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ID PMID Title PublicationDate abstract
25833812 Reversal of Arthritis by Human Monomeric IgA Through the Receptor-Mediated SH2 Domain-Cont 2015 Jul OBJECTIVE: Rheumatoid arthritis (RA), one of the most frequent chronic inflammatory rheumatic disorders, is characterized by the presence of autoantibodies and joint infiltration by activated immune cells, leading to cartilage and bone destruction. IgA occurs predominantly as monomers (mIgA) in plasma and regulates many cell responses through interaction with the Fcα receptor type I (FcαRI). FcαRI targeting by anti-FcαRI Fab inhibits activating receptors by inducing an inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) configuration through SH2 domain-containing phosphatase 1 (SHP-1) recruitment. The aim of this study was to investigate the potential utility of mIgA for the treatment of arthritis by acting as an inducer of ITAMi signaling. METHODS: The effect of plasma-derived human mIgA on inhibition of multiple heterologous receptors was evaluated on FcαRI+ cell transfectants, blood phagocytes from healthy individuals, and synovial cells from RA patients. FcαRI-transgenic mice and wild-type mice treated with mIgA were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The mice were assessed for development of arthritis using an arthritis score, and joint tissue samples were evaluated for the extent of leukocyte infiltration and expression of phosphatase. RESULTS: Treatment with mIgA impaired cell activation in an FcαRI-FcRγ-dependent manner, involving ITAMi signaling. Human mIgA or anti-FcαRI Fab were strongly effective in either preventing or attenuating CAIA or CIA in FcαRI-transgenic mice. Administration of mIgA markedly inhibited the recruitment of leukocytes to the inflamed joints of mice, which was associated with induction of SHP-1 phosphorylation in joint tissue cells. Moreover, mIgA reversed the state of inflammation in the synovial fluid of RA patients by inducing an ITAMi configuration. CONCLUSION: These results demonstrate a therapeutic potential of human mIgA in experimental arthritis. The findings support future clinical exploration of mIgA for the treatment of RA.
26222874 Development of an ELISA-Based Competitive Binding Assay for the Analysis of Drug Concentra 2016 Feb BACKGROUND: There is increasing interest in measuring both drug and antidrug antibody (ADA) levels in patients receiving anti-tumor necrosis factor treatment as part of algorithms for guiding therapeutic strategies. Many of the current assays for ADA detection have limitations with respect to specificity, sensitivity, and/or laboratory requirements. Specific identification of ADA based on their inhibitory activity in a simple competitive binding assay remains problematic. The development of an enzyme-linked immunosorbent assay (ELISA)-based method for detection of both drug and ADA in patients receiving either adalimumab or infliximab would widen availability of monitoring for these patients. METHODS: An ELISA for the specific detection of adalimumab and infliximab using widely available reagents was developed. A simple modification for the detection of ADA capable of competitively inhibiting the in vitro binding of drug to solid phase tumor necrosis factor was also developed. Drug and ADA levels were analyzed in patients with rheumatoid arthritis and inflammatory bowel disease. RESULTS: The ELISA specifically detected drug concentrations in patient sera with no evidence of positive or negative interference by rheumatoid factor positive control sera. A subset of those patients with low drug concentrations had detectable levels of ADA with inhibitory activity in a competitive binding assay. Spiking with both drugs confirmed the specificity of the ADA detected. CONCLUSIONS: A modified ELISA protocol can be used to for the detection of both drug concentrations and ADA in patients receiving either adalimumab or infliximab. The ELISA incorporates those features identified in the literature as important for the accurate analysis of these antibodies and uses laboratory facilities and reagents that are widely available. It therefore provides a relatively simple and low cost assay for therapeutic drug monitoring of inpatients receiving adalimumab or infliximab.
26841353 Activation-Induced Killer Cell Immunoglobulin-like Receptor 3DL2 Binding to HLA-B27 Licens 2016 Apr OBJECTIVE: In the spondyloarthritides (SpA), increased numbers of CD4+ T cells express killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). The aim of this study was to determine the factors that induce KIR-3DL2 expression, and to characterize the relationship between HLA-B27 and the phenotype and function of KIR-3DL2-expressing CD4+ T cells in SpA. METHODS: In total, 34 B27+ patients with SpA, 28 age- and sex-matched healthy controls (20 B27- and 8 B27+), and 9 patients with rheumatoid arthritis were studied. KIR-3DL2 expression and other phenotypic characteristics of peripheral blood and synovial fluid CD4+ T cells were studied by flow cytometry, quantitative polymerase chain reaction, and Western blotting. T cell receptor clonality was determined by template-switch anchored reverse transcription-polymerase chain reaction and sequencing analysis. Cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: Cellular activation induced KIR-3DL2 expression on both naive and effector CD4+ T cells. KIR-3DL2 binding to B27+ cells promoted expression of KIR-3DL2, the Th17-specific transcription factor retinoic acid receptor-related orphan nuclear receptor γt, and the antiapoptotic factor B cell lymphoma 2. KIR-3DL2+CD4+ T cells in patients with ankylosing spondylitis were oligoclonal and enriched for markers of T cell activation and for the gut homing receptor CCR9. In the presence of B27+ antigen-presenting cells, KIR-3DL2+CD4+ T cells produced less interleukin-2 (IL-2) but more IL-17. This effect was blocked by HC10, an antibody that inhibits the binding of KIR-3DL2 to B27 heavy chains. CONCLUSION: KIR-3DL2 binding to HLA-B27 licenses Th17 cell differentiation in SpA. These findings raise the therapeutic potential of targeting HLA-B27-KIR-3DL2 interactions for the treatment of B27+ patients with SpA.
25694608 Placental growth factor-1 and -2 induce hyperplasia and invasiveness of primary rheumatoid 2015 Mar 15 Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of PlGF transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy.
27084914 A Multifaceted Intervention to Improve Influenza, Pneumococcal, and Herpes Zoster Vaccinat 2016 Jun OBJECTIVE: Vaccination rates for influenza, pneumococcus, and zoster in patients with rheumatoid arthritis (RA) have remained low. Simple electronic or paper reminders have produced only small increases in vaccination rates. We sought to identify a more effective approach to improve vaccination rates. METHODS: We conducted a system-level intervention at an academic rheumatology clinic that included electronic reminders with linked order sets, physician auditing and feedback, patient outreach, and optional printed prescriptions for zoster vaccination at an outside pharmacy. RESULTS: We targeted 1255 eligible patients with RA. There was no change in patients' self-reported influenza vaccination rates, although the baseline self-reported rate was already high and much higher than that documented in the electronic health record. Pneumococcal vaccination rates increased from 28.7% to 45.8%; in regression analysis, the rate of change in pneumococcal vaccination increased by 9.4% per year above baseline trends (95% CI 3.9-15.5, p = 0.002). The rate of zoster vaccination increased from 2.5% to 4.5% overall (p = 0.01) and from 3.0% to 6.6% among patients not receiving biologic therapy that precluded zoster vaccination. CONCLUSION: Although the intervention improved pneumococcal and zoster vaccination rates, the improvement in pneumococcal vaccination rate was less than expected, and the zoster vaccination rate remained low even for ideal candidates. Likely barriers include lack of familiarity and difficulty using electronic reminders and order sets, uncertainty about the value and safety of recommended vaccines, and uncertainty about patients' insurance coverage and prior vaccination history. Future interventions should include strategies to address these.
26920964 Total elbow arthroplasty for non-rheumatoid patients with a fracture of the distal humerus 2016 Mar AIMS: We review our experience of Coonrad-Morrey total elbow arthroplasty (TEA) for fractures of the distal humerus in non-rheumatoid patients with a minimum of ten years follow-up. PATIENTS AND METHODS: TEA through a triceps splitting approach was peformed in 37 non-rheumatoid patients for a fracture of the distal humerus between 1996 and 2004. One patient could not be traced and 17 had died before the tenth anniversary of their surgery. This left 19 patients with a minimum follow-up of ten years to form the study group. Of these, 13 patients were alive at the time of final review. The other six had died, but after the tenth anniversary of their elbow arthroplasty. Their clinical and radiological data were included in the study. RESULTS: The mean follow-up of the 19 patients was 156 months (120 to 210). Two patients in the study group had undergone revision. One further patient had undergone a two-stage revision for infection but died before ten-year follow-up. Six other patients in the study group had evidence of loosening or wear of their bushings. Two were clinically symptomatic and were offered revision surgery. Male patients showed higher incidence of loosening and wear. Survivorship, with revision and definite loosening as end-points, was 89.5% at ten years in those patients followed for a minimum of ten years and 86% in the whole group of 36 patients. CONCLUSION: This study shows that only 53% of non-rheumatoid patients who undergo TEA for a fracture of the distal humerus survive to the tenth anniversary of their index procedure. For those that survive, TEA provides acceptable outcomes in terms of function and implant survival. TAKE HOME MESSAGE: The surgeons undertaking these procedures should be aware of the long-term revision rates and also the gender difference in the rates of loosening.
25117655 Thrombopoietin levels in systemic lupus erythematosus are linked to inflammatory cytokines 2015 Jan BACKGROUND: Thrombopoietin (TPO) is a liver-produced protein that drives megakaryocyte maturation. TPO regulates platelet production and can increase platelet and endothelial reactivity. We investigated the relationship between TPO and the occurrence of thrombocytopenia and thrombosis in patients with systemic lupus erythematosus (SLE). METHODS: We undertook a cohort study of SLE patients (n = 98) with clinical data collected simultaneously with sampling for TPO, inflammatory cytokines and autoantibody detection. TPO levels were measured by sandwich ELISA with patients with rheumatoid arthritis (RA) (n = 100) and controls (n = 79) as comparators. Disease associations were evaluated using non-parametric methods. RESULTS: TPO levels in SLE (median 8 pg/ml, mean 326, range 8992) were moderately increased compared with RA (median 8 pg/ml, mean 100, range 1659, p = 0.07) and controls (median 8, mean 94, range 2088, p = 0.1). Among SLE patients, TPO levels did not correlate with platelet count or levels of antiphospholipid antibodies. The prevalence of thrombocytopenic episodes, thrombotic events or active disease was not increased in patients with high TPO levels. TPO levels correlated with MIP-1α (Rs 0.56, p < 0.001), IL6 (Rs 0.26, p = 0.02) and IL4 (Rs 0.29, p = 0.01), and inversely correlated to C4 (Rs -0.23, p = 0.04). MIP-1α was the strongest independent predictor of increased TPO levels. CONCLUSION: TPO levels are elevated in 20% of patients, but are not closely related to the occurrence of thrombocytopenia or thrombosis in SLE. MIP1-alpha is the main factor driving higher TPO levels among patients with SLE, likely through its inhibitory effect on megakaryocyte function.
26245802 Neutrophil Extracellular Trap Mitochondrial DNA and Its Autoantibody in Systemic Lupus Ery 2015 Dec OBJECTIVE: Neutrophil extracellular traps (NETs) have been shown to play an important role in systemic lupus erythematosus (SLE) pathogenesis by activating plasmacytoid dendritic cells (PDCs) and the type I interferon (IFN) pathway. NETs composed of self-DNA are considered to be of nuclear origin and are a major source of anti-DNA autoantibody generation. This study was undertaken to evaluate whether mitochondrial DNA (mtDNA) resides in NETs, to evaluate whether mtDNA and anti-mtDNA antibodies cause dysregulation of the PDC-IFNα pathway, and to investigate the clinical implication in SLE. METHODS: Patients with SLE (n = 102), patients with rheumatoid arthritis (n = 30), and healthy donors (n = 40) were enrolled in in vitro studies. NETs were generated from phorbol 12-myristate 13-acetate (PMA)-stimulated peripheral neutrophils. Immunofluorescence staining was used to detect NET formation ex vivo and in lupus nephritis renal biopsy samples. The mtDNA levels and type I IFN-inducible gene scores were measured by quantitative polymerase chain reaction. Anti-mtDNA antibodies, anti-double-stranded DNA (anti-dsDNA) antibodies, and IFNα were detected by enzyme-linked immunosorbent assay. Purified PDCs were stimulated by isolated NETs, mtDNA, or dsDNA, combined with anti-mtDNA or dsDNA IgG, or other culture conditions. Additional patients with SLE (n = 113) were enrolled in a proof-of-concept trial. We evaluated the efficacy and safety of metformin on a background of corticosteroids and conventional immunosuppressive agents in patients with mild or moderate lupus. The primary end point was the efficacy of metformin for reducing disease flare. RESULTS: We detected mtDNA in NETs, and anti-mtDNA antibody levels were elevated in SLE patients compared with controls and significantly correlated with IFN scores and the disease activity index. The presence of anti-mtDNA antibodies was disproportionately associated with lupus nephritis, and correlated better than anti-dsDNA antibody levels with the lupus nephritis activity index. Mitochondrial DNA was deposited in NETs in lupus nephritis renal biopsy specimens. In addition, mtDNA/anti-mtDNA were greater inducers of PDC IFNα production via Toll-like receptor engagement than dsDNA/anti-dsDNA. We assessed the effect of metformin on down-regulating the NET mtDNA-PDC-IFNα pathway. Metformin decreased PMA-induced NET formation and CpG-stimulated PDC IFNα generation. A proof-of-concept trial of metformin add-on treatment of mild or moderate SLE resulted in decreases in clinical flares, prednisone exposure, and body weight. CONCLUSION: Our findings establish a link between mtDNA in NETs, anti-mtDNA antibodies, and PDC IFNα pathogenesis in SLE, and highlight that specific strategies to down-regulate this pathway, such as treatment with metformin, may be new approaches to treat SLE.
27194479 Treatment with Adenosine Receptor Agonist Ameliorates Pain Induced by Acute and Chronic In 2016 Aug Rheumatoid arthritis is an inflammatory autoimmune condition, and tumor necrosis factor-α (TNF-α) plays an important role in its pathophysiology. In vitro, (E)-N'-(3,4-dimethoxybenzylidene)-N-methylbenzohydrazide (LASSBio-1359) has exhibited anti-TNF-α properties, and in vivo these effects are mediated via activation of adenosine receptor. This work investigates the antinociceptive action of LASSBio-1359 in murine models of acute and chronic inflammatory pain. Male mice received an intraperitoneal injection of LASSBio-1359 and then were evaluated in formalin- and carrageenan-induced paw edema assays. Complete Freund's adjuvant (CFA) was used to induce a mouse model of monoarthritis. These mice were treated with LASSBio-1359 by oral gavage to evaluate thermal and mechanical hyperalgesia. TNF-α and inducible nitric oxide synthase (iNOS) expression as well as histologic features were analyzed. The time of reactivity to formalin in the neurogenic phase was reduced from 56.3 ± 6.0 seconds to 32.7 ± 2.2 seconds and 23.8 ± 2.6 seconds after treatment with LASSBio-1359 at doses of 10 mg/kg and 20 mg/kg, respectively. A reversal of the antinociceptive action of LASSBio-1359 was observed in the inflammatory phase after treatment with ZM 241385 [4-(2-[7-amino-2-(2-furly)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol], an adenosine A2A antagonist. Carrageenan-induced thermal and mechanical hyperalgesia were reduced after treatment with LASSBio-1359. Similarly, CFA-induced thermal and mechanical hyperalgesia were reduced after treatment with LASSBio-1359 (25 and 50 mg/kg). Levels of TNF-α and iNOS expression increased in the monoarthritis model and were normalized in animals treated with LASSBio-1359, which was also associated with beneficial effects in the histologic analysis. These results suggest that LASSBio-1359 represents an alternative treatment of monoarthritis.
26703771 [Analysis for differences in clinical and radiologic findings between patients with crypto 2015 Sep OBJECTIVE: To investigate the difference in clinical features and radiologic findings between patients with cryptogenic organizing pneumonia (COP) and connective tissue disorder related organizing pneumonia (CTD-OP). METHODS: A total of 30 subjects with COP and 22 subjects with CTD-OP collected from 2005 to 2013 were retrospectively reviewed in the Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, and the diagnosis of all patients were confirmed by lung biopsy. RESULTS: The common underlying diseases in patients with CTD-OP were Sjogren syndrome(SS), poly-/dermatomyositis(PM/DM), rheumatoid arthritis (RA). There were no significant differences in clinical manifestations between CTD-OP and COP. Compared with COP patients, the proportion of female patients was higher in CTD-OP. Higher positive rate for ANA was found in CTD-OP group (CTD-OP:63.6%; COP:10.0%; P<0.01). There were no significant differences in parameters of lung function between CTD-OP and COP. As to radiological findings, the most common patterns were multiple patchy, linear shadows and ground-glass opacity. Some patients showed solitary nodule or consolidation and pleural effusion. Reticular shadow was a rare pattern among these patients. Most lesions were under the pleura and/or around the bronchus. CONCLUSIONS: There are no significant differences in clinical and radiologic manifestations between COP and CTD-OP, except that the proportion of women and ANA positive rate were higher in CTD-OP.
27410490 Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selectiv 2016 Sep ASP2408 is a next-generation anti-cytotoxic T lymphocyte antigen-4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half-life with increasing doses, consistent with target-mediated disposition. The apparent bioavailability was 36.3%-56.7% across single subcutaneous doses. Sixteen RA patients (n = 8/treatment) on stable methotrexate received 3 × 3.0 mg/kg subcutaneously every 4 weeks or every 2 weeks. Similar to single-dose treatment, ASP2408 concentrations peaked 2 to 3 days postdose, with a median t1/2 of approximately 8 days. Using CD86 receptor occupancy (RO) as a mechanistic biomarker, ASP2408 demonstrated dose-dependent binding to its target. ASP2408 3.0 mg/kg subcutaneously every 4 weeks and every 2 weeks led to a mean %CD86 RO ≥ 74.7% and ≥ 81.5%, respectively, within each dosing interval. ASP2408 was well tolerated across studies with no evidence of dose-limiting toxicity or clinically significant changes in clinical laboratory test results, vital signs, or 12-lead electrocardiograms. ASP2408 elicited antidrug antibodies in the majority of patients, but with no clinical sequelae.
25714931 Disease specificity of autoantibodies to cytosolic 5'-nucleotidase 1A in sporadic inclusio 2016 Apr OBJECTIVES: The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5'-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls. METHODS: Serum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs. RESULTS: Autoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (<5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sjögren's syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%). CONCLUSIONS: In summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist.
27837109 Characterization of the Syk-Dependent T Cell Signaling Response to an Altered Peptide. 2016 Dec 15 Rheumatoid arthritis is an autoimmune disorder characterized by T cell dysregulation. We have shown that an altered peptide ligand (A9) activates T cells to use an alternate signaling pathway that is dependent on FcRγ and spleen tyrosine kinase, resulting in downregulation of inflammation. In the experiments described in this study, we have attempted to determine the molecular basis of this paradox. Three major Src family kinases found in T cells (Lck, Fyn, and Lyn) were tested for activation following stimulation by A9/I-A(q) Unexpectedly we found they are not required for T cell functions induced by A9/I-A(q), nor are they required for APL stimulation of cytokines. On the other hand, the induction of the second messenger inositol trisphosphate and the mobilization of calcium are clearly triggered by the APL A9/I-A(q) stimulation and are required for cytokine production, albeit the cytokines induced are different from those produced after activation of the canonical pathway. DBA/1 mice doubly deficient in IL-4 and IL-10 were used to confirm that these two cytokines are important for the APL-induced attenuation of arthritis. These studies provide a basis for exploring the effectiveness of analog peptides and the inhibitory T cells they induce as therapeutic tools for autoimmune arthritis.
26173602 Thymic lymphoid hyperplasia with multilocular thymic cysts diagnosed before the Sjögren s 2015 Jul 16 BACKGROUND: Thymic lymphoid hyperplasia is often present with myasthenia gravis as well as other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Of the 4 cases of thymic lymphoid hyperplasia associated with Sjögren syndrome that have been reported, no case with a thymic lesion diagnosis that led to the diagnosis of Sjögren syndrome has been reported. We herein report a case of thymic lymphoid hyperplasia with multilocular thymic cysts, diagnosed before Sjögren syndrome. CASE PRESENTATION: A 37-year-old Japanese woman had an approximate 5-cm anterior mediastinal mass detected by chest imaging. The resected lesion revealed multilocular thymic cysts that were filled with colloid-like material. Histology showed lymph follicular hyperplasia with many epithelial cysts. The epithelium consisted of thymic medullary epithelium, and no epithelial proliferation was seen in the lymphoid tissue. Lymphocytes were composed of an organized mixed population of mature T and B cells without significant atypia. The infiltrated B cells did not reveal light chain restriction or immunoglobulin heavy chain gene rearrangement. After the pathological diagnosis of thymic lesion, tests for the presence of autoantibodies were positive for antinuclear antibodies, rheumatic factor, and anti-SSA/Ro antibodies. The Schirmer's, chewing gum, and Saxon tests showed decreased salivary and lacrimal secretion. Lip biopsy showed focal lymphocytic sialadenitis. The signs and symptoms of Sjögren syndrome had not resolved, without aggravation, 1 year after the thymectomy. CONCLUSION: When a case with thymic lymphoid hyperplasia without myasthenia gravis is encountered, it is essential to consider the presence of another autoimmune disease including Sjögren syndrome.
26049964 Biosimilars in Dermatology: Current Situation (Part II). 2015 Sep The first biosimilar version of a biologic agent used to treat psoriasis (infliximab) entered the Spanish market on February 16 of this year, and more biosimilars can be expected to follow in the coming months and years. Logically, this new situation will have economic repercussions and alter prescribing patterns among dermatologists. In this second part of the review, we will look at several somewhat contentious issues, such as the extrapolation of indications, interchangeability, and automatic substitution. We will also review the biosimilars with indications for psoriasis currently in the clinical development pipeline and assess their potential to offer comparable efficacy and safety to the reference product while contributing to the sustainability of the public health care system.
27120178 Comparison of Three Assays to Quantify Infliximab, Adalimumab, and Etanercept Serum Concen 2016 Aug BACKGROUND: To optimize treatment of inflammatory diseases, interest in the measurement of anti-tumor necrosis factor alpha (anti-TNFα) serum drug concentrations is increasing. Preferably, assays for the detection of these drugs should be compared using the same reference material. In this study, 2 commercially available enzyme-linked immunosorbent assays (ELISAs) and a commercially available bioassay for the determination of anti-TNFα drugs are compared. METHODS: Serum samples from infliximab-, adalimumab-, and etanercept-treated patients, control samples from ustekinumab-treated patients, and healthy donors were obtained. ELISAs manufactured by Sanquin and Theradiag and the iLite reporter gene-based bioassay from Biomonitor were compared. RESULTS: Sanquin, Theradiag, and iLite assays concordantly (100%) detected infliximab, adalimumab, and etanercept in the relevant patient groups. The Sanquin ELISAs specifically detected the anti-TNFα drug they were designed for, whereas the Theradiag and iLite showed cross-reactivity with other anti-TNFα drugs. Ustekinumab was not detected in any of the assays. Sanquin, Theradiag, and iLite exhibited linear quantitative correlation for all drug concentration assays. However, there were statistically significant quantitative differences in measured concentrations. CONCLUSIONS: All 3 commercially available assays seem suitable for therapeutic drug monitoring of anti-TNFα drugs, allowing sensitive and comparable detection of infliximab, adalimumab, and etanercept concentrations, however with differences in specificity and recovery.
25188873 Racial difference in sarcoidosis mortality in the United States. 2015 Feb BACKGROUND: The clinical presentation and outcome of sarcoidosis varies by race. However, the race difference in mortality outcome remains largely unknown. METHODS: We studied mortality related to sarcoidosis from 1999 through 2010 by examining data on multiple causes of death from the National Center for Health Statistics. We compared the comorbid conditions between sarcoidosis-related deaths with deaths caused by car accidents (previously healthy control subjects) and rheumatoid arthritis (chronic disease control subjects) in both African Americans and Caucasians. RESULTS: From 1999 through 2010, sarcoidosis was reported as an immediate cause of death in 10,348 people in the United States with a combined overall mean age-adjusted mortality rate of 2.8 per 1 million person-years. Of these, 6,285 were African American and 3,984 Caucasian. The age-adjusted mortality rate for African Americans was 12 times higher than for Caucasians. African Americans died at an earlier age than Caucasians. African Americans living in the District of Columbia and North Carolina and Caucasians living in Vermont had higher mortality rates. Although the total sarcoidosis age-adjusted mortality rate had not changed over the 12 year period studied, this rate increased for Caucasians (R = 0.747, P = .005) but not for African Americans. Compared with the control groups, pulmonary hypertension was significantly more common in individuals with sarcoidosis. CONCLUSIONS: This nationwide population-based study exposes a significant difference in ethnicity and sex among people dying of sarcoidosis in the United States. Pulmonary hypertension investigation should be considered in all patients with sarcoidosis, especially African Americans.
26570984 Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses 2016 Jan 1 Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a combination of synovium joint inflammation, synovium hyperplasia, and destruction of cartilage and bone. Oleanolic acid acetate (OAA), a compound isolated from Vigna angularis, has been known to possess pharmacological activities, including anti-inflammation and anti-bone destruction. In this study, we investigated the effects of OAA on RA and the underlying mechanisms of action by using a type-II collagen-induced arthritis (CIA) mouse model and tumor necrosis factor (TNF)-α-stimulated RA synovial fibroblasts. Oral administration of OAA decreased the clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum total and anti-type II collagen IgG, IgG1, and IgG2a levels. OAA administration reduced Th1/Th17 phenotype CD4(+) T lymphocyte expansions and inflammatory cytokine productions in T cell activated draining lymph nodes and spleen. OAA reduced the expression and production of inflammatory mediators, such as cytokines and matrix metalloproteinase (MMP)-1/3, in the ankle joint tissue and RA synovial fibroblasts by down-regulating Akt, mitogen-activated protein kinases, and nuclear factor-κB. Our results clearly support that OAA plays a therapeutic role in RA pathogenesis by modulating helper T cell immune responses and matrix-degrading enzymes. The immunosuppressive effects of OAA were comparable to dexamethasone and ketoprofen. We provide evidences that OAA could be a potential therapeutic candidate for RA.
27193008 Preoperative prediction of anterior cruciate ligament tibial footprint size by anthropomet 2017 May PURPOSE: The purpose of this study was to evaluate whether the ACL tibial footprint size can be predicted by anthropometric variables including height, weight, leg length, femur length, tibia length, and anteroposterior and mediolateral diameters of proximal tibia. METHODS: This study included 209 out of the 378 eligible patients. The inclusion criterion was ACL with normal gross appearance. Patients with conditions that could have affected the measurement were excluded: torn ACL, osteophyte formation around the ACL tibial attachment, presence of inflammatory arthritis, or history of knee joint infection. According to the above criteria, 169 patients were excluded from this study; 138 had torn ACL, 24 had osteophyte around the ACL footprint, 5 had history of rheumatoid arthritis, and 2 had history of previous knee joint infection. The ACL tibial footprint was carefully dissected and measured during total knee arthroplasty. Anthropometric variables regarding bone lengths were measured on radiography. The association of the ACL tibial footprint size (length and width) with anthropometric variables was analysed using simple and multiple linear regression analyses. RESULTS: The height, weight, leg length, femur length, tibia length, and the size of proximal tibia were associated with the ACL tibial footprint length and width. The ACL tibial footprint length could be predicted by the equation using tibia length: ACL tibial footprint length = -9.361 + 0.759 * (tibia length in cm) (R (2) = 0.44, P < 0.001) and width by the equation using weight and tibia length: ACL tibial footprint width = -0.5615 + 0.279 * (tibia length in cm) + 0.0333 * (weight in kgs) (R (2) = 0.17, P < 0.001). The concordance correlation coefficient for the measured and predicted values of ACL tibial footprint length and width showed moderate and low agreement, respectively (0.61, 95 % CI 0.53-0.68; 0.30, 95 % CI 0.21-0.38). CONCLUSION: The ACL tibial footprint length and width are associated with anthropometric variables, especially with tibial length. The predictive equation developed from this study can serve as supplementary guides to determine the surgical techniques and graft options in preoperative planning of an individual ACL reconstruction. LEVEL OF EVIDENCE: IV.
27128679 Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Infl 2016 OBJECTIVE: Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. METHODS: We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. RESULTS: Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively). CONCLUSIONS: Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.