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ID PMID Title PublicationDate abstract
15482255 C and CX3C chemokines: cell sources and physiopathological implications. 2004 Within the fascinating world of chemokines, C and CX3C chemokines have long been regarded as two minor components, even though they present unique features and show less redundancy than the other chemokine families. Nevertheless, the body of data on their expression and role in various inflammatory disorders has grown in the past few years. The C chemokine family is represented by two chemokines, XCL1/lymphotactin-alpha and XCL2/lymphotactin-beta, whereas the CX3C chemokine family contains only one member, called CX3CL1/ fractalkine. In this review, we present an overview on the structure, expression and signaling properties of these chemokines and their respective receptors and examine how they contribute to inflammation and the regulation of leukocyte trafficking, as well as their potential role in the pathophysiology of human inflammatory diseases. Taken together, these data expand the biological importance of C and CX3C chemokines from that of simple immune modulators to a much broader biological role, even though their precise commitment within the framework of immune responses has still to be determined.
11987988 Abnormal B cell differentiation in primary Sjögren's syndrome results in a depressed perc 2002 Apr The percentage of CD27(+) B cells in peripheral blood (PB) of patients with primary Sjögren's syndrome (pSS) is significantly decreased compared to normals. In contrast, serum levels of the soluble form of CD27 (sCD27) are significantly higher in pSS patients, with a strong positive correlation between sCD27 and serum IgG levels. In vitro experiments demonstrate that normal B cells cultured under conditions driving plasma cell differentiation result in the production of substantial amounts of sCD27. Analyses of V(H)-region genes from sorted CD27(+) and CD27(-) B cells from pSS patients confirm that the CD27(+) population corresponds to the somatically mutated memory compartment, as in healthy individuals. Together our data indicate that in pSS, there is an abnormal differentiation of B cells to plasma cells resulting in a depression of the circulating memory B-cell pool and the release of significant amounts of sCD27 and IgG.
12109539 Collaborative research into outcome measures in Sjögren's syndrome. Update on disease ass 2002 Sjögren's syndrome (SS) is a multisystem immune-mediated disorder characterized by inflammation of exocrine glands leading to clinical symptoms of dryness, particularly of the eyes and mouth which can be severe and disabling. It can occur in association with other rheumatic disorders or as a primary entity (PSS), often associated with B-cell hyperreactivity manifested by hypergammaglobulinaemia and anti-Ro and/or anti-La autoantibodies. These patients are more likely to have systemic involvement, for example of the pulmonary, neurological or haematological systems, and have a 44 times increased risk of non-Hodgkins lymphoma, this being the major adverse outcome in this disorder. Clinical trials of new therapies in disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have been advanced by the development of internationally agreed assessment and outcome measures such as the American College of Rheumatology/EULAR core datasets of disease activity in RA and measures of activity and damage in SLE such as BILAG, SLEDAI, SLICC etc. No such equivalent consensus exists for SS and as a result clinical trials have all used different, unvalidated, ad hoc measures of disease assessment and outcome. One attempt to bring a coherent approach to this issue is the "Copenhagen model" or disease assessment wheel that places each disease manifestation within specific categories depending on their presumed pathogenesis. Attempts have also been made to develop this into a severity tool by grading specific manifestations according to severity. In March 2000, interested specialists from around Europe met to develop a consensus on the broad principles underpinning disease assessment in SS (particularly PSS). It was agreed to adopt the international approach of dividing assessment into: exocrine and-nonexocrine disease activity (potentially reversible and including sicca symptoms and objective measures and systemic symptoms (particularly fatigue) and clinical features), damage (present for over 6 months), health-related and generic quality of life, and standard approaches to adverse events/toxicity and health economic aspects. The workshop also began the process of developing specific measures of sicca symptoms and systemic activity and damage. In order to convert this approach into detailed, experimentally validated assessment tools, a UK-based collaboration has focused on the development of systemic and sicca symptom questionnaires and a prospective evaluation in Europe of systemic activity and damage measures is planned.
15578092 TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagoni 2004 Dec IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell-deficient IL-1Ra(-/-) mice did not develop arthritis, and transfer of IL-1Ra(-/-) T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-alpha deficiency. We found that TNF-alpha induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-alpha plays an important role in activating T cells through induction of OX40.
15388114 [166Dy]Dy/166Ho hydroxide macroaggregates: an in vivo generator system for radiation synov 2004 Dec Radiation synovectomy is an effective treatment in patients suffering from inflammatory-rheumatoid and degenerative joint diseases. The aim of this work was to examine the feasibility of preparing dysprosium-166 (166Dy)/holmium-166(166Ho) hydroxide macroaggregates ([166Dy]Dy/166Ho-HM) as an in vivo generator for radiation synovectomy evaluating whether the stability of 166Dy-HM and 166Ho-HM complexes is maintained when the daughter 166Ho is formed. The Monte Carlo (MCNP4B) theoretical depth dose profile for the in vivo [166Dy]Dy/166Ho generator system in a joint model was calculated and compared with that produced by 90Y, 153Sm and 166Ho. 166Dy was obtained by neutron irradiation of enriched 164Dy2O3 in a Triga Mark III reactor. Macroaggregates were prepared by reaction of [166Dy]DyCl3 with 0.5 M NaOH in an ultrasonic bath. [166Dy]Dy/166Ho-HM was obtained with radiochemical purity >99.5% and with the majority of particles in the 2-5 microm range. In vitro studies demonstrated that the radio-macroaggregates are stable in saline solution and human serum without a significant change in the particle size over 14 d, suggesting that no translocation of the daughter nucleus occurs subsequent to beta- decay of 166Dy. Biological studies in normal rats demonstrated high retention in the knee joint even 7 d after [166Dy]Dy/166Ho-HM administration. The Monte Carlo (MCNP4B) theoretical depth dose profiles in a joint model, showed that the in vivo [166Dy]Dy/166Ho generator system would produce 25% and 50% less radiation dose to the articular cartilage and bone surface, respectively, than that produced by 90Y or pure 166Ho in a treatment with the same therapeutic dose to the synovium surface. Despite that 153Sm showed the best depth dose profile sparing doses to healthy tissues, the use of 166Dy could provide the advantage of being applied in patients that cannot be reached within a few hours from a nuclear reactor and to produce less radiation exposure to the medical personnel during the radiopharmaceutical administration.
12784400 Validation of the Sicca Symptoms Inventory for clinical studies of Sjögren's syndrome. 2003 Jun OBJECTIVE: Oral, ocular, and other dryness are the hallmark features of Sjögren's syndrome (SS). We constructed a new measure of sicca symptoms, the Sicca Symptoms Inventory, for the evaluation of patients with primary SS. METHODS: Female Caucasian groups of patients with primary SS, systemic lupus erythematosus, and rheumatoid arthritis and healthy controls were assessed for tear and saliva production and also completed a symptoms-profiling inventory construct-validated from primary SS patients' own vocabulary, augmented with sicca items from publications and participating clinicians. Multi-item facets of sicca and other discomfort were validated by factor analysis. RESULTS: Primary SS and other "sicca" conditions were highly discriminated from other rheumatic disorders and healthy controls on each dryness-related facet of oral and ocular discomfort. Selected symptom scores were as sensitive and specific to primary SS as the scores for saliva and tears, respectively, although the severity scores of symptoms and signs were only moderately correlated. CONCLUSION: These multiple-question scales distinguish patients with primary SS from controls more precisely than previously used measures. Future studies will test if change in these symptom scores can serve as an outcome measure for clinical trials in SS.
14726437 Estrogen deficiency accelerates murine autoimmune arthritis associated with receptor activ 2004 May The aims of this study were to evaluate the in vivo effects of estrogen deficiency in MRL/lpr mice as a model for rheumatoid arthritis and to analyze the possible relationship between immune dysregulation and receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclastogenesis. Experimental studies were performed in ovariectomized (Ovx)-MRL/lpr, Ovx-MRL+/+, sham-operated-MRL/lpr, and sham-operated-MRL+/+ mice. Severe autoimmune arthritis developed in younger Ovx-MRL/lpr mice until 24 wk of age, whereas these lesions were entirely recovered by pharmacological levels of estrogen administration. A significant elevation in serum rheumatoid factor, anti-double-stranded DNA, and anti-type II collagen was found in Ovx-MRL/lpr mice and recovered in mice that underwent estrogen administration. A high proportion of CD4(+) T cells bearing RANKL was found, and an enhanced expression of RANKL mRNA and an impaired osteoprotegerin mRNA was detected in the synovium. An increase in both osteoclast formation and bone resorption pits was found. These results indicate that estrogen deficiency may play a crucial role in acceleration of autoimmune arthritis associated with RANKL-mediated osteoclastogenesis in a murine model for rheumatoid arthritis.
15582059 Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. 2004 Dec 4 BACKGROUND: The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. METHODS: We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. FINDINGS: We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2.30 (95% CI 1.22-4.33, p=0.010), and 1 year later (64 events, 21432 patients) it was 2.24 (1.24-4.02, p=0.007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0.41) or trial duration (p=0.82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0.86 [95% CI 0.75-0.99]) and could not have explained the findings of the VIGOR trial. INTERPRETATION: Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.
12637116 The prevalence of cardiorenal risk factors in patients prescribed nonsteroidal anti-inflam 2003 Jan BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to cause abnormalities in renal function. This is an important concern in patients with cardiorenal risk factors, including hypertension, congestive heart failure, edema, renal impairment, and advanced age. OBJECTIVES: The goals of this study were to determine the prevalence of cardiorenal risk factors in patients with rheumatoid arthritis (RA) or osteoarthritis and ascertain whether these risk factors are associated with prescribing patterns of cyclooxygenase (COX)-2-selective inhibitors and other NSAIDs. METHODS: This was a retrospective, longitudinal claims analysis using data from 19 large independent-practice-model managed care health plans in the United Stated. Three cohorts were identified based on claims for celecoxib, rofecoxib, or other NSAIDs from October 1, 1999, through September 30, 2000. Logistic regression models were used to explore whether baseline cardiorenal risk factors were related to choice of therapy. RESULTS: A total of 77,552 patients received celecoxib (n = 6779 [8.74%]), rofecoxib (n = 7189 [9.27%]), or other NSAIDs (n = 63,584 [81.99%]). Patients prescribed COX-2-selective inhibitors were older than those receiving other NSAIDs and had a diagnosis of RA more often. Overall, 42% of patients had >or=1 cardiorenal risk factor, and approximately one third had hypertension. Cardiorenal risk factors were not related to physicians' prescribing of celecoxib or rofecoxib, but the presence of any cardiorenal risk factor was associated with an increase in the use of COX-2-selective inhibitors compared with other NSAIDs, from 12% for cerebrovascular disease (point estimate, 1.124; P<0.001) to 74% for chronic renal failure/nephritis (point estimate, 1.738; P=0.025). RA and advanced age were associated with the use of celecoxib rather than rofecoxib. CONCLUSIONS: The prevalence of cardiorenal risk factors was found to be similar in patients prescribed celecoxib or rofecoxib for arthritis. Patients with these risk factors were more likely to receive a COX-2-selective inhibitor than other NSAIDs.
11920421 Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium tran 2002 Mar OBJECTIVE: The mechanisms by which monocyte/macrophage cells migrate to the joint involve a series of integrated adhesion and signaling events in which chemokines and their receptors are strongly implicated. This study was undertaken to investigate the hypothesis that stromal cell-derived factor 1 (SDF-1), a CXC chemokine (CXCL12), plays a critical role in monocyte/macrophage localization to synovium. METHODS: SDF-1 and CXC receptor 4 (CXCR4) expression in rheumatoid arthritis (RA) and osteoarthritis synovium and graft SDF-1, tumor necrosis factor alpha (TNF alpha), and human and murine vascular markers were examined by immunohistochemistry and double-immunofluorescence. The functional capacity of SDF-1 to modulate monocyte migration into joints was investigated by examining the localization of pro-myelomonocytic U937 cells into synovial tissue transplanted into SCID mice. SDF-1, TNF alpha, or saline was injected into graft sites and response determined by the number of fluorescently labeled U937 cells (injected intravenously) detected in grafts by ultraviolet microscopy. RESULTS: SDF-1 and CXCR4 were highly expressed in CD68+ cells in the RA synovium. SDF-1 induced U937 cell migration in vitro and in vivo in a dose-dependent manner and, in vivo, SDF-1 was more effective than TNF alpha. In contrast to TNF alpha, SDF-1 did not induce intracellular adhesion molecule 1 in transplant microvasculature. Furthermore, intragraft injection of SDF-1 did not up-regulate TNF alpha, or vice versa. CONCLUSION: This study demonstrates, for the first time, that SDF-1 is functional in vivo when injected into synovial grafts. In addition, SDF-1 is more potent than TNF alpha, and its mechanisms of action appear to be autonomous. Therefore, SDF-1 may be an important TNF-independent molecule involved in the migration to and retention of inflammatory effector cells in the joint.
11750284 Alterations of serum selenium concentrations in the acute phase of pathological conditions 2002 Feb BACKGROUND: Selenium (Se), an essential trace element, is known to be a cofactor of antioxidative selenoenzymes such as glutathione peroxidase and thioredoxin reductase. METHODS: We assessed the pathophysiological significance of selenium (Se) by comparing the concentrations of serum Se and C-reactive protein (CRP) in healthy subjects (141; M=71, F=70) vs. patients with various pathological conditions. RESULTS: In normal males in their 40s, peak serum Se concentrations were observed (2.03+/-0.30 microg/g of serum protein, 128%, P<0.001) vs. males in their 20s (1.59+/-0.20), whereas a peak was observed in females in their 30s (1.87+/-0.31, 119%, P<0.025) vs. those in their 20s (1.57+/-0.22). The serum Se concentrations in the high CRP value group (n=40, 1.07+/-0.29 microg/g, 64.1%), the rheumatoid arthritis (RA) test positive group (n=24, 1.37+/-0.29, 82.0%), the lung cancer group (n=16, 1.38+/-0.30, 82.6%), and the adult T-cell leukemia (ATL) group (n=22, 1.26+/-0.35, 75.4%) were significantly lower (P<0.001) than those in the healthy subjects (1.67+/-0.29 microg/g). This finding was confirmed by inducing acute phase response (APR) in rats by injection of lipopolysaccharide (LPS), which produced a significant decrease of Se in plasma and liver (69.5% and 81.6% vs. untreated rats, P<0.05). In contrast, the Se content in muscle, kidney, lung, spleen, heart, and thymus showed increases of <10%. Se mobilized from liver after LPS-challenge appeared to be translocated to muscle, and Se concentrations recovered by 80 h after APR to the control concentrations in parallel with the subsidence of APR. CONCLUSIONS: The reduction of Se in the liver and plasma during APR may be associated with the increased CRP synthesis in the liver.
12858469 Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an ad 2003 Jul Infliximab, a chimeric anti-tumor necrosis factor-alpha monoclonal antibody, has been demonstrated to be efficient and safe in patients with active rheumatoid arthritis and in the management of severe bouts of Crohn's disease. However, the safety of infliximab has not been evaluated in patients infected with hepatitis B virus. We report the case of a 28-year-old woman, with a positive hepatitis B virus surface antigen, who developed fulminant hepatitis 2 weeks after receiving a second infliximab infusion for a refractory adult onset Still's disease.
12111085 The chemoattraction of lymphocytes by rheumatoid arthritis - synovial fluid is not depende 2002 Jul OBJECTIVE: The objective was to study the potential role of the chemokine receptor CCR5 in the chemoattraction of lymphocytes by rheumatoid arthritis synovial fluid (RA-SF). METHODS: The expression of the CCR5 receptor was studied by flow cytometry. Chemotaxis of peripheral blood lymphocytes in response to RA-SF was analyzed on transmigration chambers. Chemotaxis of immortalized lymphocytes from individuals homozygous for the Delta32 deletion of the CCR5 gene (CCR5-/-) was analyzed. The effect of a neutralizing anti-CCR5 antibody on the migration of CCR5+/+ cells was also studied. RESULTS: We confirmed an increase in the proportion of CCR5-expressing lymphocytes in RA-SF and a preferential migration of CCR5+ lymphocytes toward RA-SF in vitro. CCR5-/- lymphocytes showed decreased chemotactic responses to the chemokine MIP-1beta but not to RA-SF. The chemotactic responses of CCR5+/+ lymphocytes to RA-SF were not modified by anti-CCR5 neutralizing antibody. CONCLUSIONS: We confirm a preferential accumulation of CCR5-expressing lymphocytes into RA-SF. However, the chemotactic responses of lymphocytes to RA-SF were not dependent on a functional CCR5 receptor, suggesting that CCR5 is a marker of a lymphocyte subset rather than a specific mediator of chemotactic responses to chemokines in RA-SF.
15157895 Inhibition of joint inflammation and destruction induced by anti-type II collagen antibody 2004 Jun 7 OBJECTIVE: Previous studies have demonstrated that neutralization of macrophage migration inhibitory factor (MIF) by anti-MIF antibody decreases joint destruction in the collagen-induced arthritis model. The present study was undertaken to investigate whether selective deletion of MIF inhibits inflammation and joint destruction of the anti-type II collagen antibody (anti-CII Ab)/lipopolysaccharide (LPS)-induced arthritis in mice, in order to determine the role of this cytokine in inflammatory arthritis. DESIGN: Anti-CII Ab/LPS-induced arthritis was induced in MIF-deficient and wild-type mice. The effects of anti-MIF polyclonal antibody administration on anti-CII Ab-induced arthritis were also evaluated. RESULTS: The expression of MIF protein and mRNA was induced in anti-CII Ab/LPS-induced arthritis joint tissues. Histopathological arthritis scores for synovial inflammation induced by anti-CII Ab/LPS -induced arthritis were significantly decreased in anti-MIF Ab-treated mice and in MIF-deficient mice compared to wild-type mice. In addition, mRNA levels of MMP-13 and MIP-2 in anti-CII Ab/LPS-induced arthritis joint tissues were significantly reduced in MIF-deficient mice compared to wild-type control mice. CONCLUSIONS: These results indicate that MIF plays a critical role in inflammation and joint destruction in the anti-CII Ab/LPS-induced arthritis model in mice, in part via induction of MMP-13 and neutrophil infiltration through the induction of MIP-2.
15194590 MMP profile in paired serum and synovial fluid samples of patients with rheumatoid arthrit 2004 Jul OBJECTIVE: To analyse matrix metalloproteinases (MMPs) and tissue inhibitor-1 of MMPs (TIMP-1) levels in the systemic circulation and synovial fluid (SF) of patients with RA and to compare these levels with inflammatory and collagen degradation markers. METHODS: ProMMP-1, -2, -3, -8, -9, TIMP-1, levels of MMP/alpha(2)-macroglobulin complexes, and collagen degradation products were measured by sandwich ELISA, activity assays, and HPLC in paired SF and serum samples from 15 patients with RA and 13 with OA. RESULTS: MMPs were higher in SF of patients with RA than in OA or controls. MMP levels in SF of patients with OA were higher than in controls. In serum, levels of proMMP-3, -8 and -9 were higher in patients with RA than in OA or controls, whereas only proMMP-8 and -9 were higher in serum of patients with OA than in controls. A strong correlation was seen between serum and SF levels of MMP-8 and -9 in RA. Increased levels of MMP/alpha(2)-macroglobulin complexes indicated an MMP/TIMP imbalance in serum and SF in RA. SF hydroxyproline correlated significantly with SF levels of proMMP-9 in RA. CONCLUSIONS: Systemic MMP-8 and -9 levels represent the situation in the inflamed joint; MMP-9 is likely to be involved in degradation of joint collagen. The hypothesis of MMP/TIMP imbalance in RA is strengthened.
14693324 Determinants of selective cyclooxygenase-2 inhibitor prescribing: are patient or physician 2003 Dec 15 BACKGROUND: Little is known about which factors influence the widespread use of selective cyclooxygenase (COX)-2 inhibitors. We examined the relative effects of patient risk factors for gastrointestinal toxicity, other patient characteristics, and physician prescribing preferences on the decision to prescribe a selective COX-2 inhibitor. METHODS: We retrospectively studied a cohort of 28,190 Medicare beneficiaries who were continuously enrolled in a large, state-run pharmacy benefits program that reimbursed for selective COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) without restrictions. Half of the study sample filled a prescription for a selective COX-2 inhibitor and the other half for a nonselective NSAID. Multivariable logistic regression models were developed to predict COX-2 inhibitor use. RESULTS: Seventeen percent of patients using a COX-2 inhibitor had no identifiable risk factor for NSAID-associated gastrointestinal toxicity, compared with 23% of those using a nonselective NSAID. Established risk factors (age > or =75 years, history of gastrointestinal hemorrhage or peptic ulcer disease, or concomitant warfarin or oral glucocorticoid use) were all significant predictors of COX-2 inhibitor use, but a multivariable model including only these risk factors discriminated poorly between the two patient groups (C statistic = 0.55). Adding other patient clinical and demographic characteristics to the model somewhat improved this association (C statistic = 0.66); however, when physician prescribing preference was included, the model had excellent ability to discriminate between the two treatment groups (C statistic = 0.83). CONCLUSION: Established risk factors for NSAID-associated gastrointestinal toxicity were poor predictors of who was prescribed a selective COX-2 inhibitor; in contrast, physician prescribing preference was an important determinant.
12755551 The cost-effectiveness of cyclooxygenase-2 selective inhibitors in the management of chron 2003 May 20 BACKGROUND: Rofecoxib and celecoxib (coxibs) effectively treat chronic arthritis pain and reduce ulcer complications by 50% compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). However, their absolute risk reduction is small and the cost-effectiveness of treatment is uncertain. OBJECTIVE: To determine whether the degree of risk reduction in gastrointestinal complications by coxibs offsets their increased cost compared with a generic nonselective NSAID. DESIGN: Cost-utility analysis. DATA SOURCES: Systematic review of MEDLINE and published abstracts. TARGET POPULATION: Patients with osteoarthritis or rheumatoid arthritis who are not taking aspirin and who require long-term NSAID therapy for moderate to severe arthritis pain. PERSPECTIVE: Third-party payer. INTERVENTIONS: Naproxen, 500 mg twice daily, and coxib, once daily. Patients intolerant of naproxen were switched to a coxib. TIME HORIZON: Lifetime. OUTCOME MEASURES: Incremental cost per quality-adjusted life-year (QALY) gained. RESULTS OF BASE-CASE ANALYSIS: Using a coxib instead of a nonselective NSAID in average-risk patients cost an incremental 275 809 dollars per year to gain 1 additional QALY. RESULTS OF SENSITIVITY ANALYSIS: The incremental cost per QALY gained decreased to 55 803 dollars when the analysis was limited to the subset of patients with a history of bleeding ulcers. The coxib strategy became dominant when the cost of coxibs was reduced by 90% of the current average wholesale price. In probabilistic sensitivity analysis, if a third-party payer was willing to pay 150 000 dollars per QALY gained, then 4.3% of average-risk patients would fall within the budget. CONCLUSIONS: The risk reduction seen with coxibs does not offset their increased costs compared with nonselective NSAIDs in the management of average-risk patients with chronic arthritis. However, coxibs may provide an acceptable incremental cost-effectiveness ratio in the subgroup of patients with a history of bleeding ulcers.
15028962 Sarcoidosis or Sjögren syndrome? Clues to defining mimicry or coexistence in 59 cases. 2004 Mar We present 5 new cases of coexisting sarcoidosis and Sjögren syndrome (SS) and review the literature for additional cases in order to analyze the clinical, immunologic, and histologic characteristics that may help physicians differentiate the mimicry of SS by sarcoidosis from a true coexistence of both autoimmune diseases. We considered the coexistence of sarcoidosis with SS to be when patients presented specific histologic patterns of both diseases, simultaneously or at different times.Fifty-nine patients were included in the analysis (54 identified in the literature search plus our 5 unpublished cases): 49 (83%) patients were female and 10 (17%) were male, with a mean age at diagnosis of 50 years. According to the histopathologic examination of the exocrine glands performed in 53 cases, we defined coexistence of sarcoidosis and SS in 28 cases, while in the remaining 25 patients, sarcoidosis mimicked SS. Clues to identifying when sarcoidosis coexists with SS were a higher prevalence of systemic manifestations (arthritis and uveitis) and positive immunologic parameters (antinuclear antibodies, rheumatoid factor, and anti-Ro/SS-A), as well as the existence of a focal sialadenitis (Chisholm-Mason score grades III-IV, with a CD4+ lymphocytic infiltration) in the salivary gland biopsy. In patients first diagnosed with primary SS, the appearance of some clinical features such as hilar adenopathies, uveitis, or hypercalcemia leads to the diagnosis of coexisting sarcoidosis. A careful application of the new American-European consensus criteria had a sensitivity of 93% and a specificity of 92% in identifying when SS coexists with sarcoidosis.In conclusion, the association of sarcoidosis with SS leads to a true coexistence of both diseases in more than half the patients described in the literature, while in the remaining patients, sarcoidosis mimics SS. In light of these results, sarcoidosis should not be considered as an exclusion criterion for the diagnosis of SS, and in patients with a suspected overlap of the two diseases, application of the new American-European consensus criteria for diagnosis of SS should be mandatory.
12716452 The relationship between predicted peptide-MHC class II affinity and T-cell activation in 2003 The HLA-DRB1*0401 MHC class II molecule (DR4) is genetically associated with rheumatoid arthritis. It has been proposed that this MHC class II molecule participates in disease pathogenesis by presenting arthritogenic endogenous or exogenous peptides to CD4+ T cells, leading to their activation and resulting in an inflammatory response within the synovium. In order to better understand DR4 restricted T cell activation, we analyzed the candidate arthritogenic antigens type II collagen, human aggrecan, and the hepatitis B surface antigen for T-cell epitopes using a predictive model for determining peptide-DR4 affinity. We also applied this model to determine whether cross-reactive T-cell epitopes can be predicted based on known MHC-peptide-TCR interactions. Using the HLA-DR4-IE transgenic mouse, we showed that both T-cell proliferation and Th1 cytokine production (IFN-gamma) correlate with the predicted affinity of a peptide for DR4. In addition, we provide evidence that TCR recognition of a peptide-DR4 complex is highly specific in that similar antigenic peptide sequences, containing identical amino acids at TCR contact positions, do not activate the same population of T cells.
15593184 Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human o 2004 Dec OBJECTIVE: To demonstrate the effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through their effects on receptor activator of nuclear factor kappaB (RANK), osteoprotegerin (OPG), and RANK ligand (RANKL). METHODS: Peripheral blood mononuclear cells (PBMCs) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) were cocultured in the presence of macrophage colony-stimulating factor, 1,25-dihydroxyvitamin D(3), and various concentrations of methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), anti-tumor necrosis factor alpha monoclonal antibody (infliximab), interleukin-4 (IL-4), and IL-10. Osteoclast formation was assayed by counting cells after staining for tartrate-resistant acid phosphatase. RANKL expression in RA FLS and RANK expression in PBMCs were assayed by Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), and real-time PCR. OPG expression was measured by enzyme-linked immunosorbent assay, RT-PCR, and real-time PCR in cultures of RA FLS. RESULTS: MTX, SSZ, infliximab, and IL-4, but not IL-10 and HCQ, each inhibited osteoclast formation in a dose-dependent manner. We observed no evidence of synergistic inhibition of osteoclast formation by IL-4 and IL-10. High doses of infliximab suppressed the expression of RANK in PBMCs. MTX, SSZ, infliximab, and IL-4 each inhibited the expression of RANKL in RA FLS in a dose-dependent manner, and also increased the secretion of OPG in RA FLS supernatants. CONCLUSION: MTX, SSZ, infliximab, and IL-4 inhibit human osteoclastogenesis by modulating the interaction of RANKL, RANK, and OPG. These results are indicative of the underlying mechanisms of the antiresorptive effects of these 4 agents.