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ID PMID Title PublicationDate abstract
29890415 Montelukast inhibits inflammatory response in rheumatoid arthritis fibroblast-like synovio 2018 Aug Montelukast, a potent selective antagonist of cysteinyl leukotriene (cysLT) receptors, has displayed its important anti-oxidative and anti-inflammatory effects in various tissues and organs. Rheumatoid arthritis (RA) is an immune disease defined by hyperplastic synovitis and joint destruction. Fibroblast-like synoviocytes in RA (RA-FLSs) are the main cell component of the hyperplastic synovium. Whether montelukast can protect against the inflammatory milieu of RA remains unclear. Here, it is shown that cysLT1R is present in FLSs and unregulated in RA-FLSs. Montelukast has an inhibitory effect on the inflammatory microenvironment of RA by decreasing the secretion of IL-6, IL-8, MMP-3 and MMP-13 in FLSs induced by IL-1β. Notably, treatment with montelukast attenuated IL-1β-induced phosphorylation of IκBα, IκBα degradation, nuclear translocation of p65 and NF-κB activity to express a luciferase reporter gene in FLSs. The findings of the current study provide evidence for a novel therapeutic strategy for RA using montelukast.
29961692 Maternal and Fetal Outcomes in a Cohort of Patients Exposed to Tumor Necrosis Factor Inhib 2018 Aug OBJECTIVE: Tumor necrosis factor inhibitors (TNFi) are increasingly used in pregnancy but are frequently withheld in the second or third trimesters. We evaluated the maternal and fetal outcomes of women who continued their TNFi throughout pregnancy compared to women who interrupted TNFi during pregnancy. METHODS: We retrospectively analyzed the outcomes of women seen in clinic with rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis (JIA), or ankylosing spondylitis, who were exposed to TNFi during pregnancy. We separated pregnancies into 2 groups based on the level of TNFi exposure and compared outcomes. RESULTS: In Group 1 (TNFi exposure in first trimester only), 11 women had 14 pregnancies and 12 live births. There were 2 first-trimester losses (2/14, 14%), one in the setting of active RA. Five pregnancies (5/14, 35.7%) were complicated by a disease flare. Eight patients (8/12, 66%) flared postpartum. In Group 2 (TNFi exposure throughout pregnancy), 29 women had 32 pregnancies and 34 live births. Three (3/28, 10.7%) adverse pregnancy outcomes were reported in 2 patients. One patient had a twin pregnancy and delivered at 33 weeks after developing preterm premature rupture of membranes at 32 weeks in the setting of a JIA flare. Her second pregnancy was complicated by active JIA before and throughout gestation, and hemolysis, elevated liver enzyme levels, and low platelet levels (HELLP) syndrome at 39 weeks. Another patient with comorbid antiphospholipid syndrome underwent a cesarean birth at 36 weeks for suspicion of HELLP syndrome. Six (6/32, 18.7%) postpartum flares occurred. CONCLUSION: Women who discontinued their TNFi during pregnancy had a higher risk of peri- or postpartum flare compared to those who continued their TNFi throughout pregnancy.
30545212 Gluten-free diet in non-celiac patients: beliefs, truths, advantages and disadvantages. 2019 Jun A gluten-free diet is the safest treatment for the treatment of patient with celiac disease (CD) and other gluten-related disorders. However, in the last years, gluten-free diet is one of the most popular diet followed by the general population and by patients affected from others clinical conditions, such as non-celiac gluten sensitivity (NCGS), irritable bowel syndrome (IBS), autism, neurological, psychiatric and rheumatologic diseases and for improving sports practice. This review highlights some questions about the appropriateness of following this trend answering to some questions such as how safe are the current gluten-free products, what are the benefits and side effects of gluten-free diet and what are clinical conditions that might benefit from gluten avoidance.
30513021 Decreased Gene Expression of Epstein-Barr Virus-Induced Gene 3 (EBI-3) may Contribute to t 2019 May BACKGROUND: Interleukin-35 (IL-35) is a member of the IL-12 family of heterodimeric cytokines produced by regulatory T (Treg) cells. This immunosuppressive cytokine can prevent exaggerated inflammatory responses like those responsible for the development of rheumatoid arthritis (RA). This study aims to determine the correlation between the gene expression of Epstein-Barr virus-induced gene 3 (EBI-3) and IL-12A (p35) subunits of IL-35 in peripheral blood leukocytes with immunological and clinical parameters in RA patients. METHODS: We recruited 47 patients with RA and 44 healthy subjects. The disease activity score-28 (DAS-28) was assessed by an expert rheumatologist and the plasma levels of neopterin and anti-cyclic citrullinated peptide (anti-CCP) was measured using ELISA method also Serum rheumatoid factor (RF) was assessed by the agglutination test. For the evaluation of IL-12A and EBI-3 gene expression, we used qPCR. RESULTS: We did not find any significant correlation between the gene expression of IL-35 subunits and DAS-28. There was a negative correlation between the plasma levels of neopterin and the gene expression of EBI-3 (p = 0.004). Inversely, we found a positive correlation between plasma level of anti-CCP and neopterin (p < 0.001) also between RF and DAS-28 (p = 0.001). CONCLUSION: Regarding the significant negative correlation between EBI-3 gene expression and plasma levels of neopterin, it can be concluded that the altered gene expression of EBI-3 may play a role in the pathogenesis of RA.
30279249 Miliary tuberculosis and herpes pharyngitis after a trip to a developing country: dangers 2018 Oct 2 The use of biologic drugs has expanded since its introduction in the late 1990s. With growing medical use and newer biologic drugs in development, opportunistic infections like Mycobacterium tuberculosis remain important adverse effects. It carries major public health concerns, yet evidence-based clinical guidelines for more routine interval screening in patients taking immunosuppressants and exposed to tuberculosis (TB) are lacking. We illustrate a case of an elderly Indian-born man living in the USA with psoriatic arthritis who was on adalimumab for 10 years. He presented with disseminated TB and herpes simplex virus type 1 (HSV-1) pharyngitis, a year after an innocuous trip to India. Our case draws attention to the adverse effects of biologic drugs and highlights the importance of regular rescreening for a high-risk population. As the use of biologic treatment increases, physicians must be vigilant in more frequent screening, monitoring and identifying related opportunistic infections, notably M. tuberculosis infections.
30551369 Ankylosing spondylitis and mesenchymal stromal/stem cell therapy: a new therapeutic approa 2019 Jan Ankylosing spondylitis (AS) is an inflammatory rheumatoid disease categorized within spondyloarthropathies (SpA) and manifested by chronic spinal arthritis. Several innate and adaptive immune cells and secreted-mediators have been indicated to play a role in AS pathogenesis. Considering the limitations of current therapeutic approaches (NSAIDs, glucocorticoids, DMARDs and biologic drugs), finding new treatments with fewer side effects and high therapeutic potentials are required in AS. Mesenchymal stem cells (MSCs) with considerable immunomodulatory and regenerative properties could be able to attenuate the inflammatory responses and help tissue repair by cell-to-cell contact and secretion of soluble factors. Moreover, MSCs do not express HLA-DR, which renders them a favorable therapeutic choice for transplantation in immune-mediated disorders. In the present review, we describe immunopathogenesis and current treatments restrictions of AS. Afterwards, immunomodulatory properties and applications of MSCs in immune-mediated disorders, as well as recent findings of clinical trials involving mesenchymal stem cell therapy (MSCT) in ankylosing spondylitis, will be discussed in detail. Additional studies are required to investigate several features of MSCT such as cell origin, dosage, administration route and, specifically, the most suitable stage of disease for ideal intervention.
30186881 Frequency of Hospitalized Infections Is Reduced in Rheumatoid Arthritis Patients Who Recei 2018 BACKGROUND: Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (ts) DMARDs are important in rheumatoid arthritis (RA) treatment. The risk of hospitalized infection associated with bDMARDs/tsDMARDs in RA patients is unclear. METHODS: We retrospectively analyzed the cases of the 275 RA patients with 449 treatment episodes who were administered a bDMARD/tsDMARD at Nagasaki University Hospital in July 2003-January 2015. We determined the incidence and risk factors of infection requiring hospitalization in the patients during a 3-year observation period. RESULTS: Thirty-five (12.7%) of the patients experienced a hospitalized infection. The hospitalized infection risk did not differ significantly among several bDMARDs/tsDMARDs. A multivariate analysis revealed that the comorbidities of chronic lung disease (adjusted HR 5.342, 95% CI 2.409-12.42, p < 0.0001) and the initiation of bDMARDs/tsDMARDs before 2010 (adjusted HR 4.266, 95% CI 1.827-10.60, p = 0.0007) are significant independent risk factors for hospitalized infection. Compared to the before-2010 group, the group of patients whose treatment initiated in 2010 or later showed higher patient ages at the initiation of bDMARD/tsDMARD treatment and a higher rate of the use of prophylaxis with an antituberculosis agent, whereas the disease activities and number of the patients who received >5 mg of prednisolone were lower in the after-2010 group. CONCLUSIONS: This is the first report that the frequency of hospitalized infection significantly decreased when the patients were treated with a bDMARD or tsDMARD after 2010. Our results indicate that the updated announcement of diagnosis and treatment criteria might contribute to a reduced risk of hospitalized infection and a better understanding of the use of bDMARDs/tsDMARDs by rheumatologists.
29343509 Efficacy and safety of tregalizumab in patients with rheumatoid arthritis and an inadequat 2018 Apr OBJECTIVE: To evaluate the efficacy, biological activity and safety of tregalizumab in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). METHODS: 321 patients were randomised (1:1:1:1) to placebo or tregalizumab 25, 100 or 200 mg once-weekly subcutaneously in addition to MTX treatment. Responders at week 12 continued the same treatment, and non-responders at week 12 were escalated to the next higher tregalizumab dose level or re-randomised from placebo to active treatment. After 24 weeks, patients could continue treatment with tregalizumab for 24 weeks (extension phase). The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Safety and biological activity were monitored through week 48. RESULTS: At week 12, ACR20 response rates were not statistically significantly different between placebo and any of the tregalizumab doses. Tregalizumab injections were well tolerated; most adverse events were mild to moderate and comparable among treatment and placebo groups. Biological activity was shown by dose-dependent CD4 downmodulation. CONCLUSION: Treatment with tregalizumab did not show significant clinical efficacy in patients with active RA compared with placebo but resulted in the expected biological effect on CD4 modulation. Tregalizumab was generally well tolerated, and no new safety findings were identified. TRIAL REGISTRATION NUMBER: NCT01999192; Results.
30340571 Early referral and control of disease's flares prevent Orthopedic and Hand Surgery Indicat 2018 Oct 20 BACKGROUND: Reconstructive joint surgery is an indicator of poor prognosis in rheumatoid arthritis (RA). Objectives of this study were to describe the incidence rate of orthopedic and hand surgery indication (OHSI) in an ongoing cohort of Hispanic early RA patients treated according to a T2T strategy and to investigate predictors. METHODS: Through February 2018, the cohort comprised 185 patients recruited from 2004 onwards, with variable follow-up, and rheumatic assessments at fixed intervals that included prospective determination of OHSI. Charts were reviewed by a single data abstractor. OHSI incidence rate was calculated. A case-control study nested within a cohort investigated the predictors; cases (OHSI patients) were paired with controls (1:4) according to age, sex and autoantibodies. A logistic regression model included baseline and cumulative (up to OHSI or equivalent) variables related to disease activity, treatment and to persistence with therapy. The IRB approved the study. RESULTS: Patients from the cohort were predominantly middle-aged (mean ± SD age: 38.5 ± 12.9 years) females (87.6%) with 5.4 ± 2.6 months of disease duration. The cohort contributed to 1538 patient-years of follow-up. Twelve patients received incidental OHSI at a follow-up of 85 ± 44.5 months. The OHSI incident global rate was 8/1000 patient-years. Longer symptom duration at cohort referral (OR: 1.313, 95%CI: 1.02-1.68, p = 0.032) and a higher number of flares/patient (OR: 1.608, 95%CI: 1.05-1.61, p = 0.015) predicted OHSI. OHSI patients had more severe flares than their counterparts, and the opposite figure was true for mild flares. CONCLUSION: Early referral for appropriate management and flare control may prevent OHSI in Hispanic recent-onset RA patients.
28984647 Functional genomics of stromal cells in chronic inflammatory diseases. 2018 Jan PURPOSE OF REVIEW: Stroma is a broad term referring to the connective tissue matrix in which other cells reside. It is composed of diverse cell types with functions such as extracellular matrix maintenance, blood and lymph vessel development, and effector cell recruitment. The tissue microenvironment is determined by the molecular characteristics and relative abundances of different stromal cells such as fibroblasts, endothelial cells, pericytes, and mesenchymal precursor cells. Stromal cell heterogeneity is explained by embryonic developmental lineage, stages of differentiation to other cell types, and activation states. Interaction between immune and stromal cell types is critical to wound healing, cancer, and a wide range of inflammatory diseases. Here, we review recent studies of inflammatory diseases that use functional genomics and single-cell technologies to identify and characterize stromal cell types associated with pathogenesis. RECENT FINDINGS: High dimensional strategies using mRNA sequencing, mass cytometry, and fluorescence activated cell-sorting with fresh primary tissue samples are producing detailed views of what is happening in diseased tissue in rheumatoid arthritis, inflammatory bowel disease, and cancer. Fibroblasts positive for CD90 (Thy-1) are enriched in the synovium of rheumatoid arthritis patients. Single-cell RNA-seq studies will lead to more discoveries about the stroma in the near future. SUMMARY: Stromal cells form the microenvironment of inflamed and diseased tissues. Functional genomics is producing an increasingly detailed view of subsets of stromal cells with pathogenic functions in rheumatic diseases and cancer. Future genomics studies will discover disease mechanisms by perturbing molecular pathways with chemokines and therapies known to affect patient outcomes. Functional genomics studies with large sample sizes of patient tissues will identify patient subsets with different disease phenotypes or treatment responses.
29369795 Cardiovascular magnetic resonance characterization of myocardial and vascular function in 2019 Jan BACKGROUND: Rheumatoid arthritis (RA) is a multisystem, autoimmune disorder and confers one of the strongest risks for cardiovascular disease (CVD) morbidity and mortality. OBJECTIVE: To assess myocardial function and vascular stiffness in RA patients with and without cardiovascular risk factors (CVRFs) using cardiovascular magnetic resonance (CMR). METHODS: Twenty-three RA patients with no CVRFs (17 female, mean age 52 ± 13 years), 46 RA patients with CVRFs (32 female, mean age 53 ± 12), 50 normal controls (32 female, mean age 50 ± 11 years), and 13 controls with CVRFs (7 female, mean age 55 ± 7 years), underwent CMR at 1.5 Tesla, including evaluation of left ventricular (LV) ejection fraction, strain, and vascular elasticity (aortic distensibility [AD] and pulse wave velocity [PWV]). Disease activity and duration were recorded for each patient. Subjects with known symptomatic CVD were excluded. RESULTS: LV volumes, mass, and ejection fraction were similar in the four groups. RA patients with CVRFs showed the greatest abnormality in mid short-axis circumferential systolic strain, peak diastolic strain rate, and vascular indices. RA patients without CVRFs showed a similar degree of vascular dysfunction and deformational abnormality as controls with CVRFs. AD and total PWV correlated with myocardial strain and RA disease activity. On multivariate regression analysis, strain was related to age, RA disease activity, AD, and PWV. CONCLUSION: CMR demonstrates impaired myocardial deformation and vascular function in asymptomatic RA patients, worse in those with CVRFs. Subclinical cardiovascular abnormalities are frequent and appear to be incremental to those due to traditional CVRFs and likely contribute to the excess CVD in RA.
29251032 Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis 2018 Sep OBJECTIVES: The objective of this study is to evaluate the safety and effectiveness of subcutaneous tocilizumab (TCZ-SC) in a real-world clinical setting in Japan. METHODS: This single arm, 26-week prospective observational study enrolled patients with RA who were either TCZ naïve or switched from TCZ-IV to TCZ-SC (TCZ-IV-SC group) (UMIN Clinical Trials Registry UMIN000011102). All patients received TCZ-SC 162 mg every 2 weeks and data were collected until week 26 or discontinuation. RESULTS: Overall 784 (78.1%) were TCZ naïve and 219 (21.8%) were in the TCZ-IV-SC group. 70.9% received disease-modifying antirheumatic drugs at baseline. Adverse events (AEs) and serious AEs occurred in 28.2% and 4.9% of patients, respectively (TCZ-naïve: 29.5% and 5.2%; TCZ-IV-SC: 23.2% and 4.1%). Infections and infestations were the most common AEs (7.4%) and serious AEs (1.7%). Two TCZ-naïve patients died. TCZ-naïve patients had an improvement in median Clinical Disease Activity Index (CDAI) score and mean Disease Activity Score in 28 joints as measured by erythrocyte sedimentation rate (DAS28-ESR) from baseline to week 26. The TCZ-IV-SC group had similar median CDAI scores and mean DAS28-ESR over 26 weeks. CONCLUSIONS: There were no unexpected safety signals with TCZ-SC. TCZ-SC was effective in reducing disease activity in TCZ-naïve patients and maintaining remission in TCZ-IV-SC patients.
30177460 A pooled analysis of the safety of tofacitinib as monotherapy or in combination with backg 2018 Dec OBJECTIVE: This post-hoc, pooled analysis of Phase 3 studies of tofacitinib examined the safety of tofacitinib 5 and 10 mg twice daily (BID) when used as monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA). METHODS: Pooled data from six double-blind, randomized controlled Phase 3 studies of tofacitinib 5 and 10 mg BID in patients with RA were analyzed for safety and stratified by administration as monotherapy (ORAL Solo: NCT00814307 and ORAL Start: NCT01039688) or in combination with csDMARDs (ORAL Sync: NCT00856544, ORAL Standard: NCT00853385, ORAL Scan: NCT00847613, and ORAL Step: NCT00960440), and by glucocorticoid use at baseline. Safety assessments included incidence rates (IRs) for serious adverse events (SAEs), discontinuations due to AEs, serious infection events, and herpes zoster (HZ), and were evaluated throughout the duration of the Phase 3 studies. RESULTS: In total, 3881 patients were included in the safety analysis (monotherapy studies: n = 1380; combination therapy studies: n = 2501). IRs for selected AEs of interest were generally numerically lower in patients who received tofacitinib 5 and 10 mg BID as monotherapy than as combination therapy (SAEs: IR [range] 6.21-6.72 versus IR 10.17-13.46; discontinuations due to AEs: IR 5.53-6.18 versus IR 10.80-11.01; serious infections: IR 1.57-1.66 versus IR 3.39-3.56; HZ: IR 1.95-2.93 versus IR 4.37-4.99, respectively), irrespective of tofacitinib dose or glucocorticoid use. There were too few patients and events within the placebo group to fully evaluate effect between combination therapy and monotherapy. CONCLUSIONS: Safety profiles were generally similar between patients receiving monotherapy and combination therapy; however, selected safety events of interest, including HZ and serious infections, showed lower IRs with non-overlapping 95% confidence intervals for tofacitinib all monotherapy versus combination therapy. Tofacitinib monotherapy may, therefore, have fewer safety events compared with combination therapy, and have a favorable risk-benefit profile in patients with active RA who are intolerant to csDMARDs.
29142037 Elevated Psychosocial Stress at Work in Patients with Systemic Lupus Erythematosus and Rhe 2018 Feb OBJECTIVE: Psychosocial stress at work not only affects the healthy working population, but also workers with chronic diseases. We aimed to investigate the psychosocial work stress levels in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: A cross-sectional study applied the Effort-Reward Imbalance (ERI) questionnaire - an internationally established instrument that measures work stress - to patients with SLE and RA who were capable of work and to a group of controls without these diseases. Participants were recruited through rheumatologists in private practices, hospitals, and from self-help groups by personal communication, paper-based flyers, and online advertisements. Because very few studies tested the ERI's applicability in patient groups, with a lack of evidence in patients with inflammatory rheumatic diseases, internal consistency and construct validity of the ERI measure were evaluated. RESULTS: Data came from 270 patients with RA and 247 with SLE, and 178 controls. Patients showed elevated psychosocial stress at work compared to controls. Across the total sample and all groups, satisfactory internal consistencies of the scales effort, reward, and overcommitment were obtained (Cronbach's alpha coefficients > 0.70), and confirmatory factor analysis replicated the theoretical structure of the ERI model (goodness-of-fit index > 0.80). CONCLUSION: We found elevated psychosocial stress at work in patients with SLE and RA compared to controls by applying the ERI model. Despite some heterogeneity in the sample, we achieved satisfactory psychometric properties of the ERI questionnaire. Our results suggest that the ERI questionnaire is a psychometrically useful tool to be implemented in epidemiological studies of employed patients with SLE and RA.
29023682 Short-term cytokine stimulation reveals regulatory T cells with down-regulated Foxp3 expr 2018 Feb The identification of regulatory T cells (Treg cells) in human peripheral blood is an important tool in diagnosis, research, and therapeutic intervention. As compared to lymphoid tissues, the frequencies of circulating Treg cells identified as CD4(+) CD25(+) Foxp3(+) are, however, low. We here show that many of these cells remain undetected due to transient down regulation of Foxp3, which rapidly decays in the absence of cytokine-mediated STAT5 signals. Short-term incubation of PBMCs or isolated CD4(+) T cells, but not of lymph node cells, with IL-2, -7, or -15 more than doubles the frequency of Foxp3(+) CD25(+) among CD4(+) T cells detectable by flow cytometry. This increase is not due to cell division but to upregulation of both proteins. At the same time, the uncovered Treg cells up-regulate CD25 and down-regulate CD127, making them accessible to viable cell sorting. "Latent" Treg cells have a demethylated FOXP3 TSDR sequence, are enriched in naïve, non-cycling cells, and are functional. The confirmation of our findings in RA and SLE patients shows the feasibility of uncovering latent Treg cells for immune monitoring in clinical settings. Finally, our results suggest that unmasking of latent Treg cells contributes to the increase in circulating CD4(+) CD25(+) Foxp3(+) cells reported in IL-2 treated patients.
30518680 Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute 2018 Dec 6 CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanistic studies in autoimmune disease are limited. This is the first study to our knowledge examining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA). We identified significant enrichment of CD141+ DC in the inflamed synovial joint, which were transcriptionally distinct from IA and healthy control (HC) blood CD141+ DC and significantly more activated, and they exhibited increased responsiveness to TLR3. Synovial CD141+ DC represent a bone fide CD141+ DC population that is distinct from CD1c+ DC. Synovial CD141+ DC induced higher levels of CD4+ and CD8+ T cell activation compared with their peripheral blood counterparts, as made evident by expression of IFN-γ, TNF-α, and granulocyte-macrophage CSF (GMCSF). Autologous synovial CD141+ DC cocultures also induce higher levels of these cytokines, further highlighting their contribution to synovial inflammation. Synovial CD141+ DC-T cell interactions had the ability to further activate synovial fibroblasts, inducing adhesive and invasive pathogenic mechanisms. Furthermore, we identify a mechanism in which synovial CD141+ DC are activated, via ligation of the hypoxia-inducible immune-amplification receptor TREM-1, which increased synovial CD141+ DC activation, migratory capacity, and proinflammatory cytokines. Thus, synovial CD141+ DC display unique mechanistic and transcriptomic signatures, which are distinguishable from blood CD141+ DC and can contribute to synovial joint inflammation.
29733455 The chemokine fragment CXCL9(74-103) diminishes neutrophil recruitment and joint inflammat 2018 Aug This study investigates if treatment with a peptide corresponding to the 30 C-terminal amino acids of CXCL9, CXCL9(74-103), ameliorates joint inflammation in a murine model of antigen-induced arthritis (AIA). AIA was induced in male C57BL/6J mice. Intravenous injection of CXCL9(74-103), simultaneously performed with a tibiofemoral challenge with methylated BSA (mBSA) as antigen in mice immunized with mBSA, diminished the accumulation of leukocytes, in particular neutrophils, in the synovial cavity. The levels of the chemokines CXCL1, CXCL2, and CXCL6 and of the cytokine IL-6 were decreased in inflamed periarticular tissue of mice treated with the CXCL9-derived peptide compared to non-treated AIA mice. In addition, CXCL9(74-103) treatment substantially reduced joint and cartilage damage. CXCL9(74-103) competes with CXCL6 and CCL3 for binding to the glycosaminoglycans heparan sulfate and chondroitin sulfate in vitro. In vivo, CXCL9(74-103) quickly binds to blood vessels in joints as observed by confocal microscopy. Next, we evaluated if later treatment with CXCL9(74-103) had a beneficial impact on joint inflammation. CXCL9(74-103) injection 6 h after mBSA challenge still reduced neutrophil accumulation in the joint, although it did not reduce chemokine and IL-6 concentrations. However, a delay of treatment until 12 h after challenge had no effect on cell recruitment and chemokine and IL-6 levels. Taken together, we demonstrated that treatment with a peptide, which interferes with the interaction between chemokines and glycosaminoglycans, from the beginning of the disease controlled the massive accumulation of neutrophils in the joint of AIA mice, greatly impacting on joint inflammation and tissue damage.
30203252 Risk of Adverse Drug Events Observed with Baricitinib 2 mg Versus Baricitinib 4 mg Once 2018 Oct BACKGROUND: On 23 April 2018, the Food and Drug Administration-based Advisory Committee approved the use of baricitinib 2 mg for the treatment of rheumatoid arthritis and suggested the possibility of serious adverse events associated with baricitinib 4 mg. Hence, we aimed to systematically compare the risk of adverse drug events observed with baricitinib 2 mg versus 4 mg for the treatment of patients with rheumatoid arthritis. METHODS: Electronic databases including the Cochrane library, MEDLINE, EMBASE and http://www.ClinicalTrials.gov were searched for relevant English publications until April 2018. Adverse drug events at 12 weeks and 24 weeks were considered as the clinical endpoints. RevMan 5.3 software was used to analyze the data whereby risk ratios (RR) and 95% confidence intervals (CI) were calculated. RESULTS: Four trials consisting of a total of 959 participants were included in this analysis. At 12 weeks, no significant difference was observed between 2 mg and 4 mg baricitinib for serious adverse events (RR 1.33; 95% CI 0.63-2.78; p = 0.46), any adverse events after the start of therapy (RR 1.09; 95% CI 0.98-1.21; p = 0.13), discontinuation of drugs due to adverse events (RR 1.19; 95% CI 0.61-2.34; p = 0.60), malignancies (RR 3.03; 95% CI 0.12-73.90; p = 0.50), and major adverse cardiac events (RR 2.95; 95% CI 0.12-71.91; p = 0.51). Infections including herpes zoster infections and serious infections were also similarly manifested. At 24 weeks, serious adverse events (RR 1.84; 95% CI 1.02-3.30; p = 0.04) were significantly higher with baricitinib 4 mg compared with the 2-mg dosage. However, total adverse events after the start of therapy, discontinuation of drug due to adverse events, malignancies, major adverse cardiac events, infections including herpes zoster, and serious infections were not significantly different between the two doses. CONCLUSIONS: No significant differences in adverse drug events were observed between baricitinib 2 mg and 4 mg at 12 weeks' follow-up. However, this analysis showed the risk of serious adverse events to be significantly higher with baricitinib 4 mg compared with baricitinib 2 mg at 24 weeks' follow-up. This hypothesis should be confirmed in larger trials with longer follow-up time periods.
29476097 Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. 2018 Feb 23 Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.
29533748 Guidelines for prophylaxis of Pneumocystis pneumonia cannot rely solely on CD4-cell count 2018 May OBJECTIVES: Guidelines for preventing Pneumocystis pneumonia (PCP) in HIV patients are based on CD4 below 200/mm3. Such cut-off value is suggested to guide prophylaxis in non-HIV conditions (NHIV) especially in autoimmune and inflammatory diseases (AD). We aimed to determine if CD4 could be used to guide PCP prophylaxis in AD. METHODS: CD4 and lymphocyte-count were retrospectively studied in patients diagnosed with PCP between January 2013 and February 2016. RESULTS: 129 patients were included. The median CD4-count was 302/mm3 in AD, which was significantly higher than in HIV patients (19/mm3; p<0.0001). Fifty percent (n=10) of AD patients had CD4 counts greater than 300/mm3. CONCLUSIONS: Prophylaxis for PCP cannot rely solely on CD4-count in NHIV patients especially in AD.