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ID PMID Title PublicationDate abstract
20149312 Anti-TNF therapy of ankylosing spondylitis in clinical practice. Results from the Czech na 2009 Nov OBJECTIVES: To estimate efficacy, safety and adherence to therapy of ankylosing spondlitis (AS) patients included in the Czech National Registry ATTRA, and to look for predictive factors for therapy discontinuation. METHODS: Patients were included according to the guidelines of the Czech Society for Rheumatology, which involve failure of previous therapy, BASDAI >4, and CRP >10 mg/l. Only patients with anti-TNF administered for the first time were analysed. Adherence to therapy was evaluated using Kaplan-Meier analysis and results were presented as cumulative survival. Comparison with data on patients with rheumatoid arthritis (RA) followed in the same registry was made. RESULTS: 310 of AS patients who had reached at least 1 year as well as those who discontinued the treatment before this time point were analysed. Drug survival was longer in patients with AS than in those with RA: 84% vs. 78% and 72% vs. 49% after 1 and 3 years of treatment. Significant risk factors for treatment discontinuation were female gender (RR 2.22, p=0.001) and CRP (RR 1.33, p=0.025). The proportion of patients with BASDAI <4 during the treatment period was higher in the etanercept group than in the infliximab group (p<0.001). The number of patients fully employed increased in the whole group from 48% to 63% after 1 year of treatment. CONCLUSION: Follow-up of patients with AS in the national registry shows that it is an effective and safe way of treatment with longer adherence to anti-TNF therapy in comparison with RA patients.
21091114 Anti-TNF-α agents in the treatment of immune-mediated inflammatory diseases: mechanisms o 2010 Nov TNF-α is a potent inducer of the inflammatory response, a key regulator of innate immunity and plays an important role in the regulation of Th1 immune responses against intracellular bacteria and certain viral infections. However, dysregulated TNF can also contribute to numerous pathological situations. These include immune-mediated inflammatory diseases (IMIDs) including rheumatoid arthritis, Crohn's disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and severe chronic plaque psoriasis. Animal and human studies concerning the role of TNF-α in IMIDs have led to the development of a therapy based on TNF blockage. This article focuses first on the potential mechanisms by which the three currently licensed agents, adalimumab, etarnecept and infliximab, decrease the inflammatory activity of patients with different IMIDs. Second, it focuses on the risks, precautions and complications of the use of TNF-α inhibitors in these patients.
19289819 Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibit 2009 Apr 7 IL-23/IL-17-induced neutrophil recruitment plays a pivotal role in rheumatoid arthritis (RA). However, the mechanism of the neutrophil recruitment is obscure. Here we report that prostaglandin enhances the IL-23/IL-17-induced neutrophil migration in a murine model of RA by inhibiting IL-12 and IFN gamma production. Methylated BSA (mBSA) and IL-23-induced neutrophil migration was inhibited by anti-IL-23 and anti-IL-17 antibodies, COX inhibitors, IL-12, or IFNgamma but was enhanced by prostaglandin E(2) (PGE(2)). IL-23-induced IL-17 production was increased by PGE(2) and suppressed by COX-inhibition or IL-12. Furthermore, COX inhibition failed to reduce IL-23-induced neutrophil migration in IL-12- or IFNgamma-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFNgamma but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNFalpha, anti-CXCL1, and anti-CXCL5 antibodies and by repertaxin (a CXCR1/2 antagonist). These treatments all inhibited mBSA- or IL-23-induced neutrophil migration. IL-17 induced neutrophil chemotaxis through a CXC chemokines-dependent pathway. Our results suggest that prostaglandin plays an important role in IL-23-induced neutrophil migration in arthritis by enhancing IL-17 synthesis and by inhibiting IL-12 and IFNgamma production. We thus provide a mechanism for the pathogenic role of the IL-23/IL-17 axis in RA and also suggest an additional mechanism of action for nonsteroidal anti-inflammatory drugs.
20167234 Phenotype markers and cytokine intracellular production by CD8+ gammadelta T lymphocytes d 2010 Apr 8 gammadelta T lymphocytes (GD) have been suggested as one of the causes of cytokine dysregulation that results in neutrophils hyperactivation in Behçet's disease (BD) patients. In addition, GD can provoke cytotoxic lesions in autoimmune diseases by interaction with MICA (MHC class I chain-related A) molecules, through NKG2D receptor on its surface. In contrast, the CD8+ subset of gammadelta T lymphocytes (GDCD8+) has been related to regulatory T activity. The aim of this study was to determine the phenotype and the intracellular cytokine profile in GD from peripheral blood, to discern if they were skewed to an effector or regulatory pattern in BD. We performed phenotype analysis, by three-colour flow cytometry, in 28 BD, 15 healthy controls (HC) and 14 patients with recurrent bucal ulcers (RBU). We studied intracellular cytokine production in 10 BD and 14 HC, after polyclonal stimulation. In addition, we analysed serum IL-15 and soluble MICA, by ELISA, in 27 BD, 21 HC and 40 rheumatoid arthritis patients. The hallmark in BD was a specific increase in CD8 expression by GD, and in GDCD8+ absolute numbers. Most of GDCD8+ presented CD8 alphaalpha homodimers and were negative for CD103, Foxp3 and CTLA-4. GDCD8+ and GDCD8- were high IFNgamma-, but poor IL-2, IL-10, TGFbeta and IL-4-producing cells, with no differences between BD and HC. NKG2D expression on CD8+ T cells, serum IL-15 and soluble MICA were not significantly increased in BD. Our results do not suggest a T regulatory profile for GDCD8+ neither in HC, nor in BD. We cannot rule out other suppression mechanisms or some heterogeneity within this subset that could contribute to regulatory function.
19254919 Kallikreins, kininogens and kinin receptors on circulating and synovial fluid neutrophils: 2009 May OBJECTIVES: Neutrophils traffic into and have the capacity to generate kinins in SF of RA patients. The aim of this study was to assess the expression of kallikreins, kininogens and kinin receptors in circulating and SF neutrophils, as well as synovial tissue of RA patients, and to assess kinin generation in SF. METHODS: Neutrophils were isolated from blood and SF of RA patients and blood of healthy volunteers. Expression of kallikreins, kininogens and kinin receptors in neutrophils and synovial tissue was assessed by immunocytochemistry using specific antibodies, with visualization by brightfield and confocal microscopy. Levels of basal and generated kinins in SF of RA patients were measured by ELISA. RESULTS: Kinin labelling was significantly reduced, indicating the loss of the kinin moiety from kininogen on circulating (P < 0.001) and SF neutrophils (P < 0.05) of RA patients. Immunolabelling of tissue kallikrein was also decreased, whereas kinin B(1) and B(2) receptor expression was increased in circulating and SF neutrophils of RA patients. Immunolabelling of kallikreins and kinin receptor proteins was similar in RA and normal synovial tissues. The basal kinin level in SF of RA patients was 5.7 +/- 6.1 ng/ml and the mean concentration of kinins generated in vitro was 80.6 +/- 56.3 ng/ml. The capacity for kinin generation was positively correlated with measures of disease activity. CONCLUSIONS: Kallikrein-kinin proteins on neutrophils play an important role in kinin generation and the pathophysiology of RA. Specific kallikrein and kinin receptor antagonists may be useful as IA therapies for inflamed joints.
19567761 Prevention of major depression in complex medically ill patients: preliminary results from 2009 May BACKGROUND: Depression is highly prevalent in patients with physical illness and is associated with a diminished quality of life and poorer medical outcomes. OBJECTIVE: The authors evaluated whether a multifaceted intervention conducted by a psychiatric consultation-liaison nurse could reduce the incidence of major depression in rheumatology inpatients and diabetes outpatients with a high level of case complexity. METHOD: Of 247 randomized patients, the authors identified 100 patients with a high level of case complexity at baseline and without major depression (65 rheumatology and 35 diabetes patients). Patients were randomized to usual care (N=53) or to a nurse-led intervention (N=47). Main outcomes were the incidence of major depression and severity of depressive symptoms during a 1-year follow-up, based on quarterly assessments with standardized psychiatric interviews. RESULTS: The incidence of major depression was 63% in usual-care patients and 36% in the intervention group. Effects of intervention on depressive symptoms were observed in outpatients with diabetes but not in rheumatology inpatients. CONCLUSION: These preliminary results based on subgroup analysis suggest that a multifaceted nurse-led intervention may prevent the occurrence of major depression in complex medically ill patients and reduce depressive symptoms in diabetes outpatients.
19783714 Examination of the effect of increasing doses of etoricoxib on oral methotrexate pharmacok 2009 Oct The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.
20683738 Extended dosing of etanercept 25 mg can be effective in patients with ankylosing spondylit 2010 Oct As a measure of healthcare cost containment, the total number of vials of entanercept (25 mg) that can be prescribed for patients with inflammatory arthritis is restricted in Korea. Consequently, attempts to extend the dosing interval while maintaining the efficacy have not been an uncommon clinical practice. The aim of this study was to determine if extended doing interval of etanercept can be effective in patients with ankylosing spondylitis (AS). We performed a retrospective analysis using medical records at a single tertiary hospital. One hundred and nine patients with AS and 79 patients with rheumatoid arthritis (RA) started on etanercept between November 2004 and November 2009 were identified. Etanercept (25 mg) was started with twice-weekly dosing schedule. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), C-reactive protein (CRP), and etanercept dosing interval for AS patients at 0, 3, 9, 15, 21 months were reviewed. Dosing interval for RA patients was analyzed for comparison. In AS, mean dosing interval was 4.7 +/- 2.1 days at 3 months and was increased to 12.1 +/- 7.0 days at 21 months. Despite the progressive increase in the dosing interval, the mean BASDAI declined rapidly at 3 months, and continued to decrease over 21 months. Mean CRP declined after 3 months of therapy and remained low thereafter. In RA, mean dosing interval was 4.0 +/- 1.2 days at 3 months and 5.1 +/- 1.8 days at 21 months. In conclusion, in AS, extended dosing of etanercept can be effective without compromising clinical and laboratory markers of disease activity as measured by BASDAI and CRP, respectively. Tapering of etanercept was less accommodating in RA when compared to AS.
18511547 Measuring quality of care for rheumatic diseases using an electronic medical record. 2009 May OBJECTIVES: The objective of this study was twofold: (1) to determine how best to measure adherence with time-dependent quality indicators (QIs) related to laboratory monitoring, and (2) to assess the accuracy and efficiency of gathering QI adherence information from an electronic medical record (EMR). METHODS: A random sample of 100 patients were selected who had at least three visits with the diagnosis of rheumatoid arthritis (RA) at Brigham and Women's Hospital Arthritis Center in 2005. Using the EMR, it was determined whether patients had been prescribed a disease-modifying antirheumatic drug (DMARD) (QI #1) and if patients starting therapy received appropriate baseline laboratory testing (QI #2). For patients consistently prescribed a DMARD, adherence with follow-up testing (QI #3) was calculated using three different methods, the Calendar, Interval and Rolling Interval RESULTS: It was found that 97% of patients were prescribed a DMARD (QI #1) and baseline tests were completed in 50% of patients (QI #2). For follow-up testing (QI #3), mean adherence was 60% for the Calendar Method, 35% for the Interval Method, and 48% for the Rolling Interval Method. Using the Rolling Interval Method, adherence rates were similar across drug and laboratory testing type. CONCLUSIONS: Results for adherence with laboratory testing QIs for DMARD use differed depending on how the QIs were measured, suggesting that care must be taken in clearly defining methods. While EMRs will provide important opportunities for measuring adherence with QIs, they also present challenges that must be examined before widespread adoption of these data collection methods.
19647103 Tumour necrosis factor antagonist therapy and cancer development: analysis of the LORHEN r 2010 Jan OBJECTIVE: The objective was to compare cancer risk in a RA cohort population treated with TNF antagonists, and identify the characteristics of the patients at higher risk. METHODS: The study involved 1114 RA patients treated with anti-TNF agents after failing to respond to traditional DMARDs, 1064 of whom were evaluable for adverse events over an average observational period of 23.32 months. The relative cancer risks (expressed as hazard ratios) in the anti-TNF treated patients were estimated using univariate and multivariate analyses. The rate of cancer in this cohort was compared with that in the general population using data from the Varese and Milan Cancer Report. RESULTS: There were 18 incident cases (1.7%), 4 of which involved lymphomas. Comparison with the general population showed that the overall cancer risk was similar, but the risk of lymphoma was about five times higher in the RA patients treated with a biological agent. Higher RR were found in males (HR 4.95, 95% CI 1.97-12.48; p=0.001) and patients aged >65 years (HR 2.72, 95% CI 1.08-6.84; p=0.034); combined therapy with methotrexate seemed to be protective (HR 0.31, 95% CI 0.11-0.87; p=0.026). CONCLUSION: The overall cancer risk in RA patients treated with anti-TNF seemed to be similar to that in the general population in the same geographical area, but the risk of haematological cancer was significantly greater. The demographic and clinical factors associated with a higher risk of cancer in our cohort were male gender and an age of >65 years.
19840317 Nodulosis in systemic onset juvenile idiopathic arthritis: an uncommon event with spontane 2009 Sep Accelerated nodulosis is a rare complication of methotrexate therapy in juvenile idiopathic arthritis. When nodulosis does occur in patients with juvenile idiopathic arthritis on methotrexate, it is almost always seen in patients with polyarthritis with rheumatoid factor seropositivity, but only occasionally in polyarthritis patients who are rheumatoid factor negative. It has been described previously in only one patient with systemic arthritis. In this study, we describe three patients with systemic arthritis, all of whom developed nodulosis while receiving methotrexate. Interestingly, it was not necessary to discontinue methotrexate in any of these patients. In fact, methotrexate dose was escalated without consequences and with complete resolution of nodules. This observation suggests that nodulosis occurring in patients with systemic arthritis already on methotrexate may not be because of methotrexate itself, but may be a component of the disease process. The other likely possibility given the fact that nodulosis occurs with other immunomodulatory agents and is not specifically related to methotrexate is that immunomodulatory agents in general precipitate the development of nodulosis. Thus, we propose that the new terminology "immunomodulatory agents induced nodulosis" rather than "methotrexate-induced nodulosis" be used in the literature.
19648304 Does sonographic needle guidance affect the clinical outcome of intraarticular injections? 2009 Sep OBJECTIVE: This randomized controlled study addressed whether sonographic needle guidance affected clinical outcomes of intraarticular (IA) joint injections. METHODS: In total, 148 painful joints were randomized to IA triamcinolone acetonide injection by conventional palpation-guided anatomic injection or sonographic image-guided injection enhanced with a one-handed control syringe (the reciprocating device). A one-needle, 2-syringe technique was used, where the first syringe was used to introduce the needle, aspirate any effusion, and anesthetize and dilate the IA space with lidocaine. After IA placement and synovial space dilation were confirmed, a syringe exchange was performed, and corticosteroid was injected with the second syringe through the indwelling IA needle. Baseline pain, procedural pain, pain at outcome (2 weeks), and changes in pain scores were measured with a 0-10 cm visual analog pain scale (VAS). RESULTS: Relative to conventional palpation-guided methods, sonographic guidance resulted in 43.0% reduction in procedural pain (p < 0.001), 58.5% reduction in absolute pain scores at the 2 week outcome (p < 0.001), 75% reduction in significant pain (VAS pain score > or = 5 cm; p < 0.001), 25.6% increase in the responder rate (reduction in VAS score > or = 50% from baseline; p < 0.01), and 62.0% reduction in the nonresponder rate (reduction in VAS score < 50% from baseline; p < 0.01). Sonography also increased detection of effusion by 200% and volume of aspirated fluid by 337%. CONCLUSION: Sonographic needle guidance significantly improves the performance and outcomes of outpatient IA injections in a clinically significant manner.
19537572 A flow chart proposed for early diagnosis of cryptococcal infection as a cause of stroke. 2009 Mar An 82-year-old woman had a transient ischemic attack and stroke of the left middle cerebral artery syndrome that turned out to be attributed to cryptococcal meningoencephalitis (CM). An initial presentation of central nervous system infection, such as fever and headache, was absent. It was masked by chronic use of corticosteroids and immunosuppressants for her rheumatoid arthritis. The diagnosis was made by the clinical setting of stroke-in-evolution and progression of hydrocephalus on the second brain imaging study. In this case, we discuss the atypical presentation of CM in an immunosuppressed patient and offer a flow chart for early diagnosis, thus improving outcome and survival rates.
20362271 Robust replication of genotype-phenotype associations across multiple diseases in an elect 2010 Apr 9 Large-scale DNA databanks linked to electronic medical record (EMR) systems have been proposed as an approach for rapidly generating large, diverse cohorts for discovery and replication of genotype-phenotype associations. However, the extent to which such resources are capable of delivering on this promise is unknown. We studied whether an EMR-linked DNA biorepository can be used to detect known genotype-phenotype associations for five diseases. Twenty-one SNPs previously implicated as common variants predisposing to atrial fibrillation, Crohn disease, multiple sclerosis, rheumatoid arthritis, or type 2 diabetes were successfully genotyped in 9483 samples accrued over 4 mo into BioVU, the Vanderbilt University Medical Center DNA biobank. Previously reported odds ratios (OR(PR)) ranged from 1.14 to 2.36. For each phenotype, natural language processing techniques and billing-code queries were used to identify cases (n = 70-698) and controls (n = 808-3818) from deidentified health records. Each of the 21 tests of association yielded point estimates in the expected direction. Previous genotype-phenotype associations were replicated (p < 0.05) in 8/14 cases when the OR(PR) was > 1.25, and in 0/7 with lower OR(PR). Statistically significant associations were detected in all analyses that were adequately powered. In each of the five diseases studied, at least one previously reported association was replicated. These data demonstrate that phenotypes representing clinical diagnoses can be extracted from EMR systems, and they support the use of DNA resources coupled to EMR systems as tools for rapid generation of large data sets required for replication of associations found in research cohorts and for discovery in genome science.
20589681 Inhibitors of p38 suppress cytokine production in rheumatoid arthritis synovial membranes: 2010 Nov OBJECTIVE: The activity of p38 MAPK regulates lipopolysaccharide (LPS)-stimulated production of key proinflammatory cytokines such as tumor necrosis factor α (TNFα). Consequently, p38 MAPK inhibitors have attracted considerable interest as potential treatments of rheumatoid arthritis (RA), and studies in murine models of arthritis have yielded promising results. However, the performance of several compounds in human clinical trials has been disappointing. At present, the reason for this poor performance is unclear. The aim of this study was to examine the effects of p38 inhibitors on both diseased and normal human tissue and cells, in order to test whether this kinase still plays a critical role in cytokine production under conditions of chronic inflammation. METHODS: Proinflammatory and antiinflammatory cytokine production was monitored after treatment of primary human monocytes, macrophages, and RA synovial membrane cultures with p38 MAPK inhibitor compounds. The following 3 inhibitors were used in these studies: SB-203580 (inhibits the α and β isoforms), BIRB-796 (inhibits the α, β, γ, and δ isoforms), and a novel, structurally distinct p38 MAPK inhibitor, SB-731445 (inhibits the α and β isoforms). RESULTS: SB-731445 and SB-203580 produced profound inhibition of spontaneous production of proinflammatory cytokines (TNFα and interleukin-1 [IL-1]) in both RA membrane cultures and LPS-stimulated primary human monocytes. However, this and other p38 MAPK inhibitors produced a significant increase in IL-6 production by LPS-stimulated primary human macrophages and a decrease in IL-10 production by all cell types examined. CONCLUSION: The potentially proinflammatory consequences of these activities (decreased IL-10 production and increased IL-6 production) may offer some explanation for the inability of p38 MAPK inhibitors to provide the therapeutic benefit that had been hoped for in RA.
19381021 Anti-TNF immunotherapy reduces CD8+ T cell-mediated antimicrobial activity against Mycobac 2009 May The incidence of tuberculosis is increased during treatment of autoimmune diseases with anti-TNF antibodies. This is a significant clinical complication, but also provides a unique model to study immune mechanisms in human tuberculosis. Given the key role for cell-mediated immunity in host defense against Mycobacterium tuberculosis, we hypothesized that anti-TNF treatment impairs T cell-directed antimicrobial activity. Anti-TNF therapy reduced the expression in lymphocytes of perforin and granulysin, 2 components of the T cell-mediated antimicrobial response to intracellular pathogens. Specifically, M. tuberculosis-reactive CD8+CCR7-CD45RA+ effector memory T cells (TEMRA cells) expressed the highest levels of granulysin, lysed M. tuberculosis, and infected macrophages and mediated an antimicrobial activity against intracellular M. tuberculosis. Furthermore, TEMRA cells expressed cell surface TNF and bound the anti-TNF therapeutic infliximab in vitro, making them susceptible to complement-mediated lysis. Immune therapy with anti-TNF was associated with reduced numbers of CD8+ TEMRA cells and decreased antimicrobial activity against M. tuberculosis, which could be rescued by the addition of CD8+ TEMRA cells. These results suggest that anti-TNF therapy triggers a reduction of CD8+ TEMRA cells with antimicrobial activity against M. tuberculosis, providing insight into the mechanism whereby key effector T cell subsets contribute to host defense against tuberculosis.
19884985 Cytokines and cytokine profiles in human autoimmune diseases and animal models of autoimmu 2009 The precise pathomechanisms of human autoimmune diseases are still poorly understood. However, a deepened understanding of these is urgently needed to improve disease prevention and early detection and guide more specific treatment approaches. In recent years, many new genes and signalling pathways involved in autoimmunity with often overlapping patterns between different disease entities have been detected. Major contributions were made by experiments using DNA microarray technology, which has been used for the analysis of gene expression patterns in chronic inflammatory and autoimmune diseases, among which were rheumatoid arthritis, systemic lupus erythematosus, psoriasis, systemic sclerosis, multiple sclerosis, and type-1 diabetes. In systemic lupus erythematosus, a so-called interferon signature has been identified. In psoriasis, researchers found a particular immune signalling cluster. Moreover the identification of a new subset of inflammatory T cells, so-called Th17 T cells, secreting interleukin (IL)-17 as one of their major cytokines and the identification of the IL-23/IL-17 axis of inflammation regulation, have significantly improved our understanding of autoimmune diseases. Since a plethora of new treatment approaches using antibodies or small molecule inhibitors specifically targeting cytokines, cellular receptors, or signalling mechanisms has emerged in recent years, more individualized treatment for affected patients may be within reach in the future.
19217782 Identification of a selective thieno[2,3-c]pyridine inhibitor of COT kinase and TNF-alpha 2009 Mar 15 COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.
20704603 Retinopathy due to antimalarial drugs in patients with connective tissue diseases: are the 2010 Aug INTRODUCTION: Antimalarial medications are basal active drugs used for the treatment of various rheumatological conditions. Their common side-effects include eye damage. AIM: The aim of this study is to determine the safety of antimalarial medications used for rheumatological conditions and the incidence of retinopathy. MATERIAL AND METHODS: Eighty-five patients with rheumatological conditions, who were followed in our rheumatology clinics between 2005 and 2009 while under chloroquine (CQ) and/or hydroxychloroquine (HQ) treatment were included in the study. Indirect ophthalmoscopic examination with 90 dioptry lens, frontal segment examination and macular visual area test were applied to all patients. Severity of retinopathy was evaluated as mild initial defect in the macula, or severe visual area loss. RESULTS: Retinopathy findings were detected in 21 out of 85 patients (24.7%). Of these patients, 12 had mild initial defects while nine had severe visual area loss. Of 21 patients, eight were on HQ and 13 were on CQ treatment. Of the patients seen with findings of retinopathy, 17 had comorbid hypertension (HT) and six had diabetes mellitus (DM). Patients receiving CQ are under higher risk compared to those on HQ treatment (P = 0.001). Patient age, disease duration, HT and DM presence had no statistically significant effect on retinopathy development (P = 0.144, P = 0.305, P = 0.258, P = 0.395, respectively). CONCLUSION: The incidence of retinopathy among patients using antimalarial medications as observed in this study was relatively high. Based on these results, it is essential to emphasize the importance of close monitoring in patients receiving antimalarial medications and evaluation of visual findings before treatment initiation.
19379726 Pyrrolidine dithiocarbamate, a NF-kappaB inhibitor, upregulates MMP-1 and MMP-13 in IL-1be 2009 Jun 24 Activated NF-kappaB plays an important role in the expression of matrix metalloproteinase (MMP)-1 and MMP-13 in rheumatoid arthritis and osteoarthritis. The objective of this study was to determine the effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) on the expression of MMPs in IL-1beta-stimulated fibroblast-like synoviocytes (FLSs) of rheumatoid arthritis patients. FLSs were treated with IL-1beta (10 ng/ml) for 24 h in the presence or absence of PDTC. The level of MMP-1 and MMP-13 increased in response to PDTC in time- and dose-dependent manners in IL-1beta-stimulated FLSs; the expressions of IL-6 and vascular endothelial growth factor (VEGF) decreased in a PDTC concentration-dependent manner. However, PDTC-mediated repression of IL-6 and VEGF expression was not observed in TNF-alpha-stimulated rheumatoid arthritis FLSs. In contrast, other NF-kappaB inhibitors, such as fenofibrate, N-acetylcysteine and MG132, decreased MMP expression in IL-1beta-stimulated FLSs. The stimulatory effect of PDTC on MMP expression was not mimicked by specific inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway. Treatments with 100 muM PDTC did not inhibit the phosphorylation of p-ERK1/2, p-P38, and p-JNK, or the transnuclear migration of NF-kappaB through degradation of IkappaB-alpha in IL-1beta-stimulated FLSs. These results suggest that the increase of MMP expression may occur in a stimuli-specific manner or by an NF-kappaB independent mechanism. Therefore, therapeutic NF-kappaB inhibitors should be thoroughly studied before their clinical use in treating rheumatoid arthritis, as undesirable genes may be upregulated through unknown mechanisms, possibly resulting in worse symptoms.