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ID PMID Title PublicationDate abstract
23900160 Panniculitis with vasculitis. 2013 Aug Panniculitides encompass a great number of different entities; however, once a vasculitis has been detected histopathologically within the subcutaneous tissue, the differential diagnosis is mainly restricted to polyarteritis (panarteritis) nodosa (PAN), nodular vasculitis (NV), and Bazin's erythema induratum (EI). Patients with PAN may have the disease confined to the skin, but must be followed over a long period because many of them develop late systemic disease. The NV/EI group represents by far the most common type of lobular panniculitis with vasculitis; we prefer keeping the distinction between the two entities by underlining the equation NV positive tuberculin skin test = EI. Other lobular panniculitides with vasculitis are exceedingly rare and set in a systemic background which can be infectious (lepromatous leprosy panniculitides) or autoimmune/dysreactive (neutrophilic lobular panniculitis in rheumatoid arthritis, lobular panniculitis in inflammatory bowel disease).
23418382 New centromere autoantigens identified in systemic sclerosis using centromere protein micr 2013 Apr OBJECTIVE: To identify novel centromere protein (CENP) targets of anticentromere antibodies (ACA), and to investigate their association with clinical manifestations of systemic sclerosis (SSc). METHODS: A CENP-focused protein microarray was fabricated by spotting 14 purified CENP. These microarrays were individually incubated with 35 ACA-positive SSc sera and 20 ACA-negative healthy control samples. Newly identified CENP autoantigens with high sensitivities were selected for validation and characterization. RESULTS: Statistical analysis revealed 11 CENP are potential target antigens of ACA in patients with SSc. Of them, 5 [CENP-P, CENP-Q, CENP-M (isoform I), CENP-J, and CENP-T] are novel, among which CENP-P and CENP-Q showed high sensitivities in ACA-positive SSc sera of 34.3% and 28.6%, respectively. Subsequently, 186 SSc sera (35 ACA-positives and 151 negatives), 69 ACA-positive sera from other various autoimmune diseases (primary Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, and primary biliary cirrhosis), and 31 healthy sera were assayed for the presence of anti-CENP-P and -Q autoantibodies by ELISA followed by Western blotting analysis. CENP-P and -Q autoantibodies were detected in ACA-positive sera of various disease groups; among them, SSc showed the highest detection rate. Anti-CENP-P was also found in 9 of the 151 ACA-negative sera. Analyses of the correlation with clinical information showed anti-CENP-P-positive patients had higher levels of IgG, IgA, and erythrocyte sedimentation rate among the ACA-positive cohort and were more vulnerable to renal disease in the ACA-negative patients with SSc. Regardless of ACA status, anti-CENP-P or Q-negative patients seem to be predominantly affected by interstitial lung disease. CONCLUSION: CENP-P and CENP-Q were identified as novel ACA autoantigens by CENP microarray assays followed by validation of ELISA and Western blotting. Both of them have prognostic utility for interstitial lung disease. CENP-P was associated with renal disease in an ACA-negative cohort.
25524867 HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hie 2014 Dec OBJECTIVE: To evaluate HLA-DRB1 genetic risk of rheumatoid arthritis (RA) in African Americans by 3 validated allele classification systems and by amino acid position and residue, and to compare genetic risk between African American and European ancestries. METHODS: Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM), de Vries (DV), and Mattey classification system alleles and separately by amino acid position and individual residues. RESULTS: TdM S2 and S3P alleles were associated with RA (odds ratio [95% confidence interval] 2.8 [2.0-3.9] and 2.1 [1.7-2.7], respectively). The DV (P = 3.2 × 10(-12)) and Mattey (P = 6.5 × 10(-13)) system alleles were both protective in African Americans. Amino acid position 11 (permutation P < 0.00001) accounted for nearly all variability explained by HLA-DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01 ≤ permutation P ≤ 0.05). The valine and aspartic acid residues at position 11 conferred the highest risk of RA in African Americans. CONCLUSION: With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to that in individuals of European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g., 11), and residue (Val11). Unlike that reported for individuals of European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (odds ratio 1 in European ancestry) corresponds to the 4-digit classical allele *09:01, which is also a risk allele for RA in Koreans.
23940951 [Changes in expression of tyrosine hydroxylase by CD4+ T lymphocytes in lymphoid tissues o 2013 May OBJECTIVE: To show the involvement of lymphocyte-derived catecholamines in the pathogenesis of rheumatoid arthritis (RA), we investigated the change in expression of tyrosine hydroxylase (TH), a rate-limiting enzyme of catecholamine synthesis, by CD4+ T lymphocytes in lymphoid tissues of DBA/1 mice with collagen-induced arthritis (CIA). METHODS: CIA model was induced by chicken type II collagen in DBA/1 mice. The joints of the mice were observed for clinical score of swelling on and after the 22nd day of primary immunization. Pathological changes of ankles were examined by staining of tissue sections with hematoxylin and eosin on the 35th and 55th day following primary immunization. Immunofluorescent histochemistry was used to identify the number of TH-positive, CD4-positive, and double-labeled cells in the mesenteric lymph nodes and the spleen. RESULTS: Paw-swelling onset was on days 29 - 32 after the first immunization in DBA/1 mice. Clinical score for swelling of the paws reached peak on day 46 after the first immunization. Compared with the ankles of intact or vehicle mice, the joints of CIA mice had these characteristics: increased inflammatory cells in the synovial tissues, proliferated synoviocytes in the multilayers, narrowed articular space, and destructed articular cartilages. Simultaneously, the number of TH-positive, CD4-positive, and double-labeled cells in the mesenteric lymph nodes and the spleen was significantly increased on days 35 and 55 following the first immunization. Between day 35 and day 55 post-immunization, there was no significant difference in the number of these positive cells. CONCLUSION: CD4+ T lymphocytes up-regulate TH expression in the process of CIA and therefore, it is suggested that endogenous catecholamines of lymphocytes involve in the pathogenesis of RA.
25428402 Frequency distribution of autoimmunity associated FCGR3B gene copy number in Indian popula 2015 Feb Amongst several human genome variations, copy number variations (CNVs) are considered as an important source of variability contributing to susceptibility to wide range of diseases. Although CNV is scattered for genes throughout the human genome, several of autoimmunity related genes have CN variation and therefore play an important role in susceptibility to autoimmune diseases. The association of the Fc gamma receptor 3B (FCGR3B) gene copy number in autoimmunity is well characterized in various populations studied. The Fc gamma receptor is a low affinity, glycosylphosphatidylinositol-linked receptor for IgG molecule predominantly expressed on human neutrophils. The variable gene copy number of FCGR3B is found to be involved in the impaired clearance of immune complexes, which significantly contribute to the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type-1 diabetes and others. The FCGR3B copy number ranged from 0 to ≥ 2 copies per diploid genome in other populations, but yet not explored in Indian population. Hence, this study aims to evaluate the variation in the frequency distribution of FCGR3B CNV in Indian population. FCGR3B gene copy number varied significantly when compared to other population of the world. This observation will help us in exploring the potential role of CNV in FCGR3B gene and its association to autoimmune disorders in Indian population.
24867307 Presymptomatic autoantibodies in Sjögren's syndrome: what significance do they hold for t 2014 Jul In a number of autoimmune diseases, for example, rheumatoid arthritis and systemic lupus erythematosus, it is known that autoantibodies are present before the clinical onset. Recently we have shown that autoantibodies can be found many years before symptom onset in primary Sjögren's syndrome. This implies that screening for autoantibodies may be used to identify individuals at risk of developing systemic autoimmune disease. Possibly, autoantibody screening may also contribute to detection of incipient malignancy. This concept stems from a novel finding, on scleroderma patients, suggesting that an anti-tumor immune response elicited by a mutated self-antigen will cross-react with the unmodified version of the self-antigen, and thus come to trigger the formation of autoantibodies.
24391212 The SOCS3-independent expression of IDO2 supports the homeostatic generation of T regulato 2014 Feb 1 Dendritic cells (DCs) are professional APCs that have a role in the initiation of adaptive immune responses and tolerance. Among the tolerogenic mechanisms, the expression of the enzyme IDO1 represents an effective tool to generate T regulatory cells. In humans, different DC subsets express IDO1, but less is known about the IDO1-related enzyme IDO2. In this study, we found a different pattern of expression and regulation between IDO1 and IDO2 in human circulating DCs. At the protein level, IDO1 is expressed only in circulating myeloid DCs (mDCs) and is modulated by PGE2, whereas IDO2 is expressed in both mDCs and plasmacytoid DCs and is not modulated by PGE2. In healthy subjects, IDO1 expression requires the presence of PGE2 and needs continuous transcription and translation, whereas IDO2 expression is constitutive, independent from suppressor of cytokine signaling 3 activity. Conversely, in patients suffering from inflammatory arthritis, circulating DCs express both IDO1 and IDO2. At the functional level, both mDCs and plasmacytoid DCs generate T regulatory cells through an IDO1/IDO2-dependent mechanism. We conclude that, in humans, whereas IDO1 provides an additional mechanism of tolerance induced by proinflammatory mediators, IDO2 is stably expressed in steady-state conditions and may contribute to the homeostatic tolerogenic capacity of DCs.
23904473 A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneou 2014 Jan OBJECTIVES: This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. RESULTS: At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups -4.0%, 95% CI -9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks. CONCLUSIONS: Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration.
23729801 Subcutaneously administered ofatumumab in rheumatoid arthritis: a phase I/II study of safe 2013 Jul OBJECTIVE: To investigate the safety and tolerability of a single subcutaneous (SC) dose of ofatumumab, a fully human anti-CD20 monoclonal antibody, in patients with rheumatoid arthritis (RA) taking background methotrexate (MTX). Secondary objectives included characterizing pharmacokinetics and pharmacodynamics. METHODS: In this single-blind, phase I/II study, 35 patients with RA were randomized in 5 cohorts to receive a single subcutaneous (SC) ofatumumab dose ranging from 0.3 to 100 mg, or placebo, following premedication with oral acetaminophen and antihistamine. Patients were followed for 24 weeks with extended followup to monitor B cell and immunoglobulin recovery for up to 2 years if required. RESULTS: Thirty-five patients received the following treatment: 0.3 mg, n = 4; 3 mg, n = 6; 30 mg, n = 8; 60 mg, n = 6; 100 mg, n = 3; placebo, n = 8. The most common adverse events in the combined ofatumumab groups were headache, nausea, and upper respiratory tract infection. Because of tolerability concerns, only 3 patients were given 100 mg. For the 30-100 mg doses, median maximum plasma concentration values ranged from 4.02 to 4.49 days. Mean elimination half-life values ranged from 5.20 to 6.83 days. Increasing peripheral median B cell depletion was observed from 0.3 mg up to 30 mg, and full target B cell depletion was achieved with 30 mg, 60 mg, and 100 mg. CONCLUSION: Treatment of RA patients with SC ofatumumab doses of 30 mg or higher resulted in profound and prolonged B cell depletion in blood. Single doses up to 60 mg were tolerated without glucocorticoid premedication. (ClinicalTrials.gov identifier NCT00686868).
23885145 Low rates of adherence for tumor necrosis factor-α inhibitors in Crohn's disease and rheu 2013 Jul 21 AIM: To investigate adherence rates in tumor necrosis factor-α (TNF-α)-inhibitors in Crohn's disease (CD) and rheumatoid arthritis (RA) by systematic review of medical literature. METHODS: A structured search of PubMed between 2001 and 2011 was conducted to identify publications that assessed treatment with TNF-α inhibitors providing data about adherence in CD and RA. Therapeutic agents of interest where adalimumab, infliximab and etanercept, since these are most commonly used for both diseases. Studies assessing only drug survival or continuation rates were excluded. Data describing adherence with TNF-α inhibitors were extracted for each selected study. Given the large variation between definitions of measurement of adherence, the definitions as used by the authors where used in our calculations. Data were tabulated and also presented descriptively. Sample size-weighted pooled proportions of patients adherent to therapy and their 95%CI were calculated. To compare adherence between infliximab, adalimumab and etanercept, the adherence rates where graphed alongside two axes. Possible determinants of adherence were extracted from the selected studies and tabulated using the presented OR. RESULTS: Three studies on CD and three on RA were identified, involving a total of 8147 patients (953 CD and 7194 RA). We identified considerable variation in the definitions and methodologies of measuring adherence between studies. The calculated overall sample size-weighted pooled proportion for adherence to TNF-α inhibitors in CD was 70% (95%CI: 67%-73%) and 59% in RA (95%CI: 58%-60%). In CD the adherence rate for infliximab (72%) was highercompared to adalimumab (55%), with a relative risk of 1.61 (95%CI: 1.27-2.03), whereas in RA adherence for adalimumab (67%) was higher compared to both infliximab (48%) and etanercept (59%), with a relative risk of 1.41 (95%CI: 1.3-1.52) and 1.13 (95%CI: 1.10-1.18) respectively. In comparative studies in RA adherence to infliximab was better than etanercept and etanercept did better than adalimumab. In three studies, the most consistent factor associated with lower adherence was female gender. Results for age, immunomodulator use and prior TNF-α inhibitors use were conflicting. CONCLUSION: One-third of both CD and RA patients treated with TNF-α inhibitors are non-adherent. Female gender was consistently identified as a negative determinant of adherence.
25038623 Latent variable indirect response joint modeling of a continuous and a categorical clinica 2014 Aug Informative exposure-response modeling of clinical endpoints is important in drug development. There has been much recent progress in latent variable modeling of ordered categorical endpoints, including the application of indirect response (IDR) models and accounting for residual correlations between multiple categorical endpoints. This manuscript describes a framework of latent-variable-based IDR models that facilitate easy simultaneous modeling of a continuous and a categorical clinical endpoint. The model was applied to data from two phase III clinical trials of subcutaneously administered ustekinumab for the treatment of psoriatic arthritis, where Psoriasis Area and Severity Index scores and 20, 50, and 70 % improvement in the American College of Rheumatology response criteria were used as efficacy endpoints. Visual predictive check and external validation showed reasonable parameter estimation precision and model performance.
25372086 Sustained remission with etanercept tapering in early rheumatoid arthritis. 2014 Nov 6 BACKGROUND: We assessed the effects of reduction and withdrawal of treatment in patients with rheumatoid arthritis who had a remission while receiving etanercept-plus-methotrexate therapy. METHODS: Patients with early active disease who had not previously received methotrexate or biologic therapy received 50 mg of etanercept plus methotrexate weekly for 52 weeks (open-label phase). We then randomly assigned patients who had qualifying responses at weeks 39 and 52 to receive 25 mg of etanercept plus methotrexate (combination-therapy group), methotrexate alone, or placebo for 39 weeks (double-blind phase). Patients who had qualifying responses at week 39 of the double-blind phase had all treatment withdrawn at that time and were followed to week 65 (treatment-withdrawal phase). The primary end point was the proportion of patients with sustained remission in the double-blind phase. RESULTS: Of 306 patients enrolled, 193 underwent randomization in the double-blind phase; 131 qualified for the treatment-withdrawal phase. More patients in the combination-therapy group than in the methotrexate-alone group or the placebo group met the criterion for the primary end point (40 of 63 [63%] vs. 26 of 65 [40%] and 15 of 65 [23%], respectively; P=0.009 for combination therapy vs. methotrexate alone; P<0.001 for combination therapy vs. placebo). At 65 weeks, 28 patients (44%) who had received combination therapy, 19 (29%) who had received methotrexate alone, and 15 (23%) who had received placebo were in remission (P=0.10 for combination therapy vs. methotrexate alone; P=0.02 for combination therapy vs. placebo; P=0.55 for methotrexate alone vs. placebo). No significant between-group differences were observed in radiographic progression of disease. Serious adverse events were reported in 3 patients (5%) in the combination-therapy group, 2 (3%) in the methotrexate-alone group, and 2 (3%) in the placebo group. CONCLUSIONS: In patients with early rheumatoid arthritis who had a remission while receiving full-dose etanercept-plus-methotrexate therapy, continuing combination therapy at a reduced dose resulted in better disease control than switching to methotrexate alone or placebo, but no significant difference was observed in radiographic progression. (Funded by Pfizer; ClinicalTrials.gov number, NCT00913458.).
24382665 Long lasting outcome of hydroxyapatite-coated implants in primary knee arthroplasty: a con 2014 Feb PURPOSE: This study is a long-term review of an hydroxyapatite (HA)-coated knee prosthesis. Our aim was to confirm that excellent previously reported results with HA knees could stand the test of time at the 15-year milestone. METHODS: A total of 270 cruciate retaining HA-Omnifit knees, implanted in the same institution by a single surgeon with the same surgical procedure, were reviewed at 15-22 years of clinical follow-up (75 knees partially-coated and 195 fully-coated). RESULTS: At review, IKS mean values were 95.6 points for knee score and 91.19 points for function score. Radiological review confirmed an excellent long-lasting fixation over years in the long run. Taking implant failure as the end-point, the survival rate was 97.1% at 20 years. CONCLUSIONS: Our results were as good, and often better, than the best cemented or porous published studies. These very encouraging results at 15-22 years make us very confident in the ultimate outcome of bioconductive coatings in knee arthroplasty.
24623505 Bone- and cartilage-protective effects of a monoclonal antibody against colony-stimulating 2014 Nov OBJECTIVE: Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA. METHODS: CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen-induced arthritis (CIA) and serum-transfer arthritis. RESULTS: CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R+. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr-1- monocytes. CONCLUSION: CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA.
25150438 Poncet's disease with high titers of rheumatoid factor and anti-citrullinated peptide anti 2015 Jan Reactive arthritis accompanying tuberculosis (TB), also known as Poncet's disease, is a rare condition. In the present report, we describe the case of a patient with Poncet's disease, who presented with high titers of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA), which mimicked rheumatoid arthritis (RA). A 69-year-old man with a childhood history of chronic left gonitis suffered from right knee arthritis for 3 years. Chronic monoarthritis in his right knee and positive results obtained on interferon-gamma release assay were suggestive of tuberculous arthritis. However, there was no evidence of TB infection. Moreover, the high titers of RF and ACPA suggested a diagnosis of RA. Surprisingly, the culture of a small sample from his bony ankylosed left knee that had no focal signs of infection, exhibited a positive result for TB infection. Thus, based on these findings, the patient was diagnosed with Poncet's disease. His symptoms improved after initiation of anti-TB therapy, which supported the accuracy of the diagnosis. In addition, we analyzed the characteristics of Poncet's disease by conducting a literature review, and identified that the presence of extra-articular manifestation and negative results for RF and ACPA tests were the features that facilitated distinguishing between typical Poncet's disease and RA; however, since tuberculous patients occasionally exhibit positive results for ACPA tests, the differential diagnosis is essential in ACPA-positive arthritic patients.
23536012 NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rh 2013 Mar 27 The early events leading to the development of rheumatoid arthritis (RA) remain unclear, but formation of autoantibodies to citrullinated protein antigens (ACPAs) is considered a key pathogenic event. Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophil extracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context of immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers, and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and from patients with osteoarthritis (OA). Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules, and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. Indeed, during NETosis, neutrophils externalized the citrullinated autoantigens implicated in RA pathogenesis, and anti-citrullinated vimentin antibodies potently induced NET formation. Moreover, the inflammatory cytokines interleukin-17A (IL-17A) and tumor necrosis factor-α (TNF-α) induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease.
24267149 Nonsteroidal anti-inflammatory drugs and their risk: a story still in development. 2013 NSAIDs are anti-inflammatory, analgesic, and antipyretic agents, and they are typically used chronically to reduce pain, decrease stiffness, and improve function in patients with osteoarthritis, rheumatoid arthritis, and other forms of arthritis. Additionally, NSAIDs are also used for the more acute treatment of pain including headache, dysmenorrhea, and postoperative pain. However, NSAID use conveys potential significant adverse events that include gastrointestinal ulcers with consequential bleeding, perforation or obstruction, renal dysfunction and consequent renal failure, cardiovascular events, as well as the risk for death. Despite the many available forms of NSAIDs, including injectable as well as topical, oral dosing is the most common route, usually the one route consistently associated with chronic use and thus the one that carries the most risk. In the last several years, several topical NSAIDs including either diclofenac ibuprofen or salicylates for chronic pain have been approved in the United States while similar drugs have been available in Europe for years. One study of a diclofenac topical liquid included an oral diclofenac comparator, and demonstrated no difference in efficacy between the two therapies in treatment for the pain of osteoarthritis in the knee.
24557630 A significant induction of neutrophilic chemoattractants but not RANKL in synoviocytes sti 2015 Jan Interleukin 17 (IL-17) is a cytokine implicated in the promotion of osteoclastogenesis. Its effect has been believed not to be directly exerted on osteoclast precursors, but rather indirectly carried out via an induction of receptor activator of NF-κB ligand (RANKL), the osteoclast differentiation factor, on osteoclast-supporting cells, which in turn exert an effect on osteoclast precursors. The mechanistic details, however, remain unclear. In this study, we first performed a transcriptome analysis of synoviocytes derived from a patient with rheumatoid arthritis cultured in the presence or absence of IL-17. We discovered that most of the genes significantly induced by IL-17 were chemokines with a chemotactic effect on neutrophils. We confirmed these results by quantitative RT-PCR and ELISA. Unexpectedly, the stimulation with IL-17 alone did not induce the expression of RANKL either at the mRNA or the protein level. The induction of RANKL was observed when IL-17 was added in combination with 1,25-dihydroxyvitamin D3 and prostaglandin E2, well-known inducers of RANKL, although the exact mechanism of this synergistic effect remains unclear. IL-6 and monocyte chemoattractant protein-1 were also significantly induced by IL-17 at both the mRNA and protein levels. Thus, it appears that IL-17 induces the migration of neutrophils and monocytes/macrophages through the activation of synoviocytes, and enhances a positive feedback loop composed of proinflammatory cytokines IL-6 and IL-17.
23212731 Osteoarthritis synovial fluid activates pro-inflammatory cytokines in primary human chondr 2013 Jan PURPOSE: Two of the most common joint diseases are rheumatoid arthritis (RA) and osteoarthritis (OA). Cartilage degradation and erosions are important pathogenetic mechanisms in both joint diseases and have presently gained increasing interest. The aim of the present study was to investigate the effects of the synovial fluid environment of OA patients in comparison with synovial fluids of RA patients on human chondrocytes in vitro. METHODS: Primary human chondrocytes were incubated in synovial fluids gained from patients with OA or RA. The detection of vital cell numbers was determined by histology and by using the Casy Cell Counter System. Cytokine and chemokine secretion was determined by a multiplex suspension array. RESULTS: Microscopic analysis showed altered cell morphology and cell shrinkage following incubation with synovial fluid of RA patients. Detection of vital cells showed a highly significant decrease of vital chondrocyte when treated with RA synovial fluids in comparison with OA synovial fluids. An active secretion of cytokines such as vascular endothelial growth factor (VEGF) of chondrocytes treated with OA synovial fluids was observed. CONCLUSIONS: Significantly increased levels of various cytokines in synovial fluids of RA, and surprisingly of OA, patients were shown. Activation of pro-inflammatory cytokines of human chondrocytes by synovial fluids of OA patient supports a pro-inflammatory process in the pathogenesis of OA.
25537884 Global analysis of methylation profiles from high resolution CpG data. 2015 Feb New high throughput technologies are now enabling simultaneous epigenetic profiling of DNA methylation at hundreds of thousands of CpGs across the genome. A problem of considerable practical interest is identification of large scale, global changes in methylation that are associated with environmental variables, clinical outcomes, or other experimental conditions. However, there has been little statistical research on methods for global methylation analysis using technologies with individual CpG resolution. To address this critical gap in the literature, we develop a new strategy for global analysis of methylation profiles using a functional regression approach wherein we approximate either the density or the cumulative distribution function (CDF) of the methylation values for each individual using B-spline basis functions. The spline coefficients for each individual are allowed to summarize the individual's overall methylation profile. We then test for association between the overall distribution and a continuous or dichotomous outcome variable using a variance component score test that naturally accommodates the correlation between spline coefficients. Simulations indicate that our proposed approach has desirable power while protecting type I error. The method was applied to detect methylation differences, both genome wide and at LINE1 elements, between the blood samples from rheumatoid arthritis patients and healthy controls and to detect the epigenetic changes of human hepatocarcinogenesis in the context of alcohol abuse and hepatitis C virus infection. A free implementation of our methods in the R language is available in the Global Analysis of Methylation Profiles (GAMP) package at http://research.fhcrc.org/wu/en.html.