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ID PMID Title PublicationDate abstract
19722359 The effect of body mass index on outcomes after total ankle replacement. 2009 Jun Total ankle replacement is an established alternative to ankle fusion in selected patients. One of the possible exclusions used is the presence of a high BMI. This is based on our experience with hip and knee replacements where poor outcomes have been associated with obesity, however little work has been done on this subject in the ankle. We report the first series solely focussing on the impact of BMI on TAR. Forty five consecutive patients were identified and followed up using the SF-36 and VAS-FA. All patients had their BMI collected prospectively and BMI at latest follow-up was calculated. There was an average 5-year follow-up with just 9 (20%) lost to follow-up. At final follow-up 8 (17.7%) patients were deceased, none of the deaths were attributable to their previous ankle surgery. We did not find an association between high BMI and reduced outcomes or need for secondary surgery. In addition there was no significant change in BMI after surgery.
20532789 [Conception and course of eight pregnancies in five women on TNF blocker etanercept treatm 2010 Dec The introduction of tumor necrosis factor (TNF)-α inhibitors s in the late 1990s considerably broadened the treatment options for, and essentially contributed to the successful management of, rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Nevertheless, their use during pregnancy is still controversially discussed since it remains unclear whether the benefits of treatment might be outweighed by potential teratogenicity or adverse effects on the course of pregnancy. In this case series report we describe the course and outcome of eight pregnancies in five women (four with RA and one with ankylosing spondylitis) at our private clinical practice treated with the TNF-α inhibitor etanercept at the time of conception and during pregnancy. The course was inconspicuous in six of the eight pregnancies; in one case a megacolon congenitum was diagnosed 2 weeks after birth, while one spontaneous abortion occurred in the 10th week of pregnancy after a disease flare following treatment discontinuation with etanercept in the 5th week of pregnancy. Based on our experience to date and the currently available literature data, we believe that continuation of treatment with TNF-α blockers is justified in pregnant patients with otherwise high disease activity and disease progression.
20935210 Direct inhibition of human RANK+ osteoclast precursors identifies a homeostatic function o 2010 Nov 15 IL-1β is a key mediator of bone resorption in inflammatory settings, such as rheumatoid arthritis (RA). IL-1β promotes osteoclastogenesis by inducing RANKL expression on stromal cells and synergizing with RANKL to promote later stages of osteoclast differentiation. Because IL-1Rs share a cytosolic Toll-IL-1R domain and common intracellular signaling molecules with TLRs that can directly inhibit early steps of human osteoclast differentiation, we tested whether IL-1β also has suppressive properties on osteoclastogenesis in primary human peripheral blood monocytes and RA synovial macrophages. Early addition of IL-1β, prior to or together with RANKL, strongly inhibited human osteoclastogenesis as assessed by generation of TRAP(+) multinucleated cells. IL-1β acted directly on human osteoclast precursors (OCPs) to strongly suppress expression of RANK, of the costimulatory triggering receptor expressed on myeloid cells 2 receptor, and of the B cell linker adaptor important for transmitting RANK-induced signals. Thus, IL-1β rendered early-stage human OCPs refractory to RANK stimulation. Similar inhibitory effects of IL-1β were observed using RA synovial macrophages. One mechanism of RANK inhibition was IL-1β-induced proteolytic shedding of the M-CSF receptor c-Fms that is required for RANK expression. These results identify a homeostatic function of IL-1β in suppressing early OCPs that contrasts with its well-established role in promoting later stages of osteoclast differentiation. Thus, the rate of IL-1-driven bone destruction in inflammatory diseases, such as RA, can be restrained by its direct inhibitory effects on early OCPs to limit the extent of inflammatory osteolysis.
20483755 Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3. 2010 Jun 15 Innate immune responses contribute to synovial inflammation in rheumatoid arthritis. The present study was designed to investigate the contribution of IFN regulatory factor (IRF)3 and IRF7 to type I IFN-regulated gene expression in synoviocytes. Fibroblast-like synoviocytes were stimulated with polyinosinic-polycytidylic acid (poly [I-C]) after transfection with IRF3 or IRF7 small interfering RNA to knockdown transcription factor expression. Western blots, luciferase assay after transfection with reporter constructs, quantitative PCR, and AP-1 DNA binding ELISA were performed to evaluate the role of IRF3 and IRF7 in poly (I-C)-induced signaling and synoviocyte gene expression. IRF3 regulates IFN-stimulated response element (ISRE) promoter activity as well as IFN-beta, IRF5, IRF7, RANTES, IFN-inducible protein-10, MCP-1, and MIP1alpha gene expression in response to poly (I-C). IRF7 knockdown modestly decreased a subset of genes and ISRE activity, although the results were not statistically significant. Surprisingly, IRF3 knockdown almost completely blocked expression of additional genes in which the ISRE is not traditionally considered a dominant promoter site in fibroblast-like synoviocytes, including matrix metalloproteinase (MMP)3, MMP9, IL-6, and IL-8. Transcription factor activation studies demonstrated a role for IRF3 in regulation of c-Jun phosphorylation and AP-1 binding. IRF3 rather than IRF7 regulates poly (I-C)-induced type I IFN responses in human synoviocytes by increasing ISRE promoter activity. IRF3 also partially regulates expression of other cytokines and MMP through activation of c-Jun and the AP-1 promoter site. Targeting synoviocyte IRF3 represents a potential approach to suppress diverse mediators while limiting suppression of IRF7-mediated immune responses.
19370536 Ligularia fischeri leaf extract suppresses proinflammatory mediators in SW982 human synovi 2009 Nov Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA) and is regarded as a major destructive element of articular bone and cartilage. This pathological process is accompanied by the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) in synoviocytes. The present study was conducted to analyse the effects of Ligularia fischeri extract (LF) on inflammatory functions in the SW982 human synovial cell system. When cells were exposed to LF, LF had a significant inhibitory effect on the production of TNF-alpha, IL-6 and MMP-3 by SW982 cells (p < 0.05). The mitogen-activated protein kinases (MAPKs) represent an attractive target for RA because they can regulate MMP and cytokine expression. The effects of LF on the activation of MAPKs and transcription factors were also examined in SW982 cells by ELISA assay. IL-1beta-induced JNK and p38 activation was inhibited by LF, and LF significantly reduced the DNA-binding activity of transcription factors NF-kappaB and AP-1. Taken together, these results suggest that LF modulates the inflammatory process involved in arthritis by suppressing the expression of various genes by inhibiting NF-kappaB and/or AP-1 activities.
19714628 Establishment of a matrix-associated transepithelial resistance invasion assay to precisel 2009 Sep OBJECTIVE: Synovial fibroblasts (SFs) contribute to several aspects of the pathogenesis of rheumatoid arthritis (RA) and have been implicated most prominently in the progressive destruction of articular cartilage. Targeting the invasive phenotype of RASFs has therefore gained increasing attention, but the precise measurement of their invasive capacity and the evaluation of potential treatment effects constitute a challenge that needs to be addressed. This study used a novel in vitro invasion assay based on the breakdown of transepithelial electrical resistance to determine the course of fibroblast invasion into extracellular matrix. METHODS: A matrix-associated transepithelial resistance invasion (MATRIN) assay was used to assess SFs from patients with RA in comparison with SFs from patients with osteoarthritis (OA). The SFs were grown on a commercially available collagen mix that was placed onto the upper side of a Transwell polycarbonate membrane. In addition, freshly isolated cartilage extracts were studied to assess the conditions in vivo. Under this membrane, a monolayer of MDCK-C7 cells was seeded to create a high electrical resistance. RESULTS: Invasion of fibroblasts into the matrix affected the integrity of the MDCK-C7 monolayer and led to a measurable decrease and subsequent breakdown of electrical resistance. Unlike in the assay with OASFs, which did not achieve a breakdown of resistance up to 72 hours, RASFs exhibited a pronounced invasiveness in this assay, with a 50% breakdown after 42 hours. Treatment of fibroblasts with either a matrix metalloproteinase inhibitor or antibodies against beta1 integrin significantly reduced the invasiveness of RASFs. CONCLUSION: The MATRIN assay is a valuable and sensitive biologic assay system that can be used to determine precisely the invasive potential of RASFs in vitro, and thus would be suitable for screening anti-invasion compounds.
21217814 Presymptomatic risk assessment for chronic non-communicable diseases. 2010 Dec 31 The prevalence of common chronic non-communicable diseases (CNCDs) far overshadows the prevalence of both monogenic and infectious diseases combined. All CNCDs, also called complex genetic diseases, have a heritable genetic component that can be used for pre-symptomatic risk assessment. Common single nucleotide polymorphisms (SNPs) that tag risk haplotypes across the genome currently account for a non-trivial portion of the germ-line genetic risk and we will likely continue to identify the remaining missing heritability in the form of rare variants, copy number variants and epigenetic modifications. Here, we describe a novel measure for calculating the lifetime risk of a disease, called the genetic composite index (GCI), and demonstrate its predictive value as a clinical classifier. The GCI only considers summary statistics of the effects of genetic variation and hence does not require the results of large-scale studies simultaneously assessing multiple risk factors. Combining GCI scores with environmental risk information provides an additional tool for clinical decision-making. The GCI can be populated with heritable risk information of any type, and thus represents a framework for CNCD pre-symptomatic risk assessment that can be populated as additional risk information is identified through next-generation technologies.
19105984 CXCL10 and autoimmune diseases. 2009 Mar CXCL10 is a 10 kDa protein, which is categorized functionally as a Th1-chemokine. It binds to the receptor CXCR3 and regulates immune responses through the activation and recruitment of leukocytes, such as, T cells, eosinophils, and monocytes. Recent reports have shown that serum and/or tissue expressions of CXCL10 are increased in various autoimmune diseases like rheumatoid arthritis (RA), systemic lupus rythematosus (SLE), Sjogren syndrome (SS), systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM). Moreover, CXCL10 and CXCR3 may have important roles in leukocyte homing to inflamed tissues and in the perpetuation of inflammation, and therefore, tissue damage. Our recent study shows that CXCL10 also has a pathogenic role in bone destruction via receptor activator of NF-kappaB ligand (RANKL) induction in inflamed synovial tissue of RA. In addition to its chemotactic effect, CXCL10 may have pleiotropic functions. Further research on the function of this chemokine and interactions between CXCL10 and other cytokines and chemokines may provide therapeutic targets in various autoimmune diseases.
20004761 Meta-analysis of genome-wide association studies with overlapping subjects. 2009 Dec Data from multiple genome-wide association studies are often analyzed together for the purposes of combining information from several studies of the same disease or comparing results across different disorders. We provide a valid and efficient approach to such meta-analysis, allowing for overlapping study subjects. The available data may contain individual participant records or only meta-analytic summary results. Simulation studies demonstrate that failure to account for overlapping subjects can greatly inflate type I error when combining results from multiple studies of the same disease and can drastically reduce power when comparing results across different disorders. In addition, the proposed approach can be substantially more powerful than the simple approach of splitting the overlapping subjects among studies, especially for comparing results across different disorders. The advantages of the new approach are illustrated with empirical data from two sets of genome-wide association studies.
19908934 Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmun 2009 Oct There is a growing evidence that both overnutrition and undernutrition negatively interfere with immune system. The overnutrition has been found to increase susceptibility to the development of inflammatory or autoimmune diseases. On the other hand, starvation or malnutrition has been more associated with increased susceptibility to infections. In the regulation of immune and inflammatory processes, white adipose tissue plays a critical role as an endocrine organ which produces number of active peptides, called adipokines. The adipokines, leptin and adiponectin represent a critical link among nutritional status, metabolism and immunity. Leptin is primarily known as a satiety factor regulating body weight by suppression of appetite and stimulation of energy expenditure, and its serum levels and gene expression in adipocytes strongly correlate with proportion of body fat stores. On the other hand, leptin is a pro-inflammatory adipokine inducing T helper 1 cells and may contribute to the development and progression of autoimmune responses. Adiponectin plays an important role as an insulin-sensitizing adipokine which production is decreased in obesity and in conditions associated with insulin resistance. Adiponectin also acts as an anti-inflammatory factor especially with regard to atherosclerosis, but in some chronic inflammatory/autoimmune diseases adiponectin may have pro-inflammatory effects and its production correlates with inflammatory markers and disease activity. This review discusses the main biological activities of leptin and adiponectin as well as their contribution to inflammatory and autoimmune processes with particular focus on rheumatoid arthritis and its experimental models.
21084326 Ten years with biologics: to whom do data on effectiveness and safety apply? 2011 Jan OBJECTIVES: During the past decade, the position of biologics in the therapeutic armamentarium, the number of approved indications and the number of available biologics have changed. Available data on (long-term) safety might thus pertain to patient populations not comparable with contemporary patients. The aim of this study was to assess the extent to which contemporary patients who start or switch biologic therapies are comparable with those patients who gave rise to the currently available data on effectiveness and safety. METHODS: We identified all adult patients with RA (n=9612), PsA (n=1417) and other SpA (n=1652) initiating a first biologic therapy between 1 January 1999 and 31 December 2008, registered in the Swedish Biologics Register (ARTIS), including information on demographics, disease characteristics and 1-year risk of first-line treatment discontinuation. RESULTS: Over calendar time, measures of disease activity at start declined substantially for all indications, and diminished between first-, second- and third-line therapy starts. One-year risks of first-line therapy discontinuation increased. Switchers to anti-TNF and non-TNF biologics had different comorbidities. Despite <50% drug retention at 5 years, most patients remained exposed to some biologic. CONCLUSIONS: The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.
19904485 The use of tumour necrosis factor alpha-blockers in daily routine. An Austrian consensus p 2010 Feb To define relevant disease parameters and their respective limits indicating the initiation of TNF-alpha-blockers in individual patients. Subsequently, to analyze retrospectively patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), who started TNF-alpha inhibition in 2006. Points to consider, regarded relevant for individual treatment decisions as well as their assessment methods, were ascertained by experts' consensus applying the Delphi technique. Subsequently, these parameters' thresholds with respect to the initiation of a TNF-alpha-blocker were identified. Thereafter, the rheumatologists representing 12 centres all over Austria agreed to retrospectively analyze their patients started on a TNF-alpha-blocker in 2006. Experts' opinion regarding disease parameters relevant to initiate TNF-alpha-blockers in RA patients only slightly differed from those applied in clinical trials, but the parameters' threshold values were considerably lower. For PsA patients, some differences and for AS patients, considerable differences between experts' opinion and clinical studies appeared, which held also true for decisive parameters' means and thresholds. Six hundred and fifty patients, started on TNF-blockers in 2006, could be analyzed retrospectively, 408 RA patients (53.3 years mean, 340 females), 93 PsA patients (48.9 years mean, 59 males) and 149 AS patients AS (42.2 years mean, 108 males), representing approximately 25% of all Austrian patients initiated on a TNF-blocker in this respective year. Far more individualized, patient-oriented treatment approaches, at least in part, are applied in daily routine compared with those derived from clinical trials or recommendations from investigative rheumatologists.
20589683 Knockdown of Fcγ receptor III in an arthritic temporomandibular joint reduces the nocicep 2010 Oct OBJECTIVE: Fcγ receptor III (FcγRIII; CD16) is a receptor expressed on immune cells that selectively binds IgG molecules. IgG binding results in cellular activation and cytokine release. IgG is an important factor in arthritis and can be found in the arthritic temporomandibular joint (TMJ). We undertook this study to test the hypothesis that a reduction in FcγRIII expression in TMJ tissues would reduce the nociceptive and inflammatory responses in an inflamed joint. METHODS: Small interfering RNA (siRNA), either naked or complexed with linear polyethyleneimine, was injected into the superior joint space of the TMJ in rats. After administration of siRNA the joint was injected with saline or with Freund's complete adjuvant to induce arthritis. Nociceptive responses were quantitated in the rat by measuring the animal's meal duration. FcγRIII expression in the TMJ tissue was assayed by immunocytochemistry or Western blotting. Cleavage of FcγRIII transcript was then assayed by 5' rapid amplification of complementary DNA ends. Interleukin-1β (IL-1β) and IgG content was measured in the TMJ tissue by enzyme-linked immunosorbent assay. RESULTS: Injection of FcγRIII siRNA reduced the amount of FcγRIII in the TMJ tissues, and the transcript was cleaved in a manner consistent with an RNA interference mechanism. Moreover, injection of FcγRIII siRNA reduced the nociceptive response of rats with an arthritic TMJ and reduced the amount of the proinflammatory cytokine IL-1β. CONCLUSION: FcγRIII contributes to the pain resulting from inflammatory arthritis of the TMJ, and siRNA has the potential to be an effective treatment for this disorder.
21194591 Golimumab: Review of the efficacy and tolerability of a recently approved tumor necrosis f 2010 Sep BACKGROUND: Golimumab (GLM) is a tumor necrosis factor-α (TNF-α) inhibitor that was approved in the United States in 2009 for use with methotrexate (MTX) in adults with moderate to severe active rheumatoid arthritis (RA), and with or without MTX or other non-biologic disease-modifying antirheumatic drugs in adults with active psoriatic arthritis (PsA) or active ankylosing spondylitis (AS). GLM is administered as a 50-mg subcutaneous injection once a month. OBJECTIVES: The goals of this article were to review the current literature on GLM and to provide recommendations for the use of GLM based on the published information. METHODS: The PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, International Pharmaceutical Abstracts, and other databases, as well as the Web sites for the American College of Rheumatology (ACR) and the European Union League Against Rheumatism, were searched for relevant articles published in English between the inception of the databases through April 2010. Search terms included golimumab and CNTO 148. Pharmacologic, pharmacokinetic, clinical, outcomes, and economic studies as well as meta-analyses, case reports, and select abstracts were eligible for inclusion. Review articles on GLM were not used except to identify other primary papers. RESULTS: Seven clinical studies were identified and used to evaluate the efficacy and tolerability of GLM: 5 in patients with RA (4 subcutaneous administration and 1 intravenous administration), 1 in patients with PsA (subcutaneous), and 1 in patients with AS (subcutaneous). In MTX-naive patients with RA, the number of patients satisfying the ACR20 response criteria (>20% improvement in ACR response rate) at 24 weeks was significantly higher for the GLM + MTX groups than for the MTX-only groups (62% vs 49%, respectively; P < 0.05). In patients with active RA despite MTX therapy, ACR20 responses at 14 to 16 weeks were significantly higher for the combined GLM + MTX groups than for the MTX groups (50%-79% vs 33%-37%, respectively; P < 0.001). GLM was more effective than placebo, both with and without MTX, in patients with RA and a history of treatment with 1 or 2 TNF-α inhibitors (ACR20 at 14 weeks, 35%-37% vs 18%, respectively; P < 0.001). Studies of other TNF-α inhibitors reported ACR20 responses in 53% to 59% of patients with active RA at 24 weeks. GLM was also more effective than placebo at 24 weeks in patients with PsA (ACR20, 52%-61% vs 12%, respectively; P < 0.001) (ASAS40 [40% improvement based on Assessment in Ankylosing Spondylitis International Working Group criteria], 44%-54% vs 15%, respectively; P < 0.001). Studies of other TNF-α inhibitors reported ACR20 responses at 24 weeks in 55% to 57% of patients with PsA and ASAS40 responses in 46% to 47% of patients with AS. The incidence of any adverse effect appeared to be comparable in the GLM (61.2%-93.9%) and placebo groups (59.3%-85.3%), but withdrawals because of adverse effects were higher in the GLM groups (0%-12.1%) than in the placebo groups (0%-5.9%). The incidence of serious infections was comparable for GLM (0%-4.4%) and placebo (0.8%-3.5%). The most frequently reported adverse effects in the GLM groups were injection-site reactions (2.7%-37.1%), nausea (2.7%-22.9%), headache (3.8%-21.2%), nasopharyngitis (1.9%-15.0%), and upper respiratory tract infections (5.7%-13.8%). CONCLUSIONS: Based on the results of the studies included in this review, GLM appeared to be more effective than placebo in patients with RA, PsA, or AS. Clinical studies have not directly compared GLM with other TNF-α inhibitors. However, according to the available efficacy and tolerability data, GLM should be considered as the first or second TNF-α inhibitor for the treatment of PsA or AS and as the second or possibly first TNF-α inhibitor in combination with MTX for the treatment of RA.
19915991 The clinical course of polymyalgia rheumatica in Chinese. 2010 Feb Polymyalgia rheumatica (PMR) is diagnosed based on clinical features that may overlap with other rheumatic conditions like rheumatoid arthritis (RA). Furthermore, a proportion of PMR patients may subsequently evolve into RA. The aim of this study was to examine the clinical characteristics of PMR patients in a Chinese cohort compared to a Caucasian series. Patients diagnosed to have PMR during 1997-2008 were reviewed for clinical features and compared to a reported Caucasian series. Rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP) antibodies were determined by immunonephelometry and enzyme-linked immunosorbent assay, respectively. Forty-four patients of southern Chinese origin were diagnosed to have PMR according to specialist opinion. Seventy-five percent of patients (n = 33) were >65 years of age at diagnosis (mean +/- standard deviation, 75.8 +/- 9.6 years). The commonest feature at disease onset was elevated erythrocyte sedimentation rate >40 mm/h (100% vs. 95.7%; p = 0.17) and bilateral shoulder pain or stiffness (95.5% vs. 90.8%; p = 0.31), comparable in frequency to the Caucasian cohort. However, Chinese patients had significantly longer duration of symptoms before diagnosis (p < 0.001) but less bilateral upper arm tenderness (p < 0.001) and generalized stiffness (p = 0.01). Twelve (27.3%) patients evolved into RA after a median duration of 2 months from onset of PMR. RF and anti-CCP antibodies were positive in 66.7% and 60% of these patients compared to 9.4% and 6.2%, respectively, among those who did not evolve into RA during the period observed. Chinese patients with PMR have modestly different clinical profile compared to the Caucasian counterpart. RF and anti-CCP antibodies were more likely to be present in those who subsequently developed into RA.
20171050 Changes in cobalt and chromium levels after metal-on-metal hip resurfacing in young, activ 2011 Jan Metal-on-metal resurfacing arthroplasty is increasingly being performed in young, active patients. Serum and urine metal ion levels are monitored in these patients to assess the physiologic effects of metal-on-metal wear on them. The aim of our prospective study was to evaluate the serum and urine levels of cobalt (Co) and chromium (Cr) in young (age, ≤50 years), active Chinese patients who had undergone metal-on-metal hybrid resurfacing arthroplasties. Levels were measured preoperatively using atomic absorption spectrometry and then sequentially at 3, 6, 9, 12, and 24 months after surgery. For both serum and urine Co and Cr, there was an initial increase to a peak at 6 months, followed by a gradual decline after 6 months, whereas renal function was normal during the study the 2-year study period. There was no radiographic evidence of component loosening. All implants were functioning well. Further long-term studies are needed to observe clinical outcomes and to determine the physiologic effects of the wearing process.
20022453 Metal-on-metal cups cemented into reinforcement rings: a possible new acetabular reconstru 2011 Jan The purpose of this study was to evaluate the clinical and radiological results of Metasul cups cemented into reinforcement rings for young and active patients. Twenty-three total hip arthroplasties with Metasul cups were cemented into Muller reinforcement rings. Mean follow-up was 6.1 years (5-10). At final follow-up, the Harris hip score increased from 62.2 (39-85) to 95.2 (84-100, P = .01): no revision was undertaken for aseptic loosening or fixation failure. Considering reoperation and bearing revision as end points, survival rates were 95.8% and 100%, respectively. The mean blood concentrations of chromium, cobalt, and titanium were 1.85 μg/L, 1.24 μg/L, and 9.62 μg/L, respectively. A longer follow-up is mandatory, but it seems possible to use hard-on-hard bearings with metallic rings in young patients during hip revisions or in dysplastic cases with encouraging intermediate follow-up results.
19210932 [Cancer in arthritis patients after anti-tumour necrosis factor therapy]. 2009 Feb 9 INTRODUCTION: The use of anti-tumour necrosis factor (anti-TNF) therapy is increasing in the treatment of rheumatoid arthritis (RA), spondyloarthropathy, psoriasis and inflammatory bowel disease. It is being debated whether treatment of patients with rheumatic diseases with anti-TNF therapy is associated with an increased cancer incidence. MATERIAL AND METHODS: A descriptive study of cancer cases among 3,688 patients with rheumatic diseases who received anti-TNF therapy was performed. The patients were identified in the nationwide database DANBIO and had a total number of treatment years of 6,092 years. All cancer cases were identified and the cancer diagnoses were subsequently confirmed by medical record review. RESULTS: A total of 30 cancers in 28 of 3,688 patients were registered in the DANBIO after initiation of anti-TNF therapy in the period from October 2000 to June 2007. Among these six men and 20 women had RA, and two men had Morbus Becterew. The following cancer types were observed: malignant lymphoma 2 (7%), lung 4 (13%), plicae vocalis 2 (7%), breast 4 (13%), pancreatic 3 (10%), colorectal 2 (7%), prostate 1 (3%), malignant melanoma 3 (10%) and non-melanoma skin cancer 9 (30%). CONCLUSION: In our descriptive study from the nationwide database DANBIO, a total of 30 cancers were observed in 3,688 patients with rheumatic diseases within a cumulated period of treatment with anti-TNF of 6,092 years. Follow-up for anti-rheumatic and adverse effects in patients in the DANBIO database will continue. Future studies must reveal whether anti-TNF therapy is associated with an increased cancer risk. Planned Danish studies will include relevant control groups and adjustment for confounders.
19797506 Monocyte derived interleukin (IL)-23 is an important determinant of synovial IL-17A expres 2009 Nov OBJECTIVE: To demonstrate gene expression of interleukin (IL)-17A, IL-23, and IL-12 and to determine the proximity of IL-17A and IL-23 producing cells in rheumatoid synovial tissue. METHODS: Total RNA was isolated from 25 synovial membranes obtained from 20 patients with rheumatoid arthritis (RA). Quantitative real-time polymerase chain reaction was used to measure IL-17A, IL-12p35, IL-23p19, p40, and GAPDH expression. Immunohistochemistry was utilized to determine cell type and proximity of IL-17A, IL-12, and IL-23 in rheumatoid synovium. RESULTS: IL-17A was present in 13/25 synovia. IL-12p35 was present in all samples while IL-23p19 was present in 23/25. p40 was present in 23/25 samples. Of the 2 p40- samples both were IL-23p19 and IL-12p35 positive. Mean expression of IL-23p19 was significantly higher in the IL-17A+ versus IL-17A- synovia (0.10 +/- 0.02 ng vs 0.05 +/- 0.01 ng; p < 0.05). There was no difference in IL-12p35 expression between IL-17A+ and IL-17A- synovia (0.5 +/- 0.21 ng vs 0.38 +/- 0.24 ng; p = 0.2). All IL-17A+ cells were in the vicinity of IL-23+ cells. IL-12+ cells were both close to and removed from IL-17A+ cells. Only a proportion of CD3+T cells appeared to produce IL-17A. CONCLUSION: IL-17A gene expression occurs in only a subset of rheumatoid synovial membranes. IL-23 gene expression is higher in IL-17A+ versus IL-17A- membranes. In keeping with this, IL-17A+ and IL-23+ cells colocalize in synovial membranes. IL-17 is not an absolute requirement in RA but may be important in amplifying the inflammatory response. Anti-IL23 therapies may have a role in those patients with IL-17A expression.
20429830 Comparison of methods for measuring dose escalation of the subcutaneous TNF antagonists fo 2010 Jul OBJECTIVES: Tumor necrosis factor (TNF) antagonists, most frequently prescribed biologics for moderate to severe rheumatoid arthritis (RA), are subject to dose escalation. Even though different methods have been employed to estimate the timing and magnitude of dose escalation, there is no consensus on which method is optimal. The purpose was to evaluate different methods for assessing dose escalation patterns for the subcutaneously delivered TNF antagonists, etanercept and adalimumab. METHODS: Five different methods to describe dose escalation patterns were compared using a large administrative claims database from US health plans. RA patients age 18 and above with >or=2 claims for etanercept or adalimumab were included. These methods included last dose versus index dose (the dose of a patient's first biologic prescription [adalimumab or etanercept]), average dose versus recommended dose, multiple (>or=2) instances of subsequent doses exceeding the index dose, subsequent doses exceeding a predetermined threshold above the index dose, and the time-trend method, comparing each subsequent dose throughout the course of therapy to the index dose. RESULTS: A total of 1369 etanercept and 461 adalimumab RA patients were evaluated for dose escalation. Estimates of dose escalation were highest for both drugs based on the average dose method (10.3% for etanercept, 33.6% for adalimumab). The time-trend method demonstrated the temporal trends in the percent of patients with dose escalation. Adalimumab patients had a higher rate of dose escalation than etanercept patients, regardless of method. The study is limited in that it could not assess the reason for or clinical outcomes associated with dose escalation. CONCLUSIONS: Different methods for evaluating dose escalation yield different numerical estimates but consistently give the same overall comparative result. The choice of method should depend on the specific research question. The average dose method may be the most useful for cost impact studies, whereas the time-trend method provides the most comprehensive information on dose patterns.