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ID PMID Title PublicationDate abstract
29667047 Investigation of the Mechanism of Therapeutic Protein-Drug Interaction Between Methotrexat 2018 Apr 17 A prominent example of human therapeutic protein-drug interaction (TP-DI) is between methotrexate (MTX) and anti-TNFα mAbs. One plausible mechanism for this TP-DI is through the pharmacodynamic effect of MTX on immunogenicity. However, there is no definitive evidence to substantiate this mechanism, and other competing hypotheses, such as MTX suppressing FcγRI expression thereby affecting mAb PK, have also been proposed. In order to understand this mechanism, a cynomolgus monkey study was conducted using golimumab as a model compound. Golimumab elicited high incidences of immunogenicity in healthy cynomolgus monkeys. Concomitant dosing of MTX delayed the onset and reduced the magnitude of anti-drug antibody (ADA) formation. The impact of MTX on golimumab PK correlated with the ADA status. Prior to ADA formation, MTX has no discernable effect on golimumab PK. Additionally, no alteration in FcγRI expression was observed following MTX treatment. The impact of MTX on golimumab immunogenicity and PK has been observed in patients with rheumatoid arthritis, psoriatic arthritis (PsA), and ankylosing spondylitis. In a representative phase 3 study of golimumab in patients with PsA, patients not receiving concomitant MTX was reported to have ~ 30% lower steady-state trough golimumab levels compared to those who received MTX. However, further analysis showed that PsA patients who were negative for ADA in both treatment groups had comparable trough levels of golimumab. Taken together, our results suggest that the mechanism of TP-DI between MTX and golimumab can mostly be attributed to the pharmacodynamic effect of MTX, i.e., the lowering of immunogenicity and immunogenicity-mediated clearance of mAbs.
29164814 Detection of Subclinical Arthritis in Mice by a Thrombin Receptor-Derived Imaging Agent. 2018 Jan OBJECTIVE: Functional imaging of synovitis could improve both early detection of rheumatoid arthritis (RA) and long-term outcomes. Given the intersection of inflammation with coagulation protease activation, this study was undertaken to examine coagulation protease activities in arthritic mice with a dual-fluorescence ratiometric activatable cell-penetrating peptide (RACPP) that has a linker, norleucine (Nle)-TPRSFL, with a cleavage site for thrombin. METHODS: K/BxN-transgenic mice with chronic arthritis and mice with day 1 passive serum-transfer arthritis were imaged in vivo for Cy5:Cy7 emission ratiometric fluorescence from proteolytic cleavage and activation of RACPP(NleTPRSFL) . Joint thickness in mice with serum-transfer arthritis was measured from days 0 to 10. The cleavage-evoked release of Cy5-tagged tissue-adhesive fragments enabled microscopic correlation with immunohistochemistry for inflammatory markers. Thrombin dependence of ratiometric fluorescence was tested by ex vivo application of RACPP(NleTPRSFL) and argatroban to cryosections obtained from mouse hind paws on day 1 of serum-transfer arthritis. RESULTS: In chronic arthritis, RACPP(NleTPRSFL) fluorescence ratios of Cy5:Cy7 emission were significantly higher in diseased swollen ankles of K/BxN-transgenic mice than in normal mouse ankles. A high ratio of RACPP(NleTPRSFL) fluorescence in mouse ankles and toes on day 1 of serum-transfer arthritis correlated with subsequent joint swelling. Foci of high ratiometric fluorescence localized to inflammation, as demarcated by immune reactivity for citrullinated histones, macrophages, mast cells, and neutrophils, in soft tissue on day 1 of serum-transfer arthritis. Ex vivo application of RACPP(NleTPRSFL) to cryosections obtained from mice on day 1 of serum-transfer arthritis produced ratiometric fluorescence that was inhibited by argatroban. CONCLUSION: RACPP(NleTPRSFL) activation detects established experimental arthritis, and the detection of inflammation by RACPP(NleTPRSFL) on day 1 of serum-transfer arthritis correlates with disease progression.
29628016 General and disease-specific pain trajectories as predictors of social and political outco 2018 Apr 9 BACKGROUND: While the heterogeniety of pain progression has been studied in chronic diseases, the extent to which patterns of pain progression among people in general as well as across different diseases affect social, civic and political engagement is unclear. We explore these issues for the first time. METHODS: Using data from the English Longitudinal Study of Ageing, latent class growth models were used to estimate trajectories of self-reported pain in the entire cohort, and within subsamples reporting diagnoses of arthritis and cancer. These were compared at baseline on physical health (e.g. body mass index, smoking) and over time on social, civic and political engagement. RESULTS: Very similar four-trajectory models fit the whole sample and arthritis subsamples, whereas a three-trajectory model fit the cancer subsample. All samples had a modal group experiencing minimal chronic pain and a group with high chronic pain that showed slight regression (more pronounced in cancer). Biometric indices were more predictive of the most painful trajectory in arthritis than cancer. In both samples the group experiencing the most pain at baseline reported impairments in social, civic and political engagement. CONCLUSIONS: The impact of pain differs between individuals and between diseases. Indicators of physical and psychological health differently predicted membership of the trajectories most affected by pain. These trajectories were associated with differences in engagement with social and civic life, which in turn were associated with poorer health and well-being.
29879214 Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody 2018 It is unclear how systemic administration of mesenchymal stem cells (MSCs) controls local inflammation. The aim of this study was to evaluate the therapeutic effects of human MSCs on inflammatory arthritis and to identify the underlying mechanisms. Mice with collagen antibody-induced arthritis (CAIA) received two intraperitoneal injections of human bone marrow-derived MSCs. The clinical and histological features of injected CAIA were then compared with those of non-injected mice. The effect of MSCs on induction of regulatory T cells was examined both in vitro and in vivo. We also examined multiple cytokines secreted by peritoneal mononuclear cells, along with migration of MSCs in the presence of stromal cell-derived factor-1 alpha (SDF-1α) and/or regulated on activation, normal T cell expressed and secreted (RANTES). Sections of CAIA mouse joints and spleen were stained for human anti-nuclear antibodies (ANAs) to confirm migration of injected human MSCs. The results showed that MSCs alleviated the clinical and histological signs of synovitis in CAIA mice. Peritoneal lavage cells from mice treated with MSCs expressed higher levels of SDF-1α and RANTES than those from mice not treated with MSCs. MSC migration was more prevalent in the presence of SDF-1α and/or RANTES. MSCs induced CD4+ T cells to differentiate into regulatory T cells in vitro, and expression of FOXP3 mRNA was upregulated in the forepaws of MSC-treated CAIA mice. Synovial and splenic tissues from CAIA mice receiving human MSCs were positive for human ANA, suggesting recruitment of MSCs. Taken together, these results suggest that MSCs migrate into inflamed tissues and directly induce the differentiation of CD4+ T cells into regulatory T cells, which then suppress inflammation. Thus, systemic administration of MSCs may be a therapeutic option for rheumatoid arthritis.
30061880 Long Non-Coding RNAs Play a Role in the Pathogenesis of Psoriatic Arthritis by Regulating 2018 Psoriatic arthritis (PsA) is an inflammatory arthritis, characterized by inflammation of entheses and synovium, leading to joint erosions and new bone formation. It affects 10-30% of patients with psoriasis, and has an estimated prevalence of approximately 1%. PsA is considered to be primarily an autoimmune disease, driven by autoreactive T cells directed against autoantigens present in the skin and in the joints. However, an autoinflammatory origin has recently been proposed. Long noncoding RNAs (lncRNAs) are RNAs more than 200 nucleotides in length that do not encode proteins. LncRNAs play important roles in several biological processes, including chromatin remodeling, transcription control, and post-transcriptional processing. Several studies have shown that lncRNAs are expressed in a stage-specific or lineage-specific manner in immune cells that have a role in the development, activation, and effector functions of immune cells. LncRNAs are thought to play a role in several diseases, including autoimmune disorders. Indeed, a few lncRNAs have been identified in systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Although several high-throughput studies have been performed to identify lncRNAs, their biological and pathological relevance are still unknown, and most transcriptome studies in autoimmune diseases have only assessed protein-coding transcripts. No data are currently available on lncRNAs in PsA. Therefore, by microarray analysis, we have investigated the expression profiles of more than 50,000 human lncRNAs in blood samples from PsA patients and healthy controls using Human Clariom D Affymetrix chips, suitable to detect rare and low-expressing transcripts otherwise unnoticed by common sequencing methodologies. Network analysis identified lncRNAs targeting highly connected genes in the PsA transcriptome. Such genes are involved in molecular pathways crucial for PsA pathogenesis, including immune response, glycolipid metabolism, bone remodeling, type 1 interferon, wingless related integration site, and tumor necrosis factor signaling. Selected lncRNAs were validated by RT-PCR in an expanded cohort of patients. Moreover, modulated genes belonging to meaningful pathways were validated by RT-PCR in PsA PBMCs and/or by ELISA in PsA sera. The findings indicate that lncRNAs are involved in PsA pathogenesis by regulating both microRNAs and genes and open new avenues for the identification of new biomarkers and therapeutical targets.
29531789 Knee joint synovitis: study of correlations and diagnostic performances of ultrasonography 2018 OBJECTIVES: Ultrasonography (US) is a fast, available and low-cost imaging tool used for detecting knee synovitis. Our aims were to assess the relationship between US and histology findings in appraising levels of inflammation and vascularity in the knee joint in subjects with inflammatory arthropathies; to determine whether differences exist in the appraisal between varying knee compartments and to compare US performances compared with gold standard histology for knee synovitis detection. METHODS: Subjects with actively inflamed knee joint having crystal arthropathies, rheumatoid arthritis, psoriatic arthritis or ostoearthritis were prospectively recruited from rheumatology clinics after giving their written consent between May and October 2015. Study was approved by the institutional ethics committee. The knee was divided into three compartments (medial, lateral, superior). Patients had a knee US followed by a knee arthroscopy with biopsies retrieval from each compartment. Biopsies were blindly scored for lining layer hyperplasia, inflammation, vascularity, CD68 and factor VIII staining. Correlation was determined using the Spearman's correlation test. RESULTS: 26 patients with active arthritis in a knee joint and recent onset of disease were prospectively included. Strong correlations were observed between US synovitis grade and histological inflammation score (r=0.63; P=0.002), US Doppler grade and histological score for vascularity (r=0.68; P<0.001); US measured synovial thickness and lining layer hyperplasia (r=0.61; P=0.002). Moderate correlation was found between US synovitis grade and CD68 score (r=0.49; P=0.02). CONCLUSION: US findings correlate with histological inflammation and vascularity scores in actively inflamed knee joints. US accurately describes knee synovitis.
29485013 Development of Microemulsion Based Nabumetone Transdermal Delivery for Treatment of Arthri 2018 BACKGROUND: Nabumetone is biopharmaceutics classification system (BCS) class II drug, widely used in the treatment of osteoarthritis and rheumatoid arthritis. The most frequently reported adverse reactions for the drug involve disturbance in gastrointestinal tract, diarrhea, dyspepsia and abdominal pain. Microemulgel has advantages of microemulsion for improving solubility for hydrophobic drug. Patent literature had shown that the work for drug has been carried on spray chilling, enteric coated tablet, and topical formulation which gave an idea for present research work for the development of transdermal delivery. OBJECTIVE: The objective of the present research work was to optimize transdermal microemulgel delivery for Nabumetone for the treatment of arthritis. METHODS: Oil, surfactant and co-surfactant were selected based on solubility study of the drug. Gelling agents used were Carbopol 934 and HPMC K100M. Optimization was carried out using 32 factorial design. Characterization and evaluation were carried out for microemulsion and microemulsion based gel. RESULTS: Field emission-scanning electron microscopy (FE-SEM) study of the microemulsion revealed globules of 50-200 nm size. Zeta potential -9.50 mV indicated good stability of microemulsion. Globule size measured by dynamic light scattering (zetasizer) was 160nm. Design expert gave optimized batch as F7 which contain 0.2% w/w drug, 4.3% w/w liquid paraffin, 0.71% w/w tween 80, 0.35% w/w propylene glycol, 0.124% w/w Carbopol 934, 0.187% w/w HPMC K100M and 11.68% w/w water. In-vitro diffusion study for F7 batch showed 99.16±2.10 % drug release through egg membrane and 99.15±2.73% drug release in ex-vivo study. CONCLUSION: Nabumetone microemulgel exhibiting good in-vitro and ex-vivo controlled drug release was optimized.
29982712 Serum immunoglobulin free light chains are sensitive biomarkers for monitoring disease act 2018 Oct 1 OBJECTIVES: Serum immunoglobulin free light chains (FLCs) are frequently elevated in B-cell-mediated autoimmune diseases, including primary SS (pSS). The objective of this study was to assess if serum FLCs can contribute to classification, mucosa-associated lymphoid tissue (MALT) lymphoma detection, monitoring of disease activity and treatment response in pSS. METHODS: Serum samples of 100 consecutive patients suspected of pSS were included. Forty-five patients fulfilled ACR-EULAR criteria for pSS. Additionally, samples of 17 pSS patients with MALT lymphoma and longitudinal samples of pSS patients treated with rituximab (n = 20), placebo (n = 10) or abatacept (n = 15) were included. Serum FLCκ/FLCλ was measured by nephelometry or turbidimetry. RESULTS: At diagnosis, FLCκ and FLCλ serum levels were significantly higher in pSS compared with non-SS sicca patients. The FLCκ/FLCλ ratio was abnormal in 11% of pSS patients. In established MALT-pSS patients, without recent rituximab treatment (n = 12), 50% had abnormal FLCκ/FLCλ ratios. FLC measurement had no additional value for pSS classification, compared with IgG and anti-SSA. FLC levels correlated significantly with systemic disease activity, assessed by EULAR SS Disease Activity Index (ESSDAI) and clinical ESSDAI, both cross-sectionally and longitudinally following treatment. Treatment with rituximab or abatacept significantly lowered FLC levels. FLCs show a large sensitivity to change and relative changes induced by treatment were higher compared with IgG. CONCLUSION: Serum FLCs are elevated in pSS, and abnormal FLCκ/FLCλ ratios may be indicative for the presence of MALT lymhoma. FLC levels can be used as a biomarker for systemic disease activity and monitoring treatment responses. FLCs are sensitive to change and have more favorable kinetics than IgG.
30223431 Severity of Sjögren's Syndrome Keratoconjunctivitis Sicca Increases with Increased Percen 2018 Sep 14 This study investigated the relationship between clinical severity and percentage of conjunctival antigen-presenting cells (APCs) in Sjögren's syndrome (SS)-associated keratoconjunctivitis sicca (KCS). KCS clinical severity was based on symptom severity, tear volume, tear break-up time, and ocular surface dye staining. Conjunctival goblet cell density (GCD) was measured in periodic acid Schiff (PAS)-stained membranes. Conjunctival cells obtained by impression cytology were used for flow cytometry to measure percentages of CD45⁺HLA-DR⁺ APCs and mature CD11c⁺CD86⁺ dendritic cells (DCs). Compared to normal conjunctiva, the percentages of HLA-DR⁺ and CD11c⁺CD86⁺ cells were higher in the conjunctiva of the KCS group (p < 0.05). The percentage of CD45⁺HLA-DR⁺ cells positively correlated with clinical severity (r = 0.71, p < 0.05) and negatively correlated with GCD (r = -0.61, p < 0.05). Clinical severity also negatively correlated with GCD (r = -0.54, p < 0.05). These findings indicate that a higher percentage of APCs and mature DCs in the conjunctiva is associated with more severe KCS in SS. These APCs may contribute to the generation of the pathogenic Th1 cells that cause goblet cell loss in KCS.
29680668 Anti-IL-7 receptor-α treatment ameliorates newly established Sjögren's-like exocrinopath 2018 Jul The levels of interleukin (IL)-7 and its receptor are elevated in the salivary glands of patients with Sjögren's syndrome (SS). Our previous study indicates that IL-7 plays a critical pathogenic role in the development and onset of SS in a mouse model of this disease. The present study aims at determining whether IL-7 also plays a role in sustaining SS pathologies after the disease onset, by using the non-obese diabetic (NOD) model. Intraperitoneal administration of a blocking antibody against the IL-7 receptor α chain (IL-7Rα) to female NOD mice aged 10 weeks, which exhibited newly onset clinical SS, for the duration of 3 weeks significantly ameliorated characteristic SS pathologies including hyposalivation and leukocyte infiltration of the submandibular glands (SMGs). These changes were accompanied by a decrease in IFN-γ-producing CD4 T- and CD8 T cells, B cells, and lymphocyte chemoattractants CXCL9, -10, -11 and -13 in the SMGs. Anti-IL-7Rα treatment markedly diminished the amount of TNF-α in the SMGs and increased the level of claudin-1 and aquaporin 5, two molecules critical for normal salivary secretion. Furthermore, neutralization of IFN-γ and TNF-α, individually or in combination, considerably improved salivary secretion, reduced leukocyte infiltration and down-regulated CXCL9 and -13 expression in the SMGs. Collectively, the results indicate that endogenous IL-7R signals promote Th1 and Tc1 responses and IFN-γ- and TNF-α production to sustain the persistence of SS-like sialadenitis in NOD mice. These findings suggest that IL-7 and Th1 cytokines could serve as promising therapeutic targets for this prevalent autoimmune disease.
30024967 The spinal NR2BR/ERK2 pathway as a target for the central sensitization of collagen-induce 2018 OBJECTIVE: Pain management is a huge challenge in the treatment of rheumatoid arthritis (RA), and central sensitization is reportedly involved in the development of pain. The current study was undertaken to explore the possible role of N-methyl-D-aspartate receptors (NMDARs) in the spinal mechanism of central sensitization in RA using a collagen-induced arthritis (CIA) model. METHODS: Mechanical hypersensitivity was assessed in C57BL/6 mice, before and after the induction of CIA via administration of chick type II collagen. Analgesic drugs, receptor antagonist, and kinase inhibitor were administrated intrathecally in the spinal cord. Protein expression and phosphorylation changes were detected via immunoblotting. RESULTS: CIA mice developed significant mechanical hypersensitivity, and spinal administration of the NMDAR antagonist D-2-amino-5-phosphonovaleric acid (D-APV) effectively attenuated peripheral pain hypersensitivity. There was specific enhancement of synaptic NR2B-containing NMDAR (NR2BR) expression in the spinal dorsal horns of the mice. Both the increased total protein expression of NR2B subunit and the enhanced total phosphorylation level of NR2B subunit at 1472 tyrosine promoted the synaptic expression of NMDAR in the mice. Intrathecal injection of tramadol suppressed synaptic NMDAR expression mainly by changing the synaptic phosphorylation state of NR2B subunit at Tyr1472. Extracellular signal-regulated protein kinases 2 (ERK2) activity synchronized with the synaptic expression of NR2BR, which was downregulated by the action of tramadol. CONCLUSION: Specific enhancement of NR2BR in the spinal dorsal horn may be vital for central sensitization in the CIA model of RA. The NR2BR/ERK2 pathway may be a promising target for pain management in RA patients.
31065150 Early Undifferentiated Arthritis: A Developing Country Perspective from Nepal. 2018 Nov Early undifferentiated arthritis is a group of inflammatory joint disease of less than 3 months duration that do not classify under any of the specific rheumatic or connective tissue disorder. Previously, inflammatory arthritis used to be treated only when there was a clear evidence of damage or deformity occurring with it. Use of disease modifying anti-rheumatic drugs were considered potentially harmful early in the course of arthritis which could be self-limiting. However, with the abundance of data on outcomes of early arthritis and identification of factors that can help to predict those outcomes lead to earlier use of such DMARDs. Better understanding of serological tests like anti-CCP antibodies and imaging modalities like high frequency ultrasound with power doppler and magnetic resonance imaging has increased the diagnostic and prognostic yield of such early arthritis cases. It is now imperative that the risk be assessed early in the course of disease and early DMARDs be instituted for better outcome in these cases. This review analyses the historical evolution of evidence in the management of early undifferentiated arthritis and summarises the treatment approach, monitoring and disease outcomes till date. Keywords: arthritides; Nepal; power doppler; rheumatoid; ultrasonography.
29936438 Methotrexate and BAFF interaction prevents immunization against TNF inhibitors. 2018 Oct OBJECTIVES: TNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this risk of immunisation. METHODS: We treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi. We investigated the effect of a single course of MTX during the first exposure to TNFi. Wild-type (WT) and BAFFtg mice were compared for B-Cell surface markers involved in MTX-related purinergic metabolism, adenosine production and regulatory B-cells (Bregs).We translated the study to macaques and patients with rheumatoid arthritis from the ABIRISK cohort to determine if there was an interaction between serum BAFF levels and MTX that prevented immuniation. RESULTS: In BAFFtg but not in WT mice or macaques, a single course of MTX prevented immunisation against TNFi and maintained drug concentration for over 52 weeks. BAFFtg mice B-cells expressed more CD73 and CD39 compared to WT mice. MTX induced adenosine release from B cells and increased Bregs and precursors. Use of CD73 blocking antibodies reversed MTX-induced tolerance. In patients from the ABIRISK cohort treated with TNFi for chronic inflammatory diseases, high BAFF serum level correlated with absence of ADA to TNFi only in patients cotreated with MTX but not in patients on TNFi monotherapy. CONCLUSION: MTX and BAFF interact in mice where CD73, adenosine and regulatory B cells were identified as key actors in this phenomenon. MTX and BAFF also interact in patients to prevent ADA formation.
29680963 Anti-inflammatory and anti-angiogenic activities in vitro of eight diterpenes from Daphne 2018 Jun Rheumatoid arthritis (RA) is one of the most prevalent chronic inflammatory and angiogenic diseases. The aim of this study was to evaluate the anti-inflammatory and anti-angiogenic activities in vitro of eight diterpenoids isolated from Daphne genkwa. LC-MS was used to identify diterpenes isolated from D. genkwa. The anti-inflammatory and anti-angiogenic activities of eight diterpenoids were evaluated on LPS-induced macrophage RAW264.7 cells and TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) using hierarchical cluster analysis (HCA) and principal component analysis (PCA). The eight diterpenes isolated from D. genkwa were identified as yuanhuaphnin, isoyuanhuacine, 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl, yuanhuagine, isoyuanhuadine, yuanhuadine, yuanhuaoate C and yuanhuacine. All the eight diterpenes significantly down-regulated the excessive secretion of TNF-α, IL-6, IL-1β and NO in LPS-induced RAW264.7 macrophages. However, only 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl markedly reduced production of VEGF, MMP-3, ICAM and VCAM in TNF-α-stimulated HUVECs. HCA obtained 4 clusters, containing 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl, isoyuanhuacine, isoyuanhuadine and five other compounds. PCA showed that the ranking of diterpenes sorted by efficacy from highest to lowest was 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl, yuanhuaphnin, isoyuanhuacine, yuanhuacine, yuanhuaoate C, yuanhuagine, isoyuanhuadine, yuanhuadine. In conclusion, eight diterpenes isolated from D. genkwa showed different levels of activity in LPS-induced RAW264.7 cells and TNF-α-stimulated HUVECs. The comprehensive evaluation of activity by HCA and PCA indicated that of the eight diterpenes, 12-O-(2'E,4'E-decadienoyl)-4-hydroxyphorbol-13-acetyl was the best, and can be developed as a new drug for RA therapy.
29894669 Succinate receptor deficiency attenuates arthritis by reducing dendritic cell traffic and 2018 Jun 12 Rheumatoid arthritis is a chronic inflammatory disease that leads to significant changes in metabolic activity. Succinate, an intermediate of the tricarboxylic acid cycle, has emerged as a metabolic mediator of the innate immune response. However, the involvement of succinate in the generation of the adaptive immune response and establishment of autoimmune response has not been addressed thus far. Here we demonstrated that the succinate-sensing receptor (Sucnr1/GPR91) plays a critical role in the development of immune-mediated arthritis. We found that Sucnr1 acts as a chemotactic gradient sensor that guides dendritic cells (DCs) into the lymph nodes, orchestrating the expansion of the T helper (T(h))17-cell population and the development of experimental antigen-induced arthritis. Sucnr1(-/-) mice show reduced articular hyperalgesia, neutrophil infiltration and inflammatory cytokines in the joint, and reduced frequency of T(h)17 cells in draining lymph nodes. Adoptive transfer of wild-type (WT) DCs into Sucnr1(-/-) mice restored the development of arthritis. Moreover, DC-depleted mice transferred with Sucnr1(-/-) DCs developed less arthritis than mice transferred with WT DCs. In contrast, succinate given together with the immunization boosted the recruitment of DCs and the frequency of T(h)17 cells in draining lymph nodes, increasing arthritis severity. Therefore, the blockade of Sucnr1 may represent a novel therapeutic target of arthritis.-Saraiva, A. L., Veras, F. P., Peres, R. S., Talbot, J., de Lima, K. A., Luiz, J. P., Carballido, J. M., Cunha, T. M., Cunha, F. Q., Ryffel, B., Alves-Filho, J. C. Succinate receptor deficiency attenuates arthritis by reducing dendritic cell traffic and expansion of T(h)17 cells in the lymph nodes.
29467856 Smoking and female sex as key risk factors associated with severe arthralgia in acute and 2018 Mar Arthralgia is a potentially incapacitating condition and a persistent symptom in chronic or acute episodes of Chikungunya fever caused by infection with the Chikungunya virus (CHIKV). To the best of our knowledge, there are no reports on risk factors associated with the intensity of arthralgias in typical acute episodes of the disease. Although a number of studies have reported on risk factors associated with the development of the chronic stage of the disease, smoking habits have not been analyzed. Smoking is an interesting factor to consider since it is the main environmental risk factor for the development of rheumatoid arthritis (RA), a similar disease to CHIKV in many aspects. In the present study, 140 patients infected with CHIKV were assessed for risk factors associated with severe arthralgia intensity in the acute phase (pain of 9/10 on the visual analog scale of 0-10) and moderate to severe intensity (according to the Routine Assessment of Patient Index Data 3) 3.5 months after infection in patients that experienced the chronic phase of the disease. Women and smokers were 2- to 3-times more likely to experience severe pain in the acute and chronic stages. Likewise, the presence of severe arthralgia during the acute disease phase resulted in a 4-fold increased risk for entering the chronic phase. Smoking was a more important risk factor in males compared with females. Smoking resulted in a 20-fold increased risk for severe arthralgia during the acute phase in men, as well as a 10-fold increased risk for developing chronic disease with moderate-to-severe pain 3.5 months after the acute stage. The presence of rash, headache, muscular weakness or conjunctivitis in the acute phase, the presence of diabetes and age >40 years were considered significant risk factors due to their influence on illness progression. In conclusion, smoking and female sex were the main risk factors associated with development of severe joint pain in the acute and chronic phases of Chikungunya fever. These risk factors are similar to those associated with the development and severity of RA, possibly because the two diseases share pathophysiological mechanisms, including elevated interleukin-6 levels.
29103180 Safety of weekly adalimumab in the treatment of juvenile idiopathic arthritis and pediatri 2018 Feb Weekly adalimumab dosing is used to treat juvenile idiopathic arthritis (JIA), uveitis, and other pediatric rheumatic diseases, but the safety of such dosing has not previously been studied. A retrospective chart review was conducted to assess the safety of weekly adalimumab. Demographic and clinical data were collected. Basic descriptive analysis was performed to assess for adverse events from weekly adalimumab. Sixty-nine patients at the University of Minnesota or Gillette Children's Hospital were identified as treated with weekly adalimumab. Sixty (87%) were eligible for the chart review. Weekly adalimumab was used most commonly to treat uveitis (28%, 17/60) and rheumatoid factor-negative polyarticular JIA (25%, 15/60). Mean age at the start of weekly dosing was 13.9 years. The majority of patients were concurrently treated with a non-steroidal anti-inflammatory drug and methotrexate. Fifty-three (90%) patients continued weekly dosing for greater than 3 months. The mean duration of weekly adalimumab was 2 years. Throughout the duration of weekly dosing, 24/60 (40%) patients had documented minor infections not requiring antimicrobials and 24/60 (40%) had documented infections requiring antimicrobial treatment. Only three patients (5%) had an infection requiring hospitalization. Two patients (3%) developed autoimmune disease. Laboratory abnormalities and injection site reactions were rare. Weekly adalimumab was used most commonly to treat uveitis and rheumatoid factor-negative polyarticular JIA, and mean duration of weekly dosing was 2 years. Serious adverse events were rare.
30203153 [Value of combining biologics with methotrexate for treatment of psoriatic arthritis-quest 2018 Nov BACKGROUND: Concomitant methotrexate (MTX) improves the therapeutic effect of biologic therapies in rheumatoid arthritis treatment. However, the influence of MTX on biologic therapy in psoriasis arthritis (PsA) has not yet been fully clarified, as data from randomized clinical studies are lacking. So far, it is only known, that PsA patients with inadequate response to MTX or non-steroidal anti-inflammatory drugs alone respond equally well to a subsequent biologic therapy. OBJECTIVES: The aim of this study is to investigate whether MTX-naive patients achieve greater disease improvement with the combination of MTX and a biologic than with biologic monotherapy alone, and whether patients on MTX in whom a biologic therapy is additionally started would worsen if MTX is discontinued. METHODS: The current data situation and its limitations are presented. Furthermore, an investigator-initiated multicenter randomized clinical study in patients with active PsA is introduced (MUST study), which investigates the influence of placebo-controlled MTX combination therapy with the interleukin 12/23 inhibitor ustekinumab (UST) in order to close the existing evidence gap. RESULTS: The primary objective of the study is to demonstrate the non-inferiority of UST monotherapy compared to MTX/UST combination therapy as measured by mean DAS28 values at week 24. Of 196 planned patients, 77 have been included so far. Recruitment is still open. CONCLUSION: The MUST study offers the ideal opportunity to investigate the influence of concomitant MTX in a controlled study design and to assess whether the addition of MTX to UST therapy or its continuation is beneficial for PsA patients.
29447014 Macrophage migration inhibitory factor (MIF) inhibitor, Z-590 suppresses cartilage destruc 2018 Apr BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator that is involved in the progression of rheumatoid arthritis (RA). Previously, we demonstrated a small molecule compound 3-[(biphenyl-4-ylcarbonyl) carbamothioyl] amino benzoic acid (Z-590) could inhibit MIF activity with docking-based virtual screening and experimental evaluation. METHODS: The LPS activated RAW264.7 macrophage cells were used to determine the anti-inflammatory effects of Z-590 in vitro. A rat adjuvant-induced arthritis (AIA) model was used to determine the anti-arthritic effects of Z-590 in vivo. RESULTS: MIF inhibitor Z-590 significantly inhibited the production of NO, TNF-α and IL-6 in LPS-activated RAW 264.7 macrophage cells and markedly inhibited LPS-induced expression of TNF-α, IL-6, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Z-590 also significantly reduced paw edema, serum level of TNF-α, IL-6 and spleen index in the adjuvant-induced arthritis (AIA) rat model. Furthermore, Z-590 markedly ameliorated joint inflammation and articular cartilage damage in AIA rat model. CONCLUSION: MIF inhibitor Z-590 possesses potent anti-arthritic activity through suppression of macrophage activation, and could be a potential therapeutic treatment for RA.
28960267 Anti-IL-23 and Anti-IL-17 Biologic Agents for the Treatment of Immune-Mediated Inflammator 2018 Jan Advancements in the immunopathogenesis of psoriasis have identified interleukin (IL)-23 and IL-17 as fundamental contributors in the immune pathways of the disease. Leveraging these promising therapeutic targets has led to the emergence of a number of anti-IL-23 and -17 biologic agents with the potential to treat multiple conditions with common underlying pathology. The unprecedented clinical efficacy of these agents in the treatment of psoriasis has paved way for their evaluation in diseases such as psoriatic arthritis, Crohn's disease, rheumatoid arthritis, in addition to other immune-mediated conditions. Here we review the IL-23/IL-17 immune pathways and discuss the key clinical and safety data of the anti-IL-23 and anti-IL-17 biologic agents in psoriasis and other immune-mediated diseases.