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ID PMID Title PublicationDate abstract
16487722 The effects of leflunomide on clinical parameters and serum levels of IL-6, IL-10, MMP-1 a 2006 Jan 21 OBJECTIVE: The purpose of this open pilot study was to assess possible mechanisms of the effects of leflunomide by studying the influence of the drug on the serum levels of MMP-1, MMP-3, IL-10, IL-6 and their possible correlation with clinical disease parameters. PATIENTS AND METHODS: Thirty patients with long standing active rheumatoid arthritis were enrolled in this study. All patients failed at least 5 DMARDs in the past and were on stable treatment for at least 3 months before starting the protocol. The patients received a loading dose of 100 mg for 3 days followed by 20 mg/day thereafter and followed up monthly for 6 months. Disease activity was assessed at baseline, 2 weeks, and every month of therapy thereafter using the following variables: tender joint count, swollen joint count, morning stiffness duration, pain, tiredness, physician's and patient's global assessment, using VAS, ESR and CRP. Clinical effects of the treatment regimen were calculated using the American College of Rheumatology (ACR) criteria for clinical response. Adverse events were recorded. Serum levels of MMP-1, MMP-3, IL-10 and IL-6 were measured before and 3 months after starting the protocol. RESULTS: Except for tiredness, a statistically significant improvement in all clinical and laboratory parameters of disease activity was reached after 3 months. At this time point the ACR-20 response rate was 46.2%. The levels of MMP-1, MMP-3, IL-6 and IL-10 decreased significantly after 3 months. A statistically significant correlation between serum levels of MMP-1, IL-10 and IL-6 and clinical and laboratory parameters was also shown. After 6 months, 16 out of 30 patients withdrew from the study [adverse events (35.4%), lack of efficacy (9.7%), and low compliance (6.4%)]. CONCLUSIONS: Leflunomide was clinically efficacious in this group of long standing resistant RA in an open study "real life" design. These results comply with those reported in previous clinical trials. Serum MMP-1, MMP-3, IL-10 and IL-6 levels decreased significantly. Despite high withdrawal rate, no serious adverse effects were recorded.
16583466 A phase I study assessing the safety, clinical response, and pharmacokinetics of an experi 2006 May OBJECTIVE: To assess safety, clinical response, and pharmacokinetics of subcutaneous (SC) and intramuscular (IM) doses of an experimental formulation of infliximab [including experimental SC doses following administration of commercially-formulated intravenous (IV) infliximab] in patients with rheumatoid arthritis (RA) refractory to methotrexate. METHODS: In this randomized, open-label, 3-stage design, 43 subjects were enrolled in 7 dose groups. In Stage I, 15 subjects received single SC doses of 0.5, 1.5, or 3.0 mg/kg. In Stage II, 21 subjects received one of 3 regimens: 100 mg SC every 2 weeks (3 injections); 3 mg/kg commercially-formulated IV infliximab every 2 weeks (2 infusions) followed by 100 mg SC every 2 weeks (3 injections); or 100 mg IM every 2 weeks (3 injections). In Stage III, 7 subjects received 100 mg SC every 4 weeks (3 injections). RESULTS: No treatment-related serious adverse events were observed, and there were no serious injection site reactions. A low-titer infliximab antibody response was detected in 27% of subjects receiving single SC doses, 5% receiving multiple SC doses, and 43% receiving IM doses. SC administration yielded roughly dose-proportional increases in Cmax and AUC. American College of Rheumatology 20% response (ACR20) was achieved 2 weeks after the last injection by 86.7% of subjects receiving single SC doses, 85.7% receiving SC doses every 2 weeks, 85.7% receiving both IV and SC doses, 57.1% receiving multiple IM doses, and 80.0% receiving SC doses every 4 weeks. CONCLUSION: SC and IM treatment with this experimental infliximab formulation was well tolerated and was associated with a favorable ACR response.
16639484 [A comparison between the Simplified Disease Activity Index (SDAI) and the Disease Activit 2006 Jan OBJECTIVE: To compare the SDAI values to DAS28 scores in RA patients undergoing different DMARD regimens. METHODS: The SDAI is an unweighted numerical sum of five outcome parameters: tender and swollen joint count (based on 28-joint assessment), patient and physician global assessment of disease activity (visual analogue scale: 0-10 cm) and level of C-reactive protein (mg/dl). 80 patients (F/M 68/12; age between 20-68 years, median 52) with active rheumatoid arthritis were prospectively enrolled in the study. The patients were randomly assigned to one of four groups according to the therapeutic regimens: group I: Methotrexate (MTX) 15 mg/weekly + salazopyrin 2 g/daily; group II: MTX 15 mg/weekly + infliximab 3 mg/Kg at time 0, 2, 4 and every 8 weeks; group III: MTX 15 mg/weekly + etanercept 25 mg/twice weekly; group IV: MTX 15 mg/weekly + adalimumab 40 mg/every other week. SDAI and DAS28 were determined at baseline and after 6 months in each patient. Mean changes in SDAI values were compared to those detected in DAS 28 at baseline and after 6 months. RESULTS: SDAI and DAS 28 were found to be significantly correlated at baseline. Moreover, changes in SDAI over time paralleled those in DAS, and were found to be significantly correlated. CONCLUSIONS: SDAI is a valid measure of response to treatment in RA patients undergoing different therapeutic regimens.
17403952 Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. 2007 Apr Targeted biologic therapies have revolutionised treatment of immune-mediated inflammatory diseases (IMIDs) due to their efficacy, speed of onset and tolerability. The discovery that clinically unrelated conditions, such as rheumatoid arthritis and Crohn's disease, share similar immune dysregulation has led to a shift in the management of IMIDs from one of organ-based symptom relief to mechanism-based treatment. The fact that anticytokine therapy has been effective in treating multiple orphan inflammatory conditions confirms the IMID paradigm. In this review we examine the biologic agents currently licensed for use in the US and Europe: infliximab, etanercept, adalimumab, rituximab, abatacept, anakinra, alefacept and efalizumab. We also discuss the rationale behind the management of IMIDs using rheumatoid arthritis, Crohn's disease, psoriasis and psoriatic arthritis as examples. For the medical profession, IMID represents a breakthrough in the way pathology is classified. In this burgeoning era of biologic therapy the prospect of complete disease remission is conceivable.
18498922 Decreased external home help use with improved clinical status in rheumatoid arthritis: an 2008 Apr OBJECTIVES: The aims of this study were to examine the relationship between external home help (EHH) use (ie, help provided by someone other than family or friends) and clinical response and patient-reported outcomes in patients with rheumatoid arthritis (RA), and to determine whether abatacept treatment in addition to methotrexate reduces the need for EHH. METHODS: EHH use was recorded monthly in the Abatacept in Inadequate responders to Methotrexate (AIM) trial, a 12-month, randomized, double-blind, placebo-controlled trial of abatacept in patients with active RA also receiving methotrexate. Clinical response was defined using American College of Rheumatology (ACR) criteria, European League Against Rheumatism (EULAR) criteria, and Disease Activity Scale (DAS)-28 score. Patient-reported outcomes included the Health Assessment Questionnaire (HAQ), 100-mm visual analog scales (VASs) for pain and fatigue, and the Medical Outcomes Study 36-item Short Form Health Survey (SF-36) for health-related quality of life. Analysis of covariance and regression analysis were performed to investigate the relationship between change in EHH use and both clinical response and patient-reported outcomes. RESULTS: Of 590 patients enrolled in the study, 232 (39.3%) were receiving EHH at baseline (mean age, 50.2 years; 88% female; 85% white; mean duration of RA, 8.8 years; mean [SD] EHH use, 15.6 [11.3] days). The level of EHH use was consistently higher with poorer scores on the HAQ, pain and fatigue VASs, DAS28, and SF-36. At 12 months, the mean reduction from baseline in EHH use was significantly greater in patients with ACR-50 or ACR-70 clinical response, EULAR good or moderate response, DAS28 remission, and clinically meaningful improvements in patient-reported outcomes. On multiple regression analysis, change in SF-36 Physical Functioning subscale score was the most important contributor to change in EHH after adjustment for other variables. The mean reduction from baseline in EHH use was significantly greater with abatacept compared with placebo over the study period (all, P<0.001). CONCLUSIONS: In this exploratory analysis of data from patients with active RA from the AIM trial, EHH use was decreased significantly with improvements in clinical response, disease activity, and patient-reported outcomes. Treatment with abatacept in addition to methotrexate was associated with significantly decreased EHH use, suggesting that abatacept may have been associated with improved function and increased physical independence in these patients with RA.
19094928 [Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to jo 2008 Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or hyperlipidemic patients treated for long periods of time with glitazones or fibrates. Additionally, cellular and animal studies are required to assess whether partial agonists of PPAR (SPPARMs) may preserve therapeutical properties with potentially less safety concern.
18771364 Anti-TNF-alpha immunotherapy is associated with increased gingival inflammation without cl 2008 Sep BACKGROUND: Because periodontitis presents many similarities with rheumatoid arthritis (RA) with regard to tumor necrosis factor-alpha (TNF-alpha)-induced bone resorption, the benefits of TNF-alpha blockade in RA prompted us to determine its efficacy in treating coexisting periodontitis. METHODS: Periodontal status was evaluated in 40 subjects with RA who were divided into two groups: Group I contained 20 subjects who had received infliximab every 6 weeks for > or =22 months at the time of periodontal evaluation. The 20 subjects in group II were evaluated before their first infusion with infliximab. Nine subjects in group II had periodontitis. These subjects were reevaluated after they received nine infusions of infliximab. RESULTS: Infliximab tended to aggravate gingival inflammation as indicated by differences in the modified gingival and papillary bleeding indices between subjects in groups I and II with coexisting periodontitis before and after treatment. Methotrexate had no effect on periodontal status. Although the plaque index revealed that bacterial infection persisted, the probing depth was equal in groups I and II and equivalent before and after treatment in subjects with periodontitis, whereas attachment loss was decreased after infliximab treatment. CONCLUSIONS: Inflammation and destruction constitute two interrelated yet separate components of periodontitis in patients with RA. Therefore, TNF-alpha blockade could be beneficial in the treatment of periodontitis.
18003817 Simultaneous detection of eight analytes in human serum by two commercially available plat 2008 Jan The accurate detection and quantitation of cytokines in serum are important in the study of disease mechanisms, pathogenesis, and treatment. Serum cytokines can reflect processes that are occurring at the cellular or tissue level and thus provide a means of indirectly monitoring these processes. Multiplex detection of cytokines allows the simultaneous measurement of multiple cytokines in a sample, increasing the efficiency of measuring the cytokines while reducing the serum sample volumes required for the testing. Two commercially available multiplex platforms were evaluated (Pierce SearchLight and Meso Scale Discovery), using multiplexes capable of simultaneously detecting eight cytokines. The cytokines analyzed in this study were gamma interferon, vascular endothelial growth factor, tumor necrosis factor alpha, interleukin-6 (IL-6), macrophage inflammatory protein 1beta, monocyte chemoattractant protein 1, IL-12p40, and IL-4. The range of quantitation of the platforms, the recovery of spiked cytokines, and the detection of the cytokines in serum samples from subjects with ulcerative colitis, Crohn's disease, rheumatoid arthritis, and psoriasis were examined. The findings showed that the detection of the cytokines was highly dependent upon the platform, with the consistency of the detection of cytokines across platforms being dependent upon the cytokine being analyzed. A careful examination of platform assay performance must be made prior to utilizing multiplex platforms in a study. While some cytokines will give similar patterns of results across platforms, others will be highly variable. The use of the same platform within a study or across studies where data will be compared is advised.
17127088 Vasculitides induced by TNFalpha antagonists: a study in 39 patients in France. 2006 Dec TNFalpha antagonists are effective in the treatment of chronic inflammatory joint disease. Despite a good overall safety profile, they can induce a number of adverse effects, including autoimmunity and infections. A link between TNFalpha antagonists and vasculitides has been suggested. METHODS: Between December 2004 and January 2005, a nationwide survey was conducted among 1200 hospital-based rheumatologists and internists in France, who were asked to report cases of vasculitis in patients taking TNFalpha antagonists. RESULTS: The survey identified 39 cases (32 women) of vasculitis during TNFalpha antagonist therapy. The joint disease was rheumatoid arthritis (RA) in 34 patients (including four without rheumatoid factor), juvenile idiopathic arthritis in two patients, ankylosing spondylitis in two patients, and psoriatic arthritis in one patient. Mean disease duration was 14.1+/-8.7 years. The TNFalpha antagonist was etanercept in 21 patients, infliximab in 15, adalimumab in 2, and another drug in 1; mean treatment duration was 9.6 months. The manifestations of vasculitis involved the skin (n=32); peripheral nervous system (n=9); kidney (n=7); central nervous system (n=3); pleura (n=2), pericardium (n=2); and the lung, gallbladder, and heart (n=1 each). Antinuclear factor (ANF) was present in 22 patients, hypocomplementemia in 6, and antineutrophil cytoplasmic antibody in 5. Histology (30 biopsies from 27 patients) showed nonnecrotizing vasculitis in 12 patients, necrotizing vasculitis in 7, an inflammatory dermal infiltrate without vasculitis in 3, extravascular necrotic granulomas in 2, chilblain lupus in 1, and cicatricial fibro-inflammatory changes in 1. Renal biopsy in three patients showed extracapillary glomerulonephritis with IgA deposits (n=2) or active floccular necrosis against a background of glomerular sclerosis (n=1). TNFalpha antagonist therapy was stopped in 33 patients, among whom 18 recovered without further treatment and 14 required high-dose glucocorticoids and/or immunosuppressant therapy, which ensured symptom resolution within a few weeks. The remaining patient died with multiple organ failures. DISCUSSION: The relative contributions of TNFalpha antagonist therapy and of the underlying disease to the development of vasculitis cannot be determined. Features that suggest a causal link between TNFalpha antagonists and vasculitis include the short time from TNFalpha antagonist initiation to vasculitis onset; the favorable response to discontinuation of TNFalpha antagonist therapy; and the development of systemic vasculitis in patients with rheumatoid factor-negative RA, in adults with juvenile-onset arthritis, and in patients with spondyloarthropathies.
17160756 [Rofecoxib-induced psychosis]. 2007 May Acute psychosis is a possible side effect of many centrally acting drugs. Its appearance is facilitated by certain conditions like advanced age, comedication, or comorbidity. We report two cases of acute psychotic syndromes with visual (Case 1 + 2) and auditory (Case 1) hallucinations under rofecoxib, a cyclooxygenase-2-inhibitor. This is one of the first reports of psychotic disorders under rofecoxib intake. We present a review of the literature on mental side effects of NSAID and on the pharmacological basis of the association of cyclooxygenase-inhibitors and mental disorders.
16610364 Heat shock proteins in immunity. 2006 This chapter focuses on immunological effects of eukaryotic and microbial heat shock proteins (HSPs), with molecular weights of about 60, 70, and 90 kDa. The search for tumor-specific antigens resulted in the identification of HSPs. They have been found to elicit a potent anti-cancer immune response mediated by the adoptive and innate immune system. Following receptor-mediated uptake of HSP (HSP70 and gp96) peptide complexes by antigen-presenting cells and representation of HSP-chaperoned peptides by MHC class I molecules, a CD8-specific T cell response is induced. Apart from chaperoning immunogenic peptides derived from tumors, bacterial and virally infected cells, they by themselves provide activatory signals for antigen-presenting cells and natural killer (NK) cells. After binding of peptide-free HSP70 to Toll-like receptors, the secretion of pro-inflammatory cytokines is initiated by antigen-presenting cells and thus results in a nonspecific stimulation of the immune system. Moreover, soluble as well as cell membrane-bound HSP70 on tumor cells can directly activate the cytolytic and migratory capacity of NK cells. Apart form cancer, HSPs of different origins, with a molecular weight of about 60, 70, and 90 kDa, also play a pivotal role in viral infections, including human and simian immunodeficiency virus (HIV, SIV), measles, and choriomeningitis. Moreover, HSPs have been found to induce tolerance against autoimmune diseases. In summary, depending on their mode of induction, intracellular/extracellular location, cellular origin (eukaryote/prokaryote), peptide loading status, intracellular ADP/ATP content, concentration, and route of application, HSPs either exert immune activation as danger signals in cancer immunity and mediate protection against infectious diseases or exhibit regulatory activities in controlling and preventing autoimmunity.
19052752 Synovial fluid RANKL and matrix metalloproteinase levels in enthesitis related arthritis s 2009 Jun In chronic arthritis cartilage and bone destruction occur as a consequence of synovial inflammation. It is mainly mediated by matrix metalloproteinases and RANKL-OPG pathways. Data on synovial fluid levels of these mediators in enthesitis related arthritis subtype (ERA) of JIA are not available. MMP-1, MMP-3, TIMP, sRANKL and OPG levels were measured in synovial fluid from patients with ERA and compared with other arthritides, polyarticular (Poly) JIA, RA and osteoarthritis (OA). sRANKL was detectable in 25/41 of ERA patients, 4/16 of Poly JIA patients. Median SF sRANKL level in patients with ERA was higher as compared to OA (p < 0.001) and poly JIA (p < 0.05) but were comparable to RA. The median OPG level in ERA was lower as compared to OA (p < 0.001), comparable to RA but was higher than poly JIA (p < 0.001). sRANKL/OPG ratio was significantly higher in ERA and Poly JIA compared to OA (p < 0.0001, p < 0.0001 respectively). The median MMP3 levels in ERA (74 microg/ml) was lower as compared to poly JIA (410 microg/ml; p < 0.0001) and RA (340 ug/ml; p < 0.0001) but was comparable to OA (107 microg/ml). The median level of ProMMP1 in ERA (0.70 microg/ml) was lower as compared to RA (2.9 microg/ml; p < 0.0001) and poly JIA but was elevated as compared to OA patients (0.1 microg/ml; p < 0.0001). TIMP1 levels in ERA were higher than poly JIA and RA patients. MMP3/TIMP1 ratio was lower in ERA compared to polyarticular JIA patients (p < 0.05). Ours is the first study reporting elevated sRANKL and reduced OPG levels and elevated sRANKL/OPG ratio in SF of children with JIA resulting in a mileu associated with bone loss. In addition, ERA patients had lower MMP level as well as MMP/TIMP ratio as compared to poly JIA which may partly explain lesser degree of joint damage seen in ERA as compared to poly JIA.
16491893 [Postponed or canceled drug challenge tests and side effects of the test drug--a report of 2006 Feb Drug challenge test (DCT) is performed to evaluate chronic pain pharmacologically and determine its medical treatment. One test drug is administered in one day for DCT and characterization of the test drug. Four patients developed side effects of the test drugs for DCT in whom other drug tests were postponed or canceled. A 58-year-old man with multiple arthritis of rheumatic arthritis and fibromyalgia had headache, nausea, and vomiting all day after ketamine test. A 76-year-old man with chronic general pain and failed back surgery syndrome had vomiting and abdominal discomfort two hours after morphine test and had redness and itching on his bilateral forearms the following day. A 78-year-old man with chronic lumbar and right lower limb pain due to L 4-5 lumbar disc herniation and postherpetic neuralgia felt dizzy, fell down and bruised on his lower back and left knee twelve hours after morphine test. A 32-year-old woman with chronic pelvic pain had skin eruption on her thigh the day after phentolamine test. Although the amount of the test drug in DCT is small and its half-life is short, long-term side effects might occur. We should decrease the amounts or frequencies of ketamine and morphine, and administer them taking long intervals before other tests.
17496242 Chronic disease and lifestyle transitions: results from the Longitudinal Aging Study Amste 2007 Jun OBJECTIVE: This article addresses the association between course of chronic disease and lifestyle. METHOD: We examined differences in unhealthy lifestyles--smoking, excessive alcohol use, being sedentary--and transitions herein after 6 years in prevalent and incident chronic disease categories--lung and cardiovascular disease, diabetes, and osteoarthritis and/or rheumatic arthritis--among 2,184 respondents aged 55 years and older from the Netherlands. We also examined if transitions in lifestyle co-occurred with changes in disease-related symptomatology. RESULTS: Proportions of respondents who smoked decreased over time, whereas proportions of respondents who were sedentary increased. Respondents with incident cardiovascular disease demonstrated more lifestyle transitions than respondents from other disease categories. Respondents demonstrating healthy lifestyle transitions did not differ from those persisting in unhealthy lifestyles in change in disease-related symptoms. DISCUSSION: Health promotion may benefit from these findings in a way that patient groups at risk for not initiating healthy lifestyles might be identified sooner.
18812196 Inhibitory CD8+ T cells in autoimmune disease. 2008 Nov Rheumatologists have long been focused on developing novel immunotherapeutic agents to manage such prototypic autoimmune diseases as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The ultimate challenge in providing immunosuppressive treatment for patients with RA and SLE has derived from the dilemma that both protective and harmful immune responses result from adaptive immune responses, mediated by highly diverse, antigen-specific T and B cells endowed with powerful effector functions and the ability for long-lasting memory. As regulatory/suppressor T cells can suppress immunity against any antigen, including self-antigens, they emerge as an ideal therapeutic target. Several distinct subtypes of CD8(+) suppressor cells (Ts) have been described that could find application in treating RA or SLE. In a xenograft model of human synovium, CD8(+)CD28(-)CD56(+) T cells effectively suppressed rheumatoid inflammation. Underlying mechanisms involve conditioning of antigen presenting cells (APC). Adoptively transferred CD8(+) T cells characterized by IL-16 secretion have also exhibited disease-inhibitory effects. In mice with polyarthritis, CD8(+) Ts suppressed inflammation by IFNgamma-mediated modulation of the tryptophan metabolism in APC. In SLE animal models, CD8(+) Ts induced by a synthetic peptide exerted suppressive activity mainly via the TGFbeta-Foxp3-PD1 pathway. CD8(+) Ts induced by histone peptides were found to downregulate disease activity by secreting TGFbeta. In essence, disease-specific approaches may be necessary to identify CD8(+) Ts optimally suited to treat immune dysfunctions in different autoimmune syndromes.
16772307 Up-regulation of IL-23p19 expression in rheumatoid arthritis synovial fibroblasts by IL-17 2007 Jan OBJECTIVE: To investigate the expression of interleukin (IL)-23p19 in human rheumatoid arthritis (RA) synovial fibroblasts and its up-regulation by IL-17 stimulation, and to define the signal pathways involved in the regulation of IL-23p19 expression in RA synovial fibroblasts. METHODS: Synovial fluid (SF) and serum levels of IL-23p19 in RA were determined by enzyme-linked immunosorbent assays. The levels of IL-23p19 mRNA and protein were measured after the RA synovial fibroblasts were treated with recombinant human IL-17 and various inhibitors of intracellular signal pathway molecules using reverse transcription (RT) polymerase chain reaction (PCR), real-time PCR and western blotting. RESULTS: Levels of IL-23p19 in the sera and SF were much higher in RA patients than in osteoarthritis patients or healthy controls. The expression of IL-23p19 mRNA and protein was enhanced in RA synovial fibroblasts by IL-17 stimulation. Such effects of IL-17 were completely blocked by inhibitors of phosphatidylinositol (PI)-kinase/Akt, nuclear factor (NF)-kappaB and p38 mitogen-activated protein kinase (MAPK). In accordance with the expression of IL-23p19, the phosphorylation of IkappaB, Akt and p38 MAPK in synovial fibroblasts also increased after IL-17 stimulation. CONCLUSION: IL-23p19 is over-expressed in RA synovial fibroblasts and IL-17 appears to up-regulate the expression of IL-23p19 in RA synovial fibroblasts via PI3-kinase/Akt, NF-kappaB- and p38-MAPK-mediated pathways. These results suggest that a disruption of interaction between IL-17 and IL-23p19 may provide a new therapeutic approach in the treatment of RA.
16150792 Long term safety of etanercept in elderly subjects with rheumatic diseases. 2006 Mar OBJECTIVES: To determine the long term safety profile of the tumour necrosis factor (TNF) antagonist etanercept in subjects with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) aged > or =65 years in comparison with subjects aged <65 years. METHODS: Safety data from an integrated database of 4322 subjects enrolled in 18 RA trials, 2 PsA trials, and 2 AS trials were analysed. Safety end points included subject incidence of all adverse events (AE), serious adverse events (SAE), infectious events (IE), medically important infections (MII), and deaths. Events of particular interest in subjects treated with TNF modulating biological treatments, including demyelinating diseases, tuberculosis, lymphomas, and cardiovascular diseases, were also evaluated. RESULTS: The incidence of AE, SAE, IE, MII, and malignancies was not significantly raised in elderly subjects in comparison with subjects aged <65 years. No cases of tuberculosis were reported in the trials. Demyelinating diseases were seen only in subjects aged <65 years. The incidence and types of death in the elderly subjects were consistent with the expected rates for subjects of comparable age. CONCLUSIONS: Etanercept is a generally safe and well tolerated biological agent for treatment of rheumatological diseases in the elderly, and the risk of AE in these studies was no greater in subjects aged > or =65 years than in younger subjects.
16859506 Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagoni 2006 Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-alpha treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-gamma. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-alpha treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-gamma-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-gamma release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-gamma upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.
16875903 Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofe 2006 Aug Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently needed for the treatment of patients with arthritis. However, long-term use of such drugs that are cyclooxygenase-2 (COX-2) selective inhibitors has been reported to increase cardiovascular risk as compared with placebo, whereas long-term, randomized controlled trials assessing the risk of traditional NSAIDs versus placebo are lacking. The MEDAL program is designed to provide a precise estimate of the relative cardiovascular event rates with the COX-2 selective inhibitor etoricoxib in comparison to the traditional NSAID diclofenac in patients with osteoarthritis and rheumatoid arthritis. The MEDAL program consists of 3 multinational, randomized, double-blind trials in patients with osteoarthritis and rheumatoid arthritis comparing etoricoxib (60 or 90 mg daily) to diclofenac (150 mg daily). All investigator-reported thrombotic cardiovascular events will be adjudicated by an independent panel of experts blinded to treatment assignment. The primary analysis is a noninferiority comparison of etoricoxib versus diclofenac for confirmed thrombotic cardiovascular events, defined as an upper bound of the 95% CI for a hazard ratio of < 1.30. With the planned 635 observed events from approximately 40,000 patient-years of exposure, using an estimated annual event rate of 1.30% in the control arm, the maximum annual event rate for etoricoxib that would meet the noninferiority criteria would be approximately 1.46%, yielding a hazard ratio of 1.12. A total of 34,701 patients have been enrolled in the MEDAL program. Roughly 13,000 and 10,000 patients will, respectively, have had > or = 18 or > or = 24 months of exposure, with maximum exposure of approximately 40 months. The MEDAL program will help to better define the risk-to-benefit ratio of 2 NSAIDs, that differ in their selectivity for COX-2, notably diclofenac and etoricoxib.
17999834 Sjögren syndrome. 2007 Jul Sjögren syndrome is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltration of the affected glands. The exocrinopathy can be encountered alone (primary Sjögren syndrome or in association with other autoimmune disorders, the three most common ones being rheumatoid arthritis, systemic lupus erythematosus, and progressive systemic sclerosis (secondary Sjögren syndrome). A revised international consensus has been designed based on symptoms and objective signs. Recent studies have broadened our understanding of the etiopathogenesis and immunopathology of primary Sjögren syndrome. Systemic therapy includes treatment of the underlying systemic disorder with steroidal and nonsteroidal agents, disease-modifying agents, and cytotoxic therapy to address the extra glandular manifestations. Medical treatment of dry eye includes aqueous enhancement therapy, anti-inflammatory therapy, and secretagogues. The surgical treatment of dry eye includes punctal occlusion, tarsorrhaphy, and botulinum toxin-induced ptosis. This review highlights recent advances in understanding the underlying mechanisms of the disease as well as the therapeutic options.