Oral delivery of RNAi for cancer therapy.

Cancer is a major health concern worldwide and is still in a continuous surge of seeking for effective treatments. Since the discovery of RNAi and their mechanism of action, it has shown promises in targeted therapy for various diseases including cancer. The ability of RNAi to selectively silence the carcinogenic gene makes them ideal as cancer therapeutics. Oral delivery is the ideal route of administration of drug administration because of its patients' compliance and convenience. However, orally administered RNAi, for instance, siRNA, must cross various extracellular and intracellular biological barriers before it reaches the site of action. It is very challenging and important to keep the siRNA stable until they reach to the targeted site. Harsh pH, thick mucus layer, and nuclease enzyme prevent siRNA to diffuse through the intestinal wall and thereby induce a therapeutic effect. After entering the cell, siRNA is subjected to lysosomal degradation. Over the years, various approaches have been taken into consideration to overcome these challenges for oral RNAi delivery. Therefore, understanding the challenges and recent development is crucial to offer a novel and advanced approach for oral RNAi delivery. Herein, we have summarized the delivery strategies for oral delivery RNAi and recent advancement towards the preclinical stages.

CADHERIN-11 regulation of myeloid phagocytes and autoimmune inflammation in murine lupus.

BACKGROUND AND OBJECTIVE: Understanding the regulation of efferocytosis by myeloid phagocytes is important in identifying novel targets in systemic lupus erythematosus (SLE). Cadherin-11 (CDH11), a cell adhesion molecule, is implicated in inflammatory arthritis and fibrosis and recently been shown to regulate macrophage phagocytosis. The extent and mechanism of this regulation is unknown. Our objective was to examine the extent to which CDH11 regulates myeloid phagocytes and contributes to autoimmunity and tissue inflammation. METHODS: We analyzed efferocytosis in macrophages and dendritic cells (DCs) from WT and Cdh11-/- mice and investigated the mechanisms in vitro. We investigated the role of CDH11 in disease development in vivo using the pristane induced lupus model. To translate the clinical relevance of CDH11 in human disease, we measured serum CDH11 levels in two independent pediatric SLE (pSLE) cohorts and healthy controls. RESULTS: Using bone marrow derived macrophages (BMDMs) and DCs (BMDCs), we found impaired efferocytosis in phagocytes from Cdh11-/- mice, mediated by downregulated efferocytosis receptor expression and RhoGTPase activation. Specifically, loss of CDH11 downregulated Mertk expression and Rac1 activation in BMDMs, and integrin αVß3 expression and Cdc42 activation in BMDCs, highlighting distinct pathways. In vivo, Cdh11-/- mice displayed defective efferocytosis and increased accumulation of apoptotic debris in pristane-induced lupus. Further, Cdh11-/- mice had enhanced systemic inflammation and autoimmune inflammation with increased anti-dsDNA autoantibodies, splenomegaly, type I interferons, and inflammatory cytokines. Paradoxically, at the tissue level, Cdh11-/- mice were protected against glomerulonephritis, indicating a dual role in murine lupus. Finally, SLE patients had increased serum CDH11 compared to controls. CONCLUSION: This study highlights a novel role of CDH11 in regulating myeloid cells and efferocytosis and its potential as a contributor to development in autoimmunity murine lupus. Despite the increase in autoimmunity, Cdh11-/- mice developed decreased tissue inflammation and damage.

Cadherin-11 and Its Role in Tissue Fibrosis.

Fibrosis is the excessive deposition of extracellular matrix that results from chronic inflammation and injury, leading to the loss of tissue integrity and function. Cadherins are important adhesion molecules that classically mediate calcium-dependent cell-to-cell adhesion and play important roles in tissue development and cellular migration but likely have functions beyond these important roles. Cadherin-11 (CDH11), a member of the cadherin family, has been implicated in several pathological processes including cancer. More recent evidence suggests that CDH11 is a central mediator of tissue fibrosis. CDH11 expression is increased in patients with fibrotic diseases such as idiopathic pulmonary fibrosis and systemic sclerosis. CDH11 expression is increased in mouse models of lung, skin, liver, cardiac, renal, and intestinal fibrosis. Targeting CDH11 in murine models of fibrosis clearly demonstrates that CDH11 is a common mediator of fibrosis across multiple tissues. Insight into potential mechanisms at the cellular and molecular level is emerging. In this review, we present the evolving evidence for the involvement of CDH11 in tissue fibrosis. We also discuss some of the proposed mechanisms and highlight the potential of CDH11 as a common therapeutic target and biomarker in different fibrotic pathologies.

The utility of erythrocyte sedimentation rate, C-reactive protein, and procalcitonin in detecting infections in patients with systemic lupus erythematosus: A systematic review.

OBJECTIVES: We conducted a systematic review with metanalysis to investigate the utility of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin (PCT) in diagnosing infections in hospitalized patients with SLE. METHODS: We searched Medline, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) with a search strategy developed by a medical librarian. We included retrospective, cross-sectional, case-control, and prospective studies in our analysis. We used the Quality Assessment of Diagnostic Studies (QUADAS-2) to assess for bias and applicability. We obtained mean differences, sensitivities, and specificities in our analysis. RESULTS: We included 26 studies in our analysis. Most studies had an unclear or high risk of bias and our results were widely heterogenous. For the diagnosis of infections, the CRP had a pooled sensitivity of 0.75 (95%CI 0.57-0.94) and specificity of 0.72 (0.59-0.85), PCT had a pooled sensitivity of 0.68 (95% CI 0.0.59-0.77) and specificity of 0.75 (0.59-0.90), and for ESR pooled estimates were not calculated but sensitivity ranged from 50 to 69.8 and specificity from 38.5 to 55.6. Modifying cut-offs improved sensitivities and specificities. The ESR, CRP, and PCT mean differences were all greater in infection groups versus non-infection (10.1, 95% CI 3.2-17.0; 46.8, 95% CI 36.5-57.0; 0.53, 95% CI 0.26-0.80; respectively). DISCUSSION: Poor sensitivities and specificities were observed for the evaluated biomarkers with substantial heterogeneity in the cut-offs used to determine infection. Although mean biomarker values were increased in the infection group compared with the non-infection, our findings do not support the widespread use of ESR, CRP, or PCT in diagnosing infection in hospitalized patients with SLE due to increased heterogeneity and risk of bias. Further investigation is needed.

Macrophages and cadherins in fibrosis and systemic sclerosis.

PURPOSE OF REVIEW: Macrophages are key players in systemic sclerosis (SSc) and fibrosis. The mechanism by which macrophages regulate fibrogenesis is unclear and understanding the origin and function of macrophages is critical to developing effective therapeutics. Novel targets on macrophages are under investigation and recently, cadherins have emerged as a potential therapeutic target on macrophages. The current review will discuss the importance of macrophages in SSc and fibrosis and summarize recent studies on the role of cadherin-11 (Cdh11) on macrophages and fibrosis. RECENT FINDINGS: Genome-wide expression studies demonstrate the importance of macrophages in SSc and fibrosis. Although M2 macrophages are associated with fibrosis, the presence of a mixed M1/M2 phenotype in fibrosis has recently been reported. Several studies aiming to identify macrophage subsets involved in fibrogenesis suggest that monocyte-derived alveolar macrophages are key players in the development of murine lung fibrosis. Recent functional studies show that Cdh11 regulates macrophages, fibroblast invasion, and adhesion of macrophages to myofibroblasts. SUMMARY: Macrophages play an important role in SSc and fibrosis. New insights into the mechanisms by which macrophages regulate fibrogenesis have been discovered on the basis of Cdh11 studies and suggest that targeting Cdh11 may be an effective target to treat fibrosis.

Interferon regulatory factor 7 (IRF7) represents a link between inflammation and fibrosis in the pathogenesis of systemic sclerosis.

OBJECTIVES: There is considerable evidence that implicates dysregulation of type I interferon signalling (or type I IFN signature) in the pathogenesis of systemic sclerosis (SSc). Interferon regulatory factor 7 (IRF7) has been recognised as a master regulator of type I IFN signalling. The objective of this study was to elucidate the role of IRF7 in dermal fibrosis and SSc pathogenesis. METHODS: SSc and healthy control skin biopsies were investigated to determine IRF7 expression and activation. The role of IRF7 in fibrosis was investigated using IRF7 knockout (KO) mice in the bleomycin-induced and TSK/+mouse models. In vitro experiments with dermal fibroblasts from patients with SSc and healthy controls were performed. RESULTS: IRF7 expression was significantly upregulated and activated in SSc skin tissue and explanted SSc dermal fibroblasts compared with unaffected, matched controls. Moreover, IRF7 expression was stimulated by IFN-α in dermal fibroblasts. Importantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-ß signalling, and IRF7 knockdown reduced profibrotic factors in SSc fibroblasts. IRF7 KO mice demonstrated attenuated dermal fibrosis and inflammation compared with wild-type mice in response to bleomycin. Specifically, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were significantly attenuated in IRF7 KO mice skin tissue. Furthermore, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression. CONCLUSIONS: IRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-ß-mediated fibrosis, and therefore may represent a promising therapeutic target in SSc.

Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics.

We discovered that Cadherin-11 (CDH11) regulates collagen and elastin synthesis, both affecting the mechanical properties and contractile function of animal tissues. Using a Cdh11-null mouse model, we observed a significant reduction in the mechanical properties [Youngs' modulus and ultimate tensile strength (UTS)] of Cdh11(-/-) as compared to wild-type (WT) mouse tissues, such as the aorta, bladder and skin. The deterioration of mechanical properties (Youngs' modulus and UTS) was accompanied by reduced collagen and elastin content in Cdh11(-/-) mouse tissues as well as in cells in culture. Similarly, knocking down CDH11 abolished collagen and elastin synthesis in human cells, and consequently reduced their ability to generate force. Conversely, engagement of CDH11 through homophilic interactions, led to swift activation of the TGF-ß and ROCK pathways as evidenced by phosphorylation of downstream effectors. Subsequently, activation of the key transcription factors, MRTF-A (also known as MKL1) and MYOCD led to significant upregulation of collagen and elastin genes. Taken together, our results demonstrate a novel role of adherens junctions in regulating extracellular matrix (ECM) synthesis with implications for many important biological processes, including maintenance of tissue integrity, wound healing and tissue regeneration.

Role of STAT3 in skin fibrosis and transforming growth factor beta signalling.

Objective: SSc is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs. IL-6 and related cytokines that signal through STAT3 have been implicated in the pathogenesis of SSc and mouse models of fibrosis. The aim of this study was to investigate the efficacy of inhibiting STAT3 in the development of fibrosis in two mouse models of skin fibrosis. Methods: Biopsy samples of skin from SSc patients and healthy control subjects were used to determine the expression pattern of phosphotyrosyl (pY705)-STAT3. C188-9, a small molecule inhibitor of STAT3, was used to treat fibrosis in the bleomycin-induced fibrosis model and Tsk-1 mice. In vitro studies were performed to determine the extent to which STAT3 regulates the fibrotic phenotype of dermal fibroblasts. Results: Increased STAT3 and pY705-STAT3 was observed in SSc skin biopsies and in both mouse models of SSc. STAT3 inhibition with C188-9 resulted in attenuated skin fibrosis, myofibroblast accumulation, pro-fibrotic gene expression and collagen deposition in both mouse models of skin fibrosis. C188-9 decreased in vitro dermal fibroblast production of fibrotic genes induced by IL-6 trans-signalling and TGF-ß. Finally, TGF-ß induced phosphotyrosylation of STAT3 in a SMAD3-dependent manner. Conclusion: STAT3 inhibition decreases dermal fibrosis in two models of SSc. STAT3 regulates dermal fibroblasts function in vitro and can be activated by TGF-ß. These data suggest that STAT3 is a potential therapeutic target for dermal fibrosis in diseases such as SSc.

Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis.

BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).

A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate.

OBJECTIVE: Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of rheumatoid arthritis (RA). The safety and efficacy of ustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and guselkumab, a human monoclonal anti-IL-23 antibody, were evaluated in adults with active RA despite methotrexate (MTX) therapy. METHODS: Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab 50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 and every 8 weeks (n=54) through week 28; all patients continued a stable dose of MTX (10-25 mg/week). The primary end point was the proportion of patients with at least a 20% improvement in the American College of Rheumatology criteria (ACR 20) at week 28. Safety was monitored through week 48. RESULTS: At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with placebo (40.0%) (p=0.101 and p=0.877, respectively). Through week 48, the proportions of patients with at least one adverse event (AE) were comparable among the treatment groups. Infections were the most common type of AE. CONCLUSIONS: Treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA. No new safety findings were observed with either treatment. TRIAL REGISTRATION NUMBER: NCT01645280.

STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation.

Lung fibrosis is the hallmark of the interstitial lung diseases. Alveolar epithelial cell (AEC) injury is a key step that contributes to a profibrotic microenvironment. Fibroblasts and myofibroblasts subsequently accumulate and deposit excessive extracellular matrix. In addition to TGF-ß, the IL-6 family of cytokines, which signal through STAT-3, may also contribute to lung fibrosis. In the current manuscript, the extent to which STAT-3 inhibition decreases lung fibrosis is investigated. Phosphorylated STAT-3 was elevated in lung biopsies from patients with idiopathic pulmonary fibrosis and bleomycin (BLM)-induced fibrotic murine lungs. C-188-9, a small molecule STAT-3 inhibitor, decreased pulmonary fibrosis in the intraperitoneal BLM model as assessed by arterial oxygen saturation (control, 84.4 ± 1.3%; C-188-9, 94.4 ± 0.8%), histology (Ashcroft score: untreated, 5.4 ± 0.25; C-188-9, 3.3 ± 0.14), and attenuated fibrotic markers such as diminished α-smooth muscle actin, reduced collagen deposition. In addition, C-188-9 decreased the expression of epithelial injury markers, including hypoxia-inducible factor-1α (HIF-1α) and plasminogen activator inhibitor-1 (PAI-1). In vitro studies show that inhibition of STAT-3 decreased IL-6- and TGF-ß-induced expression of multiple genes, including HIF-1α and PAI-1, in AECs. Furthermore, C-188-9 decreased fibroblast-to-myofibroblast differentiation. Finally, TGF-ß stimulation of lung fibroblasts resulted in SMAD2/SMAD3-dependent phosphorylation of STAT-3. These findings demonstrate that STAT-3 contributes to the development of lung fibrosis and suggest that STAT-3 may be a therapeutic target in pulmonary fibrosis.

Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo.

Although soluble factors, such as transforming growth factor ß1 (TGF-ß1), induce mesenchymal stem cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage, the role of adherens junctions in this process is not well understood. In this study, we found that cadherin-11 but not cadherin-2 was necessary for MSC differentiation into SMCs. Cadherin-11 regulated the expression of TGF-ß1 and affected SMC differentiation through a pathway that was dependent on TGF-ß receptor II (TGFßRII) but independent of SMAD2 or SMAD3. In addition, cadherin-11 activated the expression of serum response factor (SRF) and SMC proteins through the Rho-associated protein kinase (ROCK) pathway. Engagement of cadherin-11 increased its own expression through SRF, indicative of the presence of an autoregulatory feedback loop that committed MSCs to the SMC fate. Notably, SMC-containing tissues (such as aorta and bladder) from cadherin-11-null (Cdh11(-/-)) mice showed significantly reduced levels of SMC proteins and exhibited diminished contractility compared with controls. This is the first report implicating cadherin-11 in SMC differentiation and contractile function in vitro as well as in vivo.

Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2-3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.

A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations.

A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.

Detection and isolation of auto-reactive human antibodies from primary B cells.

The isolation of human monoclonal antibodies (hmAb) has emerged as a versatile platform in a wide variety of contexts ranging from vaccinology to therapeutics. In particular, the presence of high titers of circulating auto-antibodies is implicated in the pathology and outcome of autoimmune diseases. Therefore, the molecular characterization of these hmAb provides an avenue to understanding the pathogenesis of autoimmune diseases. Additionally, the phenotype of the auto-reactive B cells may have direct relevance for therapeutic intervention. In this report, we describe a high-throughput single-cell assay, microengraving, for the screening, characterization and isolation of anti-citrullinated protein antibodies (ACPA) from peripheral blood mononuclear cells (PBMC) of rheumatoid arthritis (RA) patients. Stimulated B cells are profiled at the single-cell level in a large array of sub-nanoliter nanowells (∼10(5)), assessing both the phenotype of the cells and their ability to secrete cyclic-citrullinated peptide (CCP)-specific antibodies. Single B cells secreting ACPA are retrieved by automated micromanipulation, and amplification of the immunoglobulin (Ig) heavy and light chains is performed prior to recombinant expression. The methodology offers a simple, rapid and low-cost platform for isolation of auto-reactive antibodies from low numbers of input cells and can be easily adapted for isolation and characterization of auto-reactive antibodies in other autoimmune diseases.

Risk of incident cardiovascular events with disease-modifying anti-rheumatic drugs among adults with rheumatoid arthritis: a nested case-control study.

OBJECTIVE: This study examined the risk of cardiovascular disease (CVD) associated with the disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA). METHOD: This nested case-control study used the MarketScan database (2012-2014), involving adult RA patients (aged ≥18 years) initiating either a conventional synthetic (cs) DMARD, biologic DMARD, or targeted synthetic (ts) DMARD between January 1, 2013 and December 31, 2014 (cohort entry) and had no CVD history. Cases were individuals with incident CVD identified using diagnosis codes or procedure codes from medical claims. For each case, 10 age- and sex-matched controls were selected using the incident density sampling with replacement. Prescriptions of DMARDs were measured 90 days before the event date. Conditional logistic regression examined the association of risk of CVD with DMARDs in combination treatment or individual use, with reference to methotrexate (MTX) monotherapy, adjusting for baseline confounders. Subgroup analyses were performed separately in DMARD combination therapy users or individual DMARD users, respectively. RESULTS: In total, 270 cases of incident CVD and 2700 controls were included (mean [standard deviation (SD)] age: 54 [1]; 75.6% women). The commonly prescribed DMARD therapies were csDMARD monotherapy (n = 795, 27.04%), followed by  tumor necrosis factor inhibitors (TNFi) monotherapy (n = 367, 12.48%), and TNFi in combination with MTX (n = 314, 10.68%). Compared with MTX monotherapy, overall use of DMARD agents was not associated with the differential risk of CVD, including various types of DMARD combination regimens. The findings were similar across subgroup analyses. CONCLUSIONS: The study found no differential risk of CVD with DMARDs in combination therapy or monotherapy compared to MTX monotherapy in patients with RA. Key Points • This study evaluated the risk of cardiovascular disease (CVD) associated with the disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA). • Findings suggest no differential CVD risk with DMARDs in combination with MTX or used individually compared with MTX monotherapy in patients with early RA. • Further efforts should focus on a better understanding of the mechanism of DMARD combination treatments with MTX in modifying CV risk.

Cadherin-11 targeted cell-specific liposomes enabled skin fibrosis treatment by inducing apoptosis.

Continuous and aberrant activation of myofibroblasts is the hallmark of pathological fibrosis (e.g., abnormal wound healing). The deposition of excessive extracellular matrix (ECM) components alters or increases the stiffness of tissue and primarily accounts for multiple organ dysfunctions. Among various proteins, Cadherin-11 (CDH11) has been reported to be overexpressed on myofibroblasts in fibrotic tissues. Anti-apoptotic proteins such as (B cell lymphoma-2) (BCL-2) are also upregulated on myofibroblasts. Therefore, we hypothesize that CDH11 could be a targeted domain for cell-specific drug delivery and targeted inhibition of BCL-2 to ameliorate the development of fibrosis in the skin. To prove our hypothesis, we have developed liposomes (LPS) conjugated with CDH11 neutralizing antibody (antiCDH11) to target cell surface CDH11 and loaded these LPS with a BCL-2 inhibitor, Navitoclax (NAVI), to induce apoptosis of CDH11 expressing fibroblasts. The developed LPS were evaluated for physicochemical characterization, stability, in vitro therapeutic efficacy using dermal fibroblasts, and in vivo therapeutic efficacy in bleomycin-induced skin fibrosis model in mice. The findings from in vitro and in vivo studies confirmed that selectivity of LPS was improved towards CDH11 expressing myofibroblasts, thereby improving therapeutic efficacy with no indication of adverse effects. Hence, this novel research work represents a versatile LPS strategy that exhibits promising potential for treating skin fibrosis.

Lymph node targeting of cyclosporine ameliorates ocular manifestations in a mouse model of systemic lupus erythematosus (SLE) via PD-L1.

One-third of systemic lupus erythematosus (SLE) patients experience various degrees of ocular manifestations, with immunosuppressants recommended as a treatment option. Targeted immune suppression via oral administration is challenging due to the harsh gastrointestinal tract environment combined with complex physiological barriers. Here, we report the efficacy of orally administered cyclosporine (CsA)-laden polymer nanoparticles decorated with the ligand - Gambogic Acid (P2Ns-GA-CsA) in sustained lymph node delivery. This is the first report demonstrating the CD71 specificity of P2Ns-GA-CsA in the CD71 knockout mouse model and the influence of spacer length in achieving target tissue bioavailability in a lupus mouse model. P2Ns-GA-CsA effectively regulates T-cell chemotaxis by PD-L1 at a 50 % lower dose compared to conventional CsA in a mouse model exhibiting lupus-associated corneal inflammation. Collectively, these results suggest the possibility for further development of P2Ns-GA to target a diverse range of lymphatic disorders.

Factors Associated With Adherence of Cervical Cancer Screening in Women With Systemic Lupus Erythematosus.

OBJECTIVE: The objective is to determine cervical cancer screening rates and factors associated with decreased cervical cancer screening in women with systemic lupus erythematosus (SLE). METHODS: We conducted a cross-sectional study that enrolled consecutive women (age 21-64 years) with SLE. We collected demographics, clinical characteristics, constructs of the Health Beliefs Model (HBM) (ie, susceptibility, severity, barriers, benefits, cues to action, and self-efficacy), and self-reported cervical cancer screening (confirmed with the electronic medical record). The primary outcome was adherence to cervical cancer screening according to current guidelines. Multivariable logistic regression models were used to examine the association between SLE disease activity and cervical cancer screening and explore mediation effects from HBM constructs. RESULTS: We enrolled 130 women with SLE. The median age was 42 years (interquartile range 32-52 years). The cervical cancer screening adherence rate was 61.5%. Women with high SLE disease activity were less likely to have cervical cancer screening versus those with low disease activity (odds ratio 0.59, 95% confidence interval [CI] 0.39-0.89; P = 0.01), which remained statistically significant after adjusting for baseline demographics and drug therapy in a multivariable model (odds ratio 0.25, 95% CI 0.08-0.79; P = 0.02). Regarding the HBM constructs, increased perceived barriers to cervical cancer screening (r = -0.30, P < 0.01) and decreased self-efficacy (r = -0.21, P = 0.02) correlated with decreased cervical cancer screening. CONCLUSION: Patients with SLE with high disease activity undergo cervical cancer screening less frequently than those with low disease activity. Perceived barriers to cervical cancer screening are moderately correlated with decreased screening. These data highlight the need to develop strategies to increase cervical cancer screening in this high-risk patient population.