an immunometabolic systemic disease. Dyslipidemia is one of the most important comorbidities of psoriasis. Statins, frequently used as anti-hyperlipidemic agents, may be beneficial in the treatment of several autoimmune diseases, including psoriasis, due to their anti-inflammatory and immunomodulatory characteristics. Hence, we hypothesised that using this medication was not only beneficial for reducing hyperlipidemia but also improving psoriatic conditions.AIM:We conducted a study to determine the prevalence of dyslipidemia in psoriatic patients as well as whether the addition of statins (simvastatin prescribed forms) to standard topical antipsoriatic treatment can improve skin lesions in psoriatic patients.METHODS:A group of 128 psoriatic patients and 128 healthy controls who were matched with the patients regarding ethnicity, age, and sex were enrolled, and their lipid concentrations were determined. Furthermore, sixty patients were randomly selected from the former group and divided into two treatment subgroups to evaluate the effect of statins on the severity of psoriasis using the PASI score.RESULTS:We found that the rate of dyslipidemia in the patient group was significantly higher than in the healthy group (53.9% versus 21.9%, p < 0.001), particularly the triglyceride concentration (1.86 ± 1.17 versus 1.43 ± 0.79 mg/dL, p < 0.001). Also, the PASI score reduction in the simvastatin-treated subgroup was significantly different from that in the placebo-treated one after eight weeks of therapy (8.63 ± 4.78 versus 5.34 ± 3.59, p < 0.01).CONCLUSION:This study showed that simvastatin might play a role in controlling hyperlipidemia and in turn decrease the PASI score in psoriatic patients.

Mesenchymal Stem Cells in Primary Sjögren's Syndrome: Prospective and Challenges.

Primary Sjögren's syndrome (pSS) is a chronic systemic inflammatory autoimmune disease characterized by lymphocytic infiltrates in exocrine glands. Current approaches do not control harmful autoimmune attacks or prevent irreversible damage and have considerable side effects. Mesenchymal stem cells (MSCs) have been effective in the treatment of several autoimmune diseases. The objective of this review is to illustrate the potential therapeutic role of MSCs in pSS. We summarize the recent advances in what is known about their immunomodulatory function and therapeutic applications in pSS. MSC transfusion can suppress autoimmunity and restore salivary gland secretory function in mouse models and patients with pSS by inducing regulatory T cells, suppressing Th1, Th17, and T follicular helper cell responses. In addition, MSCs can differentiate into salivary epithelial cells, presenting an option as a suitable alternative treatment. We also discuss current bioengineering methods which improve functions of MSCs for pSS. However, there remain many challenges to overcome before their wide clinical application.