Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
28303384 Spinopelvic parameter changes and low back pain improvement due to femoral neck anteversio 2018 Jan PURPOSE: The study of the interrelation between hip and spine disorders is gaining increasing importance in the last years, but the link between Hip Osteoarthritis (HOA) and Low Back Pain (LBP) remains still unclear. Aim of the study is to assess the relationship between Femoral Neck Anteversion (FNA), LBP, and spinopelvic parameters in patients undergoing Total Hip Replacement (THR) for unilateral severe primary HOA. MATERIALS AND METHODS: 91 patients were recruited. Inclusion criteria were: grade 5 or 6 unilateral HOA, according to Turmezei, and Harris Hip score (HHS) <60. Exclusion criteria were: secondary hip osteoarthritis (dysplasia of the hip, rheumatoid arthritis, and ankylosing spondylitis); previous surgery of the spine, hip or knee; scoliosis with a Cobb angle greater than 10°; spondylolisthesis; history of spine fractures; previous bone tuberculosis or any spine infections; any contraindications to CT; BMI >30. Patients were divided into two homogeneous Groups according to the presence (Group-A) or not of concomitant LBP (Group-B). All patients underwent preoperatively a hip CT scan to evaluate FNA, Acetabular Anteversion (AA), and Combined Anteversion (CA = FNA + AA). ΔFNA, ΔAA and ΔCA were calculated as the differences between the arthritic hip and the normal hip angles in each Group. Full spinal X-rays in upstanding position were performed before (baseline) and 6 months after THR (follow-up) to calculate spinopelvic parameters. The health-related quality of life (HRQoL) was evaluated at baseline and at follow-up using Visual Analogue Scale (VAS), HHS, Oswestry Disability Index (ODI), Roland-Morris Disability Questionnaire (RM), and Short-Form Health Survey (SF-36). The intra-group and inter-group variability were assessed using, respectively, paired and unpaired t tests. At baseline, the association between HRQoL scores and ΔFNA, ΔAA, and ΔCA was analysed by the Pearson correlation test. RESULTS: At baseline, in Group-A, there was a significant difference between arthritic FNA and normal hip FNA, while no differences were found in AA between the two hips. A close correlation was observed between ΔFNA and Spine-VAS (r = 0.788), ODI (r = 0.824), and RM (r = 0.775). In Group-B, there was not a significant difference in FNA and AA between the two hips. At recruitment, in Group-A patients, we recorded a higher LL, SS, PI, SVA(C7), and a lower PT and T1-SPI compared with Group-B subjects. Six months after THR, in Group-A, an improvement of all clinical scores was recorded, as well as, a significant reduction of SS, LL, T1PA, and SVA(C7) and an increment of PT. In Group-B, at follow-up, an improvement of HHS, Hip-VAS, and SF-36 was recorded, while the changes in spinopelvic parameters were not significant. CONCLUSIONS: Patients with concomitant unilateral HOA and LBP showed a marked anteverted FNA in the arthritic hip and a spinopelvic misalignment. After THR, a relief of both hip and low back pain and a change in spinopelvic parameters is observed.
27909085 A Negative Antinuclear Antibody Does Not Indicate Autoantibody Negativity in Myositis: Rol 2017 Feb OBJECTIVE: To evaluate the utility of anticytoplasmic autoantibody (anti-CytAb) in antisynthetase antibody-positive (anti-SynAb+) patients. METHODS: Anti-SynAb+ patients were evaluated for antinuclear antibody (ANA) and anti-CytAb [cytoplasmic staining on indirect immunofluorescence (IIF)] positivity. Anti-SynAb+ patients included those possessing anti-Jo1 and other antisynthetase autoantibodies. Control groups included scleroderma, systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, and healthy subjects. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy of anti-CytAb, and ANA were assessed. Anti-CytAb and ANA testing was done by IIF on human epithelial cell line 2, both reported on each serum sample without knowledge of the clinical diagnosis or final anti-SynAb results. RESULTS: Anti-SynAb+ patients (n = 202; Jo1, n = 122; non-Jo1, n = 80) between 1985-2013 with available serum samples were assessed. Anti-CytAb showed high sensitivity (72%), specificity (89%), NPV (95%), and accuracy (86%), but only modest PPV (54%) for anti-SynAb positivity. In contrast, ANA showed only modest sensitivity (50%) and poor specificity (6%), PPV (9%), NPV (41%), and accuracy (12%). Positive anti-CytAb was significantly greater in the anti-SynAb+ patients than ANA positivity (72% vs 50%, p < 0.001), and 81/99 (82%) ANA-negative patients in the anti-SynAb+ cohort had positive anti-CytAb. In contrast, the control groups showed high rates for ANA positivity (93.5%), but very low rates for anti-CytAb positivity (11.5%). Combining anti-CytAb or Jo1 positivity showed high sensitivity (92%) and specificity (89%) for identification of anti-SynAb+ patients. CONCLUSION: Assessing patients for anti-CytAb serves as an excellent screen for anti-SynAb+ patients using simple IIF. Cytoplasmic staining should be assessed and reported for patients suspected of having antisynthetase syndrome and a negative ANA should not be used to exclude this diagnosis.
27878564 The role of B7 family costimulatory molecules and indoleamine 2,3-dioxygenase in primary S 2017 Jun B7 costimulatory molecules are present on antigen-presenting cells (APCs) and influence intracellular expression of indoleamine 2,3-dioxygenase (IDO), a molecule with important immunoregulatory functions. We determined the frequency of activated (CD11b+) monocytes expressing B7-1, B7-2, B7-H1, and B7-H2 molecules, and that of CD3+ and CD4+ T cells expressing the corresponding CD28, CTLA-4, PD-1, and ICOS receptors in peripheral blood samples of 20 healthy adults and 9 SSc and 15 pSS patients using flow cytometry. We also examined the intracellular expression of IDO. The expression of CD28 was lower in both SSc and pSS patients. The frequency of CTLA-4 was increased in pSS. The expression of ICOS, a stimulator of T cell activation, was elevated in pSS, but not in SSc, while that of its corresponding costimulatory molecule, B7-H2, was strongly decreased in SSc compared to controls. The frequency of PD-1 expressing T lymphocytes was decreased in both pSS and SSc. The frequency of IDO-expressing APCs, as well as intracellular IDO content in T cells was higher in pSS than in controls. Our investigation identified a number of differences in B7 costimulation between SSc and pSS patients which may play a role in the distinct pathogenesis and clinical features of these autoimmune disorders.
28959900 Expression of activation-induced cytidine deaminase splicing variants in patients with ank 2017 Dec To investigate the expression patterns of activation-induced cytidine deaminase (AID) variants in peripheral blood mononuclear cells (PBMCs) of patients with ankylosing spondylitis (AS) and examine their clinical implications, we isolated PBMCs from healthy controls (HC, n = 33) and patients with AS (n = 62), and measured mRNA expression of AID variants and translesion synthesis (TLS) polymerases using quantitative real-time polymerase chain reaction. The proportion of patients with AS in whom AID splicing variant (sv) 2 was expressed was significantly higher than that of HC (p = .031). 80.7% of AS patients were treated with tumour necrosis factor inhibitor (TNFi). Significantly higher proportion of the TNFi-treated group expressed sv2 compared to the TNF-naïve group (p = .037). And we compared the level of AID variants expression between the TNFi-treated group and the TNF-naïve group. The expression levels of AID full-length (FL) and sv1 were significantly lower in the TNFi-treated group than the TNF-naïve group (FL: p = .002, sv1: p = .045). In addition, we investigated mRNA expression levels of translesion synthesis (TLS) polymerases in PBMCs from patients with AS and HC. The expression level of TLS pol ι was significantly lower in patients with AS than in HC (p = .007). In conclusion, AS patients expressed significantly higher levels of sv2 than HC. TNFi treatment restored the gene expression of the AID variants (FL, sv1, and sv2) in patients with AS. A clear understanding of the underlying cellular and molecular mechanisms will help to identify the pathogenesis of AS better and to develop novel therapeutic targets.
29173689 Esophageal abnormalities in juvenile localized scleroderma: is it associated with other ex 2017 Nov OBJECTIVE: To assess esophageal involvement (EI) in juvenile localized scleroderma (JLS) population and the possible association between this gastrointestinal manifestation and demographic data, clinical features, laboratory exams, treatments and outcomes. METHODS: For a period of 30 years, 5881 patients with rheumatic diseases were followed in our Pediatric Rheumatology Division. EI was defined by the presence of symptoms (solid/liquid dysphagia, heartburn, esophageal regurgitation, nausea/vomiting and epigastralgia) and confirmed by at least one EI exam abnormality: barium contrast radiography, upper gastrointestinal endoscopy and 24-hour esophageal pH-monitoring. RESULTS: JLS was observed in 56/5881 patients (0.9%), mainly linear morphea subtype. EI was observed in 23/56(41%) of JLS patients. Eight(35%) of 23 EI patients with JLS were symptomatic and presented heartburn(5/8), solid and liquid dysphagia(3/8), nausea and epigastralgia(1/8). The frequency of any cumulative extracutaneous manifestations (calcinosis, arthritis/arthralgia, central nervous system, interstitial pneumonitis, mesangial nephritis and/or arrhythmia) was significantly higher in JLS patients with EI compared to those without this complication (56% vs. 24%, p=0.024). No differences were evidenced in demographic data, JLS subtypes and in each extracutaneous manifestation in both groups (p>0.05). The frequency of methotrexate use was significantly higher in JLS patients with EI compared to those without (52% vs. 12%, p=0.002). Autoantibody profile (antinuclear antibodies, anti-SCL-70, rheumatoid factor, anticentromere, anti-cardiolipin, anti-Ro/SSA and anti-La/SSB) was similar in both groups (p>0.05). CONCLUSIONS: Our study demonstrated that EI was frequently observed in JLS patients, mainly in asymptomatic patients with linear subtype. EI occurred in JLS patients with other extracutaneous manifestations and required methotrexate therapy.
28389407 D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and bre 2017 Jul D-penicillamine (DPEN), a copper chelator, has been used in the treatment of Wilson's disease, cystinuria, and rheumatoid arthritis. Recent evidence suggests that DPEN in combination with biologically relevant copper (Cu) concentrations generates H(2)O(2) in cancer cell cultures, but the effects of this on cancer cell responses to ionizing radiation and chemotherapy are unknown. Increased steady-state levels of H(2)O(2) were detected in MB231 breast and H1299 lung cancer cells following treatment with DPEN (100µM) and copper sulfate (15µM). Clonogenic survival demonstrated that DPEN-induced cancer cell toxicity was dependent on Cu and was significantly enhanced by depletion of glutathione [using buthionine sulfoximine (BSO)] as well as inhibition of thioredoxin reductase [using Auranofin (Au)] prior to exposure. Treatment with catalase inhibited DPEN toxicity confirming H(2)O(2) as the toxic species. Furthermore, pretreating cancer cells with iron sucrose enhanced DPEN toxicity while treating with deferoxamine, an Fe chelator that inhibits redox cycling, inhibited DPEN toxicity. Importantly, DPEN also demonstrated selective toxicity in human breast and lung cancer cells, relative to normal untransformed human lung or mammary epithelial cells and enhanced cancer cell killing when combined with ionizing radiation or carboplatin. Consistent with the selective cancer cell toxicity, normal untransformed human lung epithelial cells had significantly lower labile iron pools than lung cancer cells. These results support the hypothesis that DPEN mediates selective cancer cell killing as well as radio-chemo-sensitization by a mechanism involving metal ion catalyzed H(2)O(2)-mediated oxidative stress and suggest that DPEN could be repurposed as an adjuvant in conventional cancer therapy.
28770711 Chinese lupus treatment and research group (CSTAR) registry: X. family history in relation 2018 Jan OBJECTIVES: This study aimed to examine the associations between family history and clinical manifestations and immunologic characteristics of lupus in China. METHODS: Based on their family history, lupus patients from the Chinese lupus treatment and research group (CSTAR) registry were categorised: familial lupus (FL), family history of other rheumatic disorders (RD), and sporadic lupus (SL). Demographic data, clinical manifestations, and laboratory data were compared among these three groups. RESULTS: A total of 2,104 patients from CSTAR were included, with 34 (1.6%) in the FL group, 50 (2.4%) in the RD group, and 2,020 (96.0%) in the SL group. There were no significant differences in age or gender among these groups (p=0.36 and p=0.75, respectively). The prevalence of discoid rash and positivity of anti-RNP antibodies differed significantly among the three groups. Photosensitivity and neurological disorder were marginally significantly different among the three groups (p=0.05). No statistical differences were observed in other clinical manifestations or laboratory results. In the FL group, first-degree relatives (25/34, 73.5%) had higher susceptibility to lupus. Rheumatoid arthritis (RA) (35/50, 70.0%) was the most frequent non-lupus rheumatic disorder in the RD group. CONCLUSIONS: Among lupus patients, the rate of familial lupus was lower in Chinese patients than among other ethnicities. Familial lupus cases are found mainly among their first-degree relatives. A family history of lupus did not significantly affect clinical phenotypes, except for higher frequency of discoid rash and anti-RNP in the FL group, and more anti-RNP positivity in the RD group.
27989618 Pharmacokinetic Interactions Between Pelubiprofen and Eperisone Hydrochloride: A Randomize 2017 Jan PURPOSE: Pelubiprofen is a novel nonsteroidal anti-inflammatory, analgesic, and antipyretic drug with at least similar efficacy and better tolerability compared with other nonsteroidal anti-inflammatory, analgesic, and antipyretic drugs such as naproxen and aceclofenac. Eperisone hydrochloride is a centrally acting muscle relaxant that performs by blocking calcium channels. The combined use of pelubiprofen and eperisone hydrochloride is increasingly anticipated to promote the clinical effectiveness of pelubiprofen in relieving musculoskeletal symptoms of osteoarthritis, rheumatoid arthritis, and low back pain. No published data are yet available, however, regarding the pharmacokinetic interactions between these 2 drugs when administered concurrently. The objective of this study was to evaluate any pharmacokinetic interactions between pelubiprofen and eperisone hydrochloride in healthy Korean male volunteers. METHODS: This was a randomized, open-label, crossover study. Each participant was randomly assigned to 1 of 6 treatment sequences and orally received either 45-mg sustained-release pelubiprofen, 75-mg sustained-release eperisone hydrochloride, or both as a single dose in each treatment period, with a 7-day washout period between each treatment. Serial blood samples were collected over 24 hours after dosing, and plasma concentrations of each drug and the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen) were determined by using a validated HPLC-MS/MS system. Pharmacokinetic analyses were conducted by using noncompartmental methods. FINDINGS: A total of 24 men (mean ± standard deviation of: age, 29 ± 4 years; weight, 72.5 ± 7.8 kg; body mass index, 23.4 ± 1.9 kg/m(2)) were enrolled, and 23 participants completed the study. For pelubiprofen, the geometric mean ratios (90% CIs) of C(max) and AUC(0-∞) were 1.02 (0.87-1.19) and 0.97 (0.88-1.07), respectively. For the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), the geometric mean ratios (90% CIs) of C(max) and AUC(0-∞) were 1.05 (0.98-1.13) and 1.04 (1.01-1.07). For eperisone, the geometric mean ratios (90% CIs) of C(max) and AUC(0-∞) were 0.87 (0.67-1.15) and 1.05 (0.85-1.30). None of the study participants experienced serious adverse events during the study. IMPLICATIONS: No clinically significant changes were noted in the pharmacokinetic interactions of pelubiprofen, the major active metabolite of pelubiprofen (trans-alcohol pelubiprofen), and eperisone hydrochloride between monotherapy and combination therapy with 45-mg sustained-release pelubiprofen and 75-mg sustained-release eperisone hydrochloride.
27821712 Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity i 2017 Jan Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.
27687304 Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders 2017 Feb 1 BACKGROUND: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. PATIENTS AND METHODS: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. RESULTS: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. CONCLUSIONS: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.
26809250 Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Imm 2017 Mar 1 BACKGROUND: Prenatal inflammatory mechanisms may play a role in the pathogenesis of psychiatric disorders and could be relevant for attention-deficit/hyperactivity disorder (ADHD). We investigated maternal chronic somatic diseases with immune components as possible risk factors for ADHD in offspring. METHODS: We performed a population-based nested case-control study by linking data from longitudinal Norwegian registers. We included all individuals born during the period 1967-2008 and alive at record linkage (2012). Individuals receiving ADHD medication during the years 2004-2012 were defined as patients with ADHD (N = 47,944), and all remaining individuals (N = 2,274,713) were defined as control subjects. The associations between maternal diseases and ADHD in offspring were analyzed using logistic regression models. RESULTS: The following chronic diseases with immune components were related to ADHD in offspring: multiple sclerosis (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2-2.5), rheumatoid arthritis (adjusted OR = 1.7; 95% CI = 1.5-1.9), type 1 diabetes (adjusted OR = 1.6; 95% CI = 1.3-2.0), asthma (adjusted OR = 1.5; 95% CI = 1.4-1.6), and hypothyroidism (adjusted OR = 1.2; 95% CI = 1.1-1.4). In contrast, chronic hypertension and type 2 diabetes showed no significant associations. Estimates were almost unchanged with additional adjustment for parental ADHD, infant birth weight, and gestational age. Although point estimates for male and female offspring were different for some diseases (e.g., maternal asthma [adjusted OR = 1.7; 95% CI = 1.5-1.8 for female offspring and adjusted OR = 1.5; 95% CI = 1.4-1.6 for male offspring]), none of the associations differed significantly by offspring sex. CONCLUSIONS: Several maternal somatic diseases with immune components were found to increase the risk of ADHD in offspring. The associations could involve several causal pathways, including common genetic predisposition and environmental factors, and increased insight into the mechanisms behind these relationships could enhance our understanding of the etiology of ADHD.
29096716 Galectin-1 and galectin-3 expression in equine mesenchymal stromal cells (MSCs), synovial 2017 Nov 2 BACKGROUND: Mesenchymal stromal cells (MSCs) can be used intra-articularly to quell inflammation and promote cartilage healing; however, mechanisms by which MSCs mitigate joint disease remain poorly understood. Galectins, a family of β-galactoside binding proteins, regulate inflammation, adhesion and cell migration in diverse cell types. Galectin-1 and galectin-3 are proposed to be important intra-articular modulators of inflammation in both osteoarthritis and rheumatoid arthritis. Here, we asked whether equine bone marrow-derived MSCs (BMSCs) express higher levels of galectin-1 and -3 relative to synovial fibroblasts and chondrocytes and if an inflammatory environment affects BMSC galectin expression and motility. METHODS: Equine galectin-1 and -3 gene expression was quantified using qRT-PCR in cultured BMSCs, synoviocytes and articular chondrocytes, in addition to synovial membrane and articular cartilage tissues. Galectin gene expression, protein expression, and protein secretion were measured in equine BMSCs following exposure to inflammatory cytokines (IL-1β 5 and 10 ng/mL, TNF-α 25 and 50 ng/mL, or LPS 0.1, 1, 10 and 50 μg/mL). BMSC focal adhesion formation was assessed using confocal microscopy, and BMSC motility was quantified in the presence of inflammatory cytokines (IL-1β or TNF-α) and the pan-galectin inhibitor β-lactose (100 and 200 mM). RESULTS: Equine BMSCs expressed 3-fold higher galectin-1 mRNA levels as compared to cultured synovial fibroblasts (p = 0.0005) and 30-fold higher galectin-1 (p < 0.0001) relative to cultured chondrocytes. BMSC galectin-1 mRNA expression was significantly increased as compared to carpal synovial membrane and articular cartilage tissues (p < 0.0001). IL-1β and TNF-α treatments decreased BMSC galectin gene expression and impaired BMSC motility in dose-dependent fashion but did not alter galectin protein expression. β-lactose abrogated BMSC focal adhesion formation and inhibited BMSC motility. CONCLUSIONS: Equine BMSCs constitutively express high levels of galectin-1 mRNA relative to other articular cell types, suggesting a possible mechanism for their intra-articular immunomodulatory properties. BMSC galectin expression and motility are impaired in an inflammatory environment, which may limit tissue repair properties following intra-articular administration. β-lactose-mediated galectin inhibition also impaired BMSC adhesion and motility. Further investigation into the effects of joint inflammation on BMSC function and the potential therapeutic effects of BMSC galectin expression in OA is warranted.
28962588 Decoy TRAIL receptor CD264: a cell surface marker of cellular aging for human bone marrow- 2017 Sep 29 BACKGROUND: Mesenchymal stem cells (MSCs) are a mixture of progenitors that are heterogeneous in their regenerative potential. Development of MSC therapies with consistent efficacy is hindered by the absence of an immunophenotype of MSC heterogeneity. This study evaluates decoy TRAIL receptor CD264 as potentially the first surface marker to detect cellular aging in heterogeneous MSC cultures. METHODS: CD264 surface expression, regenerative potential, and metrics of cellular aging were assessed in vitro for marrow MSCs from 12 donors ages 20-60 years old. Male and female donors were age matched. Expression of CD264 was compared with that of p16, p21, and p53 during serial passage of MSCs. RESULTS: When CD264(+) cell content was 20% to 35%, MSC cultures from young (ages 20-40 years) and older (ages 45-60 years) donors proliferated rapidly and differentiated extensively. Older donor MSCs containing < 35% CD264(+) cells had a small size and negligible senescence despite the donor's advanced chronological age. Above the 35% threshold, CD264 expression inversely correlated with proliferation and differentiation potential. When CD264(+) cell content was 75%, MSCs were enlarged and mostly senescent with severely compromised regenerative potential. There was no correlation of the older donors' chronological age to either CD264(+) cell content or the regenerative potential of the donor MSCs. CD264 was upregulated after p53 and had a similar expression profile to that of p21 during serial passage of MSCs. No sex-linked differences were detected in this study. CONCLUSIONS: These results suggest that CD264 is a surface marker of cellular age for MSCs, not the chronological age of the MSC donor. CD264 is first upregulated in MSCs at an intermediate stage of cellular aging and remains upregulated as aging progresses towards senescence. The strong inverse correlation of CD264(+) cell content to the regenerative potential of MSCs has possible application to assess the therapeutic potential of patient MSCs, standardize the composition and efficacy of MSC therapies, and facilitate aging research on MSCs.
31548534 Antagonist Anti-CD28 Therapeutics for the Treatment of Autoimmune Disorders. 2017 Nov 21 The effector functions of T lymphocytes are responsible for most autoimmune disorders and act by directly damaging tissues or by indirectly promoting inflammation and antibody responses. Co-stimulatory and co-inhibitory T cell receptor molecules are the primary pharmacological targets that enable interference with immune-mediated diseases. Among these, selective CD28 antagonists have drawn special interest, since they tip the co-stimulation/co-inhibition balance towards efficiently inhibiting effector T cells while promoting suppression by pre-existing regulatory T-cells. After having demonstrated outstanding therapeutic efficacy in multiple models of autoimmunity, inflammation and transplantation, and safety in phase-I studies in humans, selective CD28 antagonists are currently in early clinical development for the treatment of systemic lupus erythematous and rheumatoid arthritis. Here, we review the available proof of concept studies for CD28 antagonists in autoimmunity, with a special focus on the mechanisms of action.
28993061 Risk comparison for prenatal use of analgesics and selected birth defects, National Birth 2017 Oct PURPOSE: To compare the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or opioids to the use of acetaminophen without NSAIDs or opioids with respect to associations with birth defects. METHODS: We used data from the National Birth Defects Prevention Study (1997-2011). Exposure was self-reported maternal analgesic use from the month before through the third month of pregnancy (periconceptional). Adjusted odds ratios (aORs) were calculated to examine associations with 16 birth defects. RESULTS: Compared to acetaminophen, mothers reporting NSAIDs were significantly more likely to have offspring with gastroschisis, hypospadias, cleft palate, cleft lip with cleft palate, cleft lip without cleft palate, anencephaly, spina bifida, hypoplastic left heart syndrome, pulmonary valve stenosis, and tetralogy of Fallot (aOR range, 1.2-1.6). Opioids were associated with tetralogy of Fallot, perimembranous ventricular septal defect, and ventricular septal defect with atrial septal defect (aOR range, 1.8-2.3), whereas use of both opioids and NSAIDs was associated with gastroschisis, cleft palate, spina bifida, hypoplastic left heart syndrome, and pulmonary valve stenosis (aOR range, 2.0-2.9). CONCLUSIONS: Compared to periconceptional use of acetaminophen, selected birth defects occurred more frequently among infants of women using NSAIDs and/or opioids. However, we could not definitely determine whether these risks relate to the drugs or to indications for treatment.
28433815 Patterns and predictors of persistent opioid use following hip or knee arthroplasty. 2017 Sep OBJECTIVE: The relationship between arthroplasty and long-term opioid use in patients with knee or hip osteoarthritis is not well studied. We examined the prevalence, patterns and predictors of persistent opioid use after hip or knee arthroplasty. METHOD: Using claims data (2004-2013) from a US commercial health plan, we identified adults who underwent hip or knee arthroplasty and filled ≥1 opioid prescription within 30 days after the surgery. We defined persistent opioid users as patients who filled ≥1 opioid prescription every month during the 1-year postoperative period based on group-based trajectory models. Multivariable logistic regression was used to determine preoperative predictors of persistent opioid use after surgery. RESULTS: We identified 57,545 patients who underwent hip or knee arthroplasty. The mean ± SD age was 61.5 ± 7.8 years and 87.1% had any opioid use preoperatively. Overall, 7.6% persistently used opioids after the surgery. Among patients who used opioids in 80% of the time for ≥4 months preoperatively (n = 3023), 72.1% became persistent users. In multivariable analysis, knee arthroplasty vs hip, a longer hospitalization stay, discharge to a rehabilitation facility, preoperative opioid use (e.g., a longer duration and greater dosage and frequency), a higher comorbidity score, back pain, rheumatoid arthritis, fibromyalgia, migraine and smoking, and benzodiazepine use at baseline were strong predictors for persistent opioid use (C-statistic = 0.917). CONCLUSION: Over 7% of patients persistently used opioids in the year after hip or knee arthroplasty. Given the adverse health effects of persistent opioid use, strategies need to be developed to prevent persistent opioid use after this common surgery.
28166724 Association between IL-17 and IgA in the joints of patients with inflammatory arthropathie 2017 Feb 6 BACKGROUND: Hyperactive secretion and pathogenic effects of interleukin (IL)-17 and IgA have been detected in different arthropathies. Recent evidence has revealed that T(H)17 cytokines regulate mucosal IgA secretion. However, it is unknown whether and how IL-17 mediates synovial IgA production. Here we aim to investigate the connection of synovial IL-17 with IgA production in the joint. In this study we included synovial fluids (SF) from patients with rheumatoid arthritis (RA; n = 66), spondyloarthritis (SpA; n = 18) and osteoarthritis (OA; n = 36). The levels of IL-17, IL-6, transforming growth factor (TGF)-β(1), B-cell-activating factor of the TNF family (BAFF) and anti-lipopolyssacharide (LPS) immunoglobulin (Ig)A were investigated by enzyme-linked immunosorbent assay (ELISA). Total IgA was measured by radial immunodiffusion assay. Synovial fluid-derived mononuclear cells (SFMC) were stimulated with bacterial antigens or SF-conditioned media, and cytokines and IgA were analyzed in the supernatants. RESULTS: IL-17, IL-6 and TGF-β(1) were increased in SF from both RA and SpA compared with OA patients. Concentration of IL-17 correlated with the disease activity score (DAS)-28, IL-6 and anti-LPS IgA levels. Bacterial-stimulated SFMCs from RA and SpA patients secreted higher IL-17 than vehicle-stimulated SFMCs. Conditioned media with SF containing IL-17 induced anti-LPS IgA production by SFMCs which was independent of IL-6 activity. Concentrations of synovial TGF-β(1) and BAFF correlated with anti-LPS and total IgA levels, respectively. Blockade of IL-17 decreased the production of TGF-β(1) and anti-LPS IgA by SF-stimulated SFMCs. CONCLUSIONS: This study reports a connection between IL-17 and IgA secretion in the joint. In addition, it demonstrates that enterobacterial antigens trigger synovial IL-17 production, and that TGF-β(1) and BAFF may mediate the effect of IL-17 on IgA production. This circuit may contribute to the pathogenesis of inflammatory joint diseases.
28087670 Plant Lectins Activate the NLRP3 Inflammasome To Promote Inflammatory Disorders. 2017 Mar 1 Plant-derived dietary lectins have been reported to be involved in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, diabetes, rheumatoid arthritis, and celiac disease, but little is known about the molecular mechanisms underlying lectin-induced inflammation. In this study, we showed that plant lectins can induce caspase-1 activation and IL-1β secretion via the NLRP3 inflammasome. Lectins were internalized and subsequently escaped from the lysosome and then translocated to the endoplasmic reticulum. Endoplasmic reticulum-loaded plant lectins then triggered Ca(2+) release and mitochondrial damage, and inhibition of Ca(2+) release and mitochondrial reactive oxygen species by chemical inhibitors significantly suppressed NLRP3 inflammasome activation. In vivo, plant lectin-induced inflammation and tissue damage also depended on the NLRP3 inflammasome. Our findings indicate that plant lectins can act as an exogenous "danger signal" that can activate the NLRP3 inflammasome and suggest that dietary lectins might promote inflammatory diseases via the NLRP3 inflammasome.
27766695 Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α 2017 Apr Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions. Currently, five anti-TNFα agents are approved by the European Medicines Agency (EMA), including the monoclonal anti-TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFα-receptor/IgG-Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFα inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population.
28770708 The interaction between anti-Ro/SSA and anti-La/SSB autoantibodies and anti-infectious ant 2017 Nov OBJECTIVES: The presence of anti-Ro/SSA and anti-La/SSB antibodies has been linked with autoimmunity in general and with several autoimmune diseases (AID) in particular. In the current study we evaluated these antibodies in a wide spectrum of AID as well as the links between them and anti-infectious antibodies. METHODS: We examined 2082 sera from patients with 16 different AID compared to 524 sera from geographically-matched healthy controls, for the presence and titres of anti-Ro/SSA and anti-La/SSB. All samples were also tested for a variety of anti-infectious agents' antibodies using the BioPlex 2200-immunoassay (Bio-Rad, USA). RESULTS: Anti-Ro/SSA was more prevalent, with significantly higher titre in 5 autoimmune diseases namely Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) both primary and APS linked to SLE, systemic sclerosis (SSc) and primary biliary cirrhosis (PBC). Anti-La/SSB was more prevalent with higher titers in SS, SLE, APS linked to SLE and PBC. Prevalence, but not titers, of both antibodies were higher also in polymyositis (PM). Additionally, we found a correlation between anti-Ro/SSA antibodies and antibodies of the IgM and IgG subtypes directed at cytomegalovirus as well as IgG-antibodies directed at Epstein-Barr virus (EBV) and toxoplasma (p<0.001). Anti-La/SSB antibodies correlated with the presence of IgG antibodies against EBV early antigen (p<0.001). CONCLUSIONS: In a large cohort of patients with autoimmune diseases we found an association between anti-Ro/SSA and anti-La/SSB antibodies and 6 autoimmune diseases, amongst which primary APS and PM. Additionally, we observed linkages between these autoantibodies and anti-infectious antibodies directed at Epstein-Barr virus, toxoplasma and cytomegalovirus. Our findings support the concept of interplay between infectious agents and autoimmunity, such as the plausibility of an infectious agent that trigger the immune system to produce specific antibodies which will later result in a unique group of AID.