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ID PMID Title PublicationDate abstract
23289593 Three-dimensionally engineered biomimetic tissue models for in vitro drug evaluation: deli 2013 Mar INTRODUCTION: Three-dimensionally (3D) engineered biomimetic tissue models are sought after due to their high fidelity in mimicking various native tissues of the human body, this quality of which gives them an important role at the forefront of drug discovery and development. A multitude of studies have consistently indicated that gene expression profiles, cellular phenotypes, differentiation capabilities and functionalities are all affected by tissue architecture. Thus, the drug evaluation process will stand to gain immense benefits from the fairly accurate predictions of cellular responses displayed by 3D-engineered tissue models when exposed to the drugs of interest in vitro. Stemming from this fact, many studies have set out to capitalize on developing tissue models that are tailored to specific aspects of drug evaluation including the tests of novel drug delivery systems, drug efficacy and toxicity. AREAS COVERED: The areas covered include fabrication methods and usage of 3D in vitro tumor models in cancer research, focusing on the evaluation of delivery and efficacy of various anticancer drugs or other therapeutic agents. Also covered are the use of 3D in vitro inflammatory tissue models in anti-inflammation research, centering on osteoarthritis (OA) and rheumatoid arthritis (RA) and the use of 3D in vitro tissue models designed for drug toxicity evaluation specifically with liver-mimetic tissues. EXPERT OPINION: Currently available 3D tissue models in various fields of research have already displayed their capabilities in predicting cellular responses to various therapeutic agents and delivery methods with better accuracy than their 2D counterparts, albeit being in need of much refinement before they can be successfully applied for reliable drug evaluation. Given further development and improvement, it is highly probable that the 3D-engineered tissue models may perform as living platforms for dynamic drug evaluation in vitro.
25205192 Characterization and biological evaluation of six new dimeric lignans with an unusual α,Π2014 Oct 1 Investigation of the bark of Zanthoxylum simulans afforded six new dimeric lignans zanthpodocarpins C-H (1-6) bearing an unusual α,β-unsaturated ketone group. The new structures of 1-6 were determined by using detailed spectroscopic analysis. All of the isolated compounds were examined for their inhibitory effects against rat joint synovial cell and splenocyte proliferation. Compounds 1-6 showed potent anti-inflammatory activities with IC50 values ranging from 18.6 to 36.1μM, and 13.8 to 74.3μM.
24561412 Intra-articular, bursa, and tendon sheath injections: a survey of practice patterns among 2014 Mar OBJECTIVE: The objective of this study was to survey members of the American College of Rheumatology (ACR) regarding intra-articular and soft tissue (musculoskeletal [MSK]) injections and to determine if injection techniques vary depending on type of practice and years of experience. METHODS: A survey was e-mailed to the members of the ACR to obtain demographics of the respondents, MSK injection practices, and adverse events seen. RESULTS: The most common indications for MSK injections were rheumatoid arthritis, osteoarthritis, and bursitis. Written consent and time-out procedures were more common in academic/government practices when compared with private practice. There was variation in the type of corticosteroid used. The most common preparations were methylprednisolone actetate (45.0%), triamcinolone acetonide (26.1%), triamcinolone hexacetonide (22.1%). This survey showed good agreement on the dosage of corticosteroid for MSK injections; however, as years of experience increased, clinicians were more likely to prescribe lower doses for shoulder and knee injections. CONCLUSIONS: In this survey of ACR members, we found self-reported differences in the type of corticosteroid used for MSK injections. There was general agreement on frequency of injections, but more experienced practitioners reported using lower doses of corticosteroid.
23354839 Tumor necrosis factor receptor-associated factor 1 influences KRN/I-Ag7 mouse arthritis au 2013 May PURPOSE: Recently, genomewide association analysis has revealed that the Tumor Necrosis Factor Receptor-associated factor 1-Complement 5 (TRAF1-C5) containing locus on chromosome 9 was associated with an increased risk for RA. Studies in model systems suggested that either gain- or loss-of-function TRAF1 mutations have immune effects that could plausibly lead to or exacerbate the arthritis phenotype. KRN/I-A(g7) (KxB/N) is a genetic mouse model of inflammatory arthritis. We aimed to assess the impact of TRAF1 deficiency on KRN/I-A(g7) mice. METHODS: We have bred KRN/I-A(g7) mice onto a TRAF1-deficient background and followed cohorts for the spontaneous appearance of arthritis. We have also transferred KxB/N serum to B6.I-A(g7) TRAF1KO recipients. In addition, systemic autoimmunity was induced through cGVH by injecting bm12 splenocytes into TRAF1KO recipient mice. RESULTS: TRAF1-deficient KRN/I-A(g7) mice spontaneously developed severe, progressive arthritis, comparable to that seen in TRAF1-intact KRN/I-A(g7) mice. However, the anti-GPI antibody titer was significantly lower in the former group. Interestingly, the TRAF1KO mice that had background levels of anti-GPI antibodies still showed severe arthritis, although with a brief delay compared to TRAF1 sufficient mice. In addition, TRAF1KO mice were fully susceptible to passive, serum transfer experiments. In another model of autoimmunity, TRAF1KO had no effect on cGVH autoantibodies production; nor was the response to an exogenous antigen impaired. CONCLUSION: The pathogenesis of spontaneous KRN/I-A(g7) arthritis can largely proceed by TRAF1-independent pathways. The production of anti-GPI autoantibody, but not other autoantibody or antibody responses, was markedly impaired by TRAF1 deficiency. The spontaneous arthritis model in KRN mice appears to be much less antibody dependent than previously believed.
24749771 Rebamipide attenuates autoimmune arthritis severity in SKG mice via regulation of B cell a 2014 Oct Oxidative stress is involved in the pathophysiology of rheumatoid arthritis (RA). We investigated the therapeutic potential of rebamipide, a gastroprotective agent with a property of reactive oxygen species scavenger, on the development of inflammatory polyarthritis and the pathophysiological mechanisms by which rebamipide might confer anti-arthritic effects in SKG mice, an animal model of RA. Intraperitoneal (i.p.) injection of rebamipide attenuated the severity of clinical and histological arthritis. Rebampide treatment reduced the number of T helper type 1 (Th1), Th2, Th17, inducible T cell co-stimulator (ICOS)(+) follicular helper T (Tfh) transitional type (T2) and mature B cells in the spleen, but increased the number of regulatory T (Treg ), CD19(+) CD1d(high) CD5(high) , CD19(+) CD25(high) forkhead box protein 3 (FoxP3)(+) regulatory B (Breg ) cells, memory B cells, and transitional type 1 (T1) B cells. In addition, flow cytometric analysis revealed significantly decreased populations of FAS(+) GL-7(+) germinal centre B cells and B220(-) CD138(+) plasma cells in the spleens of rebamipide-treated SKG mice compared to controls. Rebamipide decreased germinal centre B cells and reciprocally induced Breg cells in a dose-dependent manner in vitro. Rebamipide-induced Breg cells had more suppressive capacity in relation to T cell proliferation and also inhibited Th17 differentiation from murine CD4(+) T cells. Together, these data show that i.p. administration of rebamipide suppresses arthritis severity by inducing Breg and Treg cells and suppressing Tfh and Th17 cells in a murine model of RA.
23449952 Contrast-enhanced MR imaging of hand and finger joints in patients with early rheumatoid a 2013 Jul PURPOSE: To investigate the diagnostic value of a half dose compared with a full dose of gadobenate dimeglumine in the assessment of synovitis or tenosynovitis in the wrist and finger joints in patients with early rheumatoid arthritis (RA) and a disease activity score greater than 3.2. MATERIALS AND METHODS: With institutional review board approval and informed consent, 57 patients with early RA underwent 3-T magnetic resonance (MR) imaging with two different doses of contrast media. The contrast enhancement was measured in inflamed synovial tissue at half dose (0.05 mmol per kilogram of body weight) and at full dose (0.1 mmol/kg) by using T1-weighted sequences with fat saturation. The differences and the correlation of signal intensities (SIs) at half- and full-dose sequences were compared by using the paired t test and Pearson correlations. Image quality, Rheumatoid Arthritis MRI Score (RAMRIS), and tenosynovitis score on half- and full-dose images were compared by two observers using the Wilcoxon test. Interrater agreement was assessed by using κ statistics. RESULTS: A significant difference in SI was found between half-dose and full-dose gadobenate dimeglumine-enhanced synovial tissue (mean: 914.35 ± 251.1 vs 1022 ± 244.5, P < .001). Because the SI showed high correlation between the ratio at half dose and full dose (r = 0.875), the formula, ratio of synovial enhancement to saline syringe at full dose = 0.337 + 1.070 × ratio of synovial enhancement to saline syringe at half dose, can be used to convert the normalized value of half dose to full dose. However, no difference in RAMRIS (score 0 in 490 of 1026 joints; score 1 in 344; score 2 in 158; and score 3 in 34) or tenosynovitis scores in grading synovitis or tenosynovitis in image quality and in assessment of synovial enhancement was detected between half-dose and full-dose images (P = 1). CONCLUSION: Postcontrast synovial SIs showed high correlation between half dose and full dose, and image quality was rated identically. Therefore, half-dose gadobenate dimeglumine at 3-T MR imaging may be sufficient for assessing synovitis or tenosynovitis in early RA.
25205591 Heterozygote genotypes for PADI4_89 were protectively associated with susceptibility to tu 2015 Apr The aim of this study was to determine whether peptidyl arginine deiminase (PADI) genes could affect susceptibility to tuberculosis (TB), which can be a presumptive base to explain the increased incidence of TB in patients with rheumatoid arthritis (RA) in Korean. The study population consisted of 47 patients with active TB, 35 patients with nontuberculous mycobacterial disease, 50 RA patients, and 83 healthy controls who had received comprehensive medical testing. Genomic DNA was isolated from peripheral blood mononuclear cells using a standard protocol. All of the patients and healthy controls were genotyped for two nonsynonymous SNPs in PADI4, namely PADI4_89, PADI4_90, and one synonymous SNP in PADI4_104. There was the complete linkage between PADI4_89 and PADI4_90 SNPs. In the allele and haplotype analyses of PADI4_89 and PADI4_104, no significant associations are observed between disease groups and control groups. The frequencies of heterozygote (A/G) for PADI4_89 were significantly lower in patients with active TB than in controls [adjusted odd ratios (OR) = 0.35, p values = 0.020]. When the analysis was conducted by overdominant model, more significant associations are observed (adjusted OR = 0.34, p values = 0.005). We found that heterozygote genotypes for PADI4_89 were protectively associated with susceptibility to TB.
24558457 Accelerated development of cervical spine instabilities in rheumatoid arthritis: a prospec 2014 OBJECTIVE: To clarify the incidence and predictive risk factors of cervical spine instabilities which may induce compression myelopathy in patients with rheumatoid arthritis (RA). METHODS: Three types of cervical spine instability were radiographically categorized into "moderate" and "severe" based on atlantoaxial subluxation (AAS: atlantodental interval >3 mm versus ≥10 mm), vertical subluxation (VS: Ranawat value <13 mm versus ≤10 mm), and subaxial subluxation (SAS: irreducible translation ≥2 mm versus ≥4 mm or at multiple). 228 "definite" or "classical" RA patients (140 without instability and 88 with "moderate" instability) were prospectively followed for >5 years. The endpoint incidence of "severe" instabilities and predictors for "severe" instability were determined. RESULTS: Patients with baseline "moderate" instability, including all sub-groups (AAS(+) [VS(-) SAS(-)], VS(+) [SAS(-) AAS(±)], and SAS(+) [AAS(±) VS(±)]), developed "severe" instabilities more frequently (33.3% with AAS(+), 75.0% with VS(+), and 42.9% with SAS(+)) than those initially without instability (12.9%; p<0.003, p<0.003, and p = 0.061, respectively). The incidence of cervical canal stenosis and/or basilar invagination was also higher in patients with initial instability (17.5% with AAS(+), 37.5% with VS(+), and 14.3% with SAS(+)) than in those without instability (7.1%; p = 0.028, p<0.003, and p = 0.427, respectively). Multivariable logistic regression analysis identified corticosteroid administration, Steinbrocker stage III or IV at baseline, mutilating changes at baseline, and the development of mutilans during the follow-up period correlated with the progression to "severe" instability (p<0.05). CONCLUSIONS: This prospective cohort study demonstrates accelerated development of cervical spine involvement in RA patients with pre-existing instability--especially VS. Advanced peripheral erosiveness and concomitant corticosteroid treatment are indicators for poor prognosis of the cervical spine in RA.
25006585 Low levels of CD36 in peripheral blood monocytes in subclinical atherosclerosis in rheumat 2014 Patients with rheumatoid arthritis (RA) have a higher risk for atherosclerosis. There is no clinical information about scavenger receptor CD36 and the development of subclinical atherosclerosis in patients with RA. The aim of this study was to evaluate the association between membrane expression of CD36 in peripheral blood mononuclear cells (PBMC) and carotid intima-media thickness (cIMT) in patients with RA. METHODS: We included 67 patients with RA from the Rheumatology Department of Hospital Civil "Dr. Juan I. Menchaca," Guadalajara, Jalisco, Mexico. We evaluated the cIMT, considering subclinical atherosclerosis when >0.6 mm. Since our main objective was to associate the membrane expression of CD36 with subclinical atherosclerosis, other molecules related with cardiovascular risk such as ox-LDL, IL-6, and TNFα were tested. RESULTS: We found low CD36 membrane expression in PBMC from RA patients with subclinical atherosclerosis (P < 0.001). CD36 mean fluorescence intensity had negative correlations with cIMT (r = -0.578, P < 0.001), ox-LDL (r = -0.427, P = 0.05), TNFα (r = -0.729, P < 0.001), and IL-6 (r = -0.822, P < 0.001). CONCLUSION: RA patients with subclinical atherosclerosis showed low membrane expression of CD36 in PBMC and increased serum proinflammatory cytokines. Further studies are needed to clarify the regulation of CD36 in RA.
25566581 Multiple cutaneous abscesses revealing disseminated nocardiosis in a patient with chronic 2014 Dec Nocardiosis is a challenging infection that is difficult to diagnose and treat. Delayed recognition and prolonged illness are major concerns. We report the case of a 65-year-old man who underwent treatment with corticosteroids for rheumatoid arthritis and then presented with multiple abscesses on the right leg. A complete assessment performed by the dermatologist led to the diagnosis of disseminated nocardiosis with involvement of the lungs and central nervous system. The patient's history revealed development of pulmonary disease approximately 1 year prior to the appearance of the skin lesions, which was not recognized by several specialists. Long-term antibiotic therapy was effective in treating the skin and central nervous system lesions, while the chest radiologic profile improved more slowly.
23925956 Better functional and similar pain outcomes in osteoarthritis compared to rheumatoid arthr 2013 Dec OBJECTIVE: To determine the association of the underlying diagnosis with limitation in activities of daily living (ADL) and pain in patients undergoing primary total knee arthroplasty (TKA). METHODS: Prospectively collected data from the Mayo Clinic Total Joint Registry were used to assess the association of diagnosis with moderate-severe limitation in ADL and moderate-severe pain at 2 and 5 years after primary TKA, using multivariable-adjusted logistic regression analyses. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: There were 7,139 primary TKAs at 2 years and 4,234 at 5 years. In multivariable-adjusted analyses, compared with rheumatoid arthritis (RA)/inflammatory arthritis, osteoarthritis (OA) was associated with significantly lower moderate-severe ADL limitation at 2 years (OR 0.5 [95% CI 0.3-0.8]) (P = 0.004) and at 5 years (OR 0.5 [95% CI 0.3-0.9]) (P = 0.02). There was no significant association of diagnosis of OA with moderate-severe pain at 2 years (OR 1.2 [95% CI 0.5-2.7]) (P = 0.68) or at 5 years (OR 1.0 [95% CI 0.3-3.7]) (P = 1.0). CONCLUSION: We found that patients with OA who underwent primary TKA had better ADL outcomes compared to patients with RA/inflammatory arthritis at 2 and 5 years. On the other hand, the pain outcomes after primary TKA did not differ in OA versus RA. This suggests a discordant effect of underlying diagnosis on pain and function outcomes after TKA. These novel findings can be used to better inform both patients and surgeons about expected pain and function outcomes after primary TKA.
24760466 Late-onset deep surgical-site infection after posterior lumbar interbody fusion in a patie 2014 May PURPOSE: To describe a case of late-onset deep surgical-site infection (SSI) after posterior lumbar interbody fusion in a patient treated with tocilizumab (TCZ) for rheumatoid arthritis (RA), with emphasis on the clinical symptoms and changes in inflammatory markers such as white blood cell (WBC) count and C-reactive protein (CRP) level. CASE REPORT: A 74-year-old woman with 3-year history of RA underwent posterior lumbar interbody fusion at the L4/5/S1 level. After confirmation of no clinical symptom of SSI postoperatively, we decided to use TCZ for the patient after 2 months postoperatively. At 8 months after beginning of TCZ, she suffered from sudden onset of severe low back pain (LBP) with fever (38 °C) 1 day after administration of TCZ. Local tissues around the operative wound showed no sign of redness, warmth, or swelling. Increases in body temperature, WBC count, and CRP level were well suppressed by TCZ. Magnetic resonance imaging performed 2 weeks after onset of LBP revealed deep SSI. After surgical debridement and administration of the sensitive antibiotics, no clinical signs of recurrent spondylitis or osteolysis of vertebral body have been seen for 3 years. CONCLUSIONS: As TCZ strongly suppresses inflammatory reactions, detecting deep SSI based on local and systemic findings and laboratory data is quite difficult. Care must be taken regarding SSI when patients treated with TCZ complain of long-lasting LBP after lumbar surgery.
24348674 Modulatory effect of 1,25-dihydroxyvitamin D 3 on IL1 β -induced RANKL, OPG, TNF α , and 2013 Receptor activator of nuclear factor κ B ligand (RANKL) plays a crucial role in the bone erosion of rheumatoid arthritis (RA) by prompting osteoclastogenesis. Considering that 1,25(OH)2D3 has been suggested as a potent inducer of RANKL expression, it should clarify whether vitamin D supplement could result in RANKL overexpression and thereby facilitate excessive osteoclastogenesis and bone resorption in RA. Here, we investigated modulatory effect of 1,25(OH)2D3 on the expression of RANKL and its decoy receptor osteoprotegerin (OPG) in an inflammatory condition of human rheumatoid synoviocyte MH7A. MH7A cells were stimulated with IL1 β and then treated with different concentrations of 1,25(OH)2D3 for 48 h. A significantly elevated OPG/RANKL ratio and markedly decreased levels of IL-6 and TNF β mRNA expression in cells and IL-6 protein in supernatants were observed in IL1 β -induced MH7A in the presence of 1,25(OH)2D3 compared with those in the absence of it. Osteoclast formation was obviously decreased when RAW264.7 cells were treated with both 1,25(OH)2D3 and IL1 β . In summary, although it has a biological function to induce RANKL expression, 1,25(OH)2D3 could upregulate OPG/RANKL ratio and mediate anti-inflammatory action in an inflammatory milieu of synoviocyte, contributing to the inhibition of inflammation-induced osteoclastogenesis in RA.
24287433 A preliminary study on the characterization of follicular helper T (Tfh) cells in rheumato 2014 Apr Rheumatoid arthritis (RA) is a chronic and systematic autoimmune inflammatory disease. Recently, a novel T cell subset, follicular helper CD4 T cell (Tfh cells) was found in relation to the pathogenesis and progression of RA, and increased numbers of circulating Tfh cells were found in RA patients. However, there is little evidence regarding the localization of Tfh cells in synovium tissues from RA patients, owing to the lack of an available method to characterize their localization in tissue. The aim of our present study was to characterize the Tfh cells in rheumatoid synovium tissues from RA patients by using immunohistochemistry and triple-fluorescence immunostaining methods. Our results showed that specific staining of CD4, CXCR5 and ICOS could be found on infiltrating immune cells in rheumatoid synovium tissues. The use of triple-fluorescence immunostaining and confocal laser scanning showed immunolocalization of CD4(+)CXCR5(+)ICOS(+)T cells (Tfh cells) in the rheumatoid synovium tissues, whereas these signals were absent in osteoarthritis (OA) synovium and in normal synovium tissues. Thus the data from our present preliminary study support the notion that CD4(+)CXCR5(+)ICOS(+)Tfh cells could be found in rheumatoid synovium tissues from RA patients, indicating the possibility that this T cell subset in synovium tissues may have important roles in the pathogenesis and progression of RA.
24423111 Efficient haplotype block recognition of very long and dense genetic sequences. 2014 Jan 14 BACKGROUND: The new sequencing technologies enable to scan very long and dense genetic sequences, obtaining datasets of genetic markers that are an order of magnitude larger than previously available. Such genetic sequences are characterized by common alleles interspersed with multiple rarer alleles. This situation has renewed the interest for the identification of haplotypes carrying the rare risk alleles. However, large scale explorations of the linkage-disequilibrium (LD) pattern to identify haplotype blocks are not easy to perform, because traditional algorithms have at least Θ(n2) time and memory complexity. RESULTS: We derived three incremental optimizations of the widely used haplotype block recognition algorithm proposed by Gabriel et al. in 2002. Our most efficient solution, called MIG ++, has only Θ(n) memory complexity and, on a genome-wide scale, it omits >80% of the calculations, which makes it an order of magnitude faster than the original algorithm. Differently from the existing software, the MIG ++ analyzes the LD between SNPs at any distance, avoiding restrictions on the maximal block length. The haplotype block partition of the entire HapMap II CEPH dataset was obtained in 457 hours. By replacing the standard likelihood-based D' variance estimator with an approximated estimator, the runtime was further improved. While producing a coarser partition, the approximate method allowed to obtain the full-genome haplotype block partition of the entire 1000 Genomes Project CEPH dataset in 44 hours, with no restrictions on allele frequency or long-range correlations. These experiments showed that LD-based haplotype blocks can span more than one million base-pairs in both HapMap II and 1000 Genomes datasets. An application to the North American Rheumatoid Arthritis Consortium (NARAC) dataset shows how the MIG ++ can support genome-wide haplotype association studies. CONCLUSIONS: The MIG ++ enables to perform LD-based haplotype block recognition on genetic sequences of any length and density. In the new generation sequencing era, this can help identify haplotypes that carry rare variants of interest. The low computational requirements open the possibility to include the haplotype block structure into genome-wide association scans, downstream analyses, and visual interfaces for online genome browsers.
23380023 Remission in early, aggressive rheumatoid arthritis: a multicentre prospective observation 2013 May OBJECTIVES: To provide a survey of disease activity in patients treated with standard care in Italian clinical practice. METHODS: This was an observational prospective cohort study in patients with early, aggressive rheumatoid arthritis (RA; duration ≤2 years but ≥6 weeks; DAS28 >3.2) naïve to anti-tumour necrosis factor (TNF) therapy who were treated with disease-modifying anti-rheumatic drugs (DMARDs) and/or biologics according to standard practice at 15 Italian ARPA (Artrite Reumatoide Precoce Aggressiva) centres. Patients were evaluated at baseline and after 6, 12 and 24 months. The primary endpoint was the proportion of patients achieving remission, as defined by disease activity score in 28 joints (DAS28) <2.6, after 1 year. RESULTS: Among the 152 patients enrolled, 92 were evaluable after 1 year and 77 after 2 years for DAS28. At baseline, patients had a mean DAS28 of 6.1±1.0. At 12 months, 62.6% of patients were treated with DMARDs (in monotherapy or in combination), and 37.4% with anti-TNFs (in monotherapy or in association with DMARDs). At 24 months, 35.1% were receiving anti-TNF therapy. The rate of DAS28 remission rates at 12 months and 24 months were 28.3% (95% confidence interval [CI] 19.1-37.5) and 41.6% (95% confidence interval [CI] 30.6-52.6), respectively. CONCLUSIONS: The remission rate was lower at 12 months compared with previous large randomised clinical trials for early, aggressive RA, but significantly improved at 24 months. These results suggest that patients in real-world clinical settings in Italy may experience a delay in receiving the best possible care.
25461298 The association between dry eye disease and depression and anxiety in a large population-b 2015 Mar PURPOSE: To investigate the association between dry eye disease and each of depression and anxiety. DESIGN: Retrospective, case-control study. METHODS: setting: University of North Carolina outpatient clinics. study population: All patients over the age of 18 years seen between July 2008 and June 2013 were included in the analysis. observation procedure: Cases were defined according to ICD-9 diagnosis codes for dry eye disease, anxiety, and depression. outcome measure: Separate odds ratios were calculated for dry eye disease and each of anxiety and depression. Similar odds ratios were also calculated between dry eye disease and rheumatoid arthritis, a systemic disease with a known association with dry eye, as a way of validating our approach. RESULTS: A total of 460 611 patients were screened; 7207 patients with dry eye were included, while 20 004 patients with anxiety and 30 100 patients with depression were included. The adjusted odds ratio for dry eye disease and anxiety was 2.8 (95% confidence interval [CI] 2.6-3.0). For dry eye disease and depression, the odds ratio was 2.9 (95% CI 2.7-3.1). CONCLUSIONS: We identified a statistically significant association between dry eye disease and each of depression and anxiety. Such an association has implications for ophthalmologists in the management and treatment of dry eye disease.
23587548 Do follow-on therapeutic substitutes induce price competition between hospital medicines? 2013 Jun OBJECTIVE: The pricing of follow-on drugs, that offer only limited health benefits over existing therapeutic alternatives, is a recurring health policy debate. This study investigates whether follow-on therapeutic substitutes create price competition between branded hospital medicines. METHODS: New follow-on drugs and their incumbent therapeutic competitors were identified from Danish sales and product registration data on hospital pharmaceuticals using medically relevant criteria. We examined whether follow-on drugs adopt lower prices than their incumbent competitors, and whether incumbent competitors react to entry of follow-ons through price adjustments using a random intercept panel model. RESULTS: We found no evidence that follow-on drugs adopt lower prices than their incumbent competitors. Furthermore, potentially due to low sample size, we found no evidence that prices for incumbent pioneer products were significantly reduced as a reaction to competition from follow-on drugs. CONCLUSION: Competition between patented therapeutic substitutes did not seem to increase price competition and containment of pharmaceutical expenditures in the Danish hospital market. Strengthening hospitals' incentives to consider the price of alternative treatment options paired with a more active formulary management may increase price competition between therapeutic substitutes in the Danish hospital sector in the future.
25318612 Treatment of rheumatoid arthritis with methotrexate alone and in combination with other co 2015 Feb The aim of this study was to evaluate the effect of treatment with methotrexate (MTX), by itself or combined with other non-biological disease-modifying antirheumatic drugs (DMARDs) (methotrexate, MTX with prednisolone, MTX with leflunomide, MTX with chloroquine, and MTX with sulfasalazine) on clinimetric outcomes in a retrospective cohort with a 6-month follow-up and under a Treat to Target (T2T) approach. Patients in treatment with conventional DMARDs and classified as moderate disease activity (MDA) and high disease activity (HDA) were included. Changes in disease activity score (DAS28), health assessment questionnaire (HAQ), tender joint count (TJC), and swollen joint count (SJC) are compared using the Wilcoxon nonparametric test for paired data. Hypothesis contrasts were raised in order to look for differences between the different exposure groups and the outcomes defined by means of the Kruskal-Wallis (KW) nonparametric test. Follow-up was documented in 307 patients, including 250 (81.4%) women. At the onset, 243 subjects (79.2%) were classified as MDA and 64 (20.9%) in HDA. A total of 247 subjects (80.4%) presented some degree of improvement, with 156 subjects (51%) entering remission, which is a significant number (p value = 0.047). There were no differences in the level of severity between the treatment groups (p = 0.98). This study, developed in a cohort of patients with RA with moderate or severe disease activity who were treated with MTX by itself or combined with other non-biological DMARDs under T2T strategy, showed a decrease in the severity of disease activity in 80% of patients. The difference between monotherapy (MTX) and the combinations with other non-biological DMARDs could not be established.
24982240 Endogenous MMP-9 and not MMP-2 promotes rheumatoid synovial fibroblast survival, inflammat 2014 Dec OBJECTIVE: The aim of this study was to investigate the effect of endogenous matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) on the invasive characteristics of RA synovial fibroblasts. METHODS: Synovial fibroblasts isolated from patients with RA or OA were treated with MMP small interfering RNA (siRNA), inhibitors and recombinant proteins or TNF-α, with or without cartilage explants. Cell viability and proliferation were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and 5-bromo-2-deoxyuridine (BrdU) proliferation assays, respectively; apoptosis by an in situ cell death detection kit; migration and invasion by CytoSelect invasion assay, scratch migration and collagen gel assays; cartilage degradation by 1,9-dimethylmethylene blue assay; and inflammatory mediators and MMPs by ELISA, western blot and zymography. RESULTS: MMP-2 was expressed by both OA and RA synovial fibroblasts, whereas only RA synovial fibroblasts expressed MMP-9. Suppressing MMP-2 or MMP-9 reduced RA synovial fibroblast proliferation equally. However, MMP-9 siRNA had greater effects compared with MMP-2 siRNA on promoting apoptosis and suppressing RA synovial fibroblast viability, migration and invasion. Suppression/inhibition of MMP-9 also decreased the production of IL-1β, IL-6, IL-8 and TNF-α, inactivated nuclear factor κB (NF-κB), extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) and suppressed RA synovial fibroblast-mediated cartilage degradation. In contrast, suppression/inhibition of MMP-2 stimulated TNF-α and IL-17 secretion and activated NF-κB, while recombinant MMP-2 (rMMP-2) inactivated NF-κB and suppressed RA synovial fibroblast-mediated cartilage degradation. Results using specific inhibitors and rMMPs provided supportive evidence for the siRNA results. CONCLUSION: Endogenous MMP-2 or MMP-9 contribute to RA synovial fibroblast survival, proliferation, migration and invasion, with MMP-9 having more potent effects. Additionally, MMP-9 stimulates RA synovial fibroblast-mediated inflammation and degradation of cartilage, whereas MMP-2 inhibits these parameters. Overall, our data indicate that MMP-9 derived from RA synovial fibroblasts may directly contribute to joint destruction in RA.