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ID PMID Title PublicationDate abstract
16819260 [Retinoid therapy for autoimmune diseases]. 2006 Jun Retinoid is a collective term for compounds which bind to and activate retinoic acid receptors (RARalpha, beta, gamma and RXRalpha, beta, gamma), members of nuclear hormone receptor superfamily. The most important endogeneous retinoid is all-trans-retinoic acid (ATRA) which is an RARalpha, beta and gamma ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and some skin diseases. Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, tamibarotene (Am80) is an RARalpha- and RARbeta-specific (but RARgamma- and RXRs-nonbinding) synthetic retinoid that is effective in the treatment of psoriasis patients and relapsed APL. Experimentally, this compound is also active in animal models of rheumatoid arthritis and experimental autoimmune encephalomyelitis. On this background, possible application of retinoids for the treatment of autoimmune diseases was discussed. In particular, Th1 dominant autoimmune diseases may be the targets of the retinoids.
16705046 Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: 2006 Dec BACKGROUND: Anti-tumour necrosis factor-alpha (TNF-alpha) therapies represent an important advancement in therapy for rheumatoid arthritis (RA). However, there remains a proportion of patients who do not improve despite therapy. These drugs are expensive and have the potential of serious toxicity. Therefore, it would be ideal to predict the patients who will respond, so that the use of these drugs can be targetted. OBJECTIVE: To identify the clinical factors present at the start of anti-TNF-alpha therapy that are associated with response at 6 months in patients with RA. METHODS: The British Society for Rheumatology (BSR) Biologics Register collects detailed data on all patients with a rheumatic disease receiving biologic therapy in the UK. We studied all patients with RA who had started etanercept (ETA) or infliximab (INF) and had achieved a minimum 6 months follow-up by 1 October, 2004. The disease status at the baseline and at 6 months was assessed using the Disease Activity Score (DAS28). The response was classified according to the European League against Rheumatism (EULAR) improvement criteria. The effect of baseline characteristics on response was studied using multivariate ordinal logistic regression. RESULTS: 2879 patients were included in this analysis (1267 ETA, 1612 INF). At the start of therapy, the mean age was 55 yrs, disease duration 14 yrs, baseline DAS28 6.7 and health assessment questionnaire (HAQ) 2.1. In all, 28% of ETA and 86% of INF patients were receiving methotrexate. After 6 months, 18% had a good EULAR response, of whom 9% were considered to be in remission and 50% had a moderate response. There was no overall difference in response rate between the two anti-TNF-alpha therapies. A higher baseline HAQ score correlated with a lower response rate while a better response was associated with the current use of NSAIDs and the use of methotrexate (MTX), although the latter only reached statistical significance with ETA [OR 1.82 (95% CI 1.38-2.40)]. There was a lower response rate among current smokers, particularly in patients receiving INF [OR 0.77 (95% CI 0.60-0.99)]. Age, disease duration, rheumatoid factor and the previous number of disease-modifying antirheumatic drugs (DMARDs) did not predict response to either drug. However, females were less likely to achieve remission. CONCLUSIONS: These data support an improved outcome among patients receiving MTX in combination with anti-TNF-alpha therapies. However, the most disabled patients were less likely to respond, despite concurrent MTX. The benefits of NSAIDs may reflect the relative absence of comorbidities in patients who can tolerate these drugs or the continuing presence of reversible inflammatory symptoms. The association of smoking and poor outcome with INF is a novel finding and may reflect alterations in pharmacokinetics. The inability of other baseline disease characteristics to predict the outcome suggests that other factors, including potential genetic differences in drug metabolism, may be influencing the response to anti-TNF-alpha therapies.
15881487 Lumiracoxib in the treatment of osteoarthritis, rheumatoid arthritis and acute postoperati 2005 Jan OBJECTIVES: Overview of three dose-response studies demonstrating the efficacy of lumiracoxib, a novel COX-2 selective inhibitor, for chronic pain associated with osteoarthritis (0A), or rheumatoid arthritis (RA) and acute pain following dental extraction. METHODS: OA and RA: 4-week, randomized, placebo- and active-controlled studies of similar design. Patients (OA, n = 583; RA, n = 571) received lumiracoxib 50 mg, 100 mg or 200 mg twice daily (bid), lumiracoxib 400 mg once daily (od), diclofenac 75 mg bid or placebo. Dental: 12-h, single-center, randomized, placebo- and active-controlled study. Patients (n = 202) received single oral doses of lumiracoxib 100 mg or 400 mg, ibuprofen 400 mg or placebo. MAIN OUTCOME MEASURES: OA: pain intensity (PI) in the target joint (visual analogue scale [VAS]) and WOMAC score at Week 4; RA: overall PI (VAS) and ACR20 response at Week 4; Dental: difference (PID, categorical and VAS) score over 12h post dose, time to onset of analgesia. RESULTS: Throughout the OA study, all lumiracoxib doses provided superior reductions in PI versus placebo and at Week 4, all lumiracoxib doses provided efficacy similar to each other and to diclofenac. In the RA study, lumiracoxib 100 mg bid, 200 mg bid and 400mg od were significantly better than placebo in PI at Weeks 1 and 2 (all p < 0.05) but demonstrated borderline significance at Week 4 (lumiracoxib 400 mg od, p = 0.06). In pain following dental surgery, PID scores for both lumiracoxib doses were superior to placebo from 1.5 h onwards and always comparable, or superior, to ibuprofen. Lumiracoxib 400 mg had the fastest onset of analgesia, measured as median time to confirmed first perceptible pain relief using the two-stopwatch method (37.4 min, superiority versus placebo, p < 0.001). Lumiracoxib was well tolerated in all studies. CONCLUSIONS: These studies provide initial evidence that lumiracoxib is an effective, well-tolerated agent for the treatment of chronic and acute pain.
16997599 Use of tumor necrosis factor inhibitors in rheumatoid arthritis: a national survey of prac 2006 Dec OBJECTIVES: To determine the prescribing practices, laboratory monitoring protocols, and perceived barriers of United States rheumatologists in prescribing tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA). METHODS: A survey questionnaire was mailed to 1970 rheumatologists who were randomly selected from a national sample of 3008 rheumatologists. A one-page non-response questionnaire was mailed to approximately 200 randomly selected non-responding rheumatologists to assess non-response bias. RESULTS: Two mailings yielded a response rate of 22.3% (428 completed, usable surveys out of 1922 deliverable surveys). Rheumatologists reported using all three agents in patients with moderate RA (82-87%), severe RA (94-96%), and in newly diagnosed and mild RA patients (10-18%). In patients with severe RA who inadequately responded to methotrexate, 91% of rheumatologists reported using a TNF inhibitor with one other disease modifying anti-rheumatic drug. Over 94% of rheumatologists reported switching patients from one TNF inhibitor to a different TNF inhibitor due to inadequate response or side effects. Most rheumatologists (96%) ordered the purified protein derivative test for tuberculosis, with almost 82% conducting this test at baseline. Costs to patients and insurance coverage were perceived as major barriers to prescribing these agents although the perception was slightly lower with infliximab than with adalimumab or etanercept. CONCLUSIONS: The use of TNF inhibitors is not restricted to patients with moderate and severe RA. Rheumatologists are fairly similar in their utilization of the three TNF inhibitors although some variation exists in terms of laboratory practices and perceived barriers regarding the use of these agents.
16327720 [Topical silver sulfadiazine-induced acute renal failure]. 2005 Nov INTRODUCTION: Prolonged topical application of silver sulfadiazine cream can induce argyria and adverse effects of sulphonamides. We report a case of a woman with acute renal failure following repeated applications of topical silver sulfadiazine on pyoderma gangrenosum wounds. CASE REPORT: A 61 year-old woman suffering from rheumatoid arthritis, Sjogren's syndrome and scleroderma was treated with corticosteroids (1 mg/kg/day) and topical application of silver sulfadiazine cream (200 g/day) for extensive pyoderma gangrenosum wounds on the legs. Three weeks later, the patient was transferred to intensive care because of pulmonary edema, oligoanuria and disrupted consciousness. Laboratory data revealed leukopenia (1100/mm(3)) with neutropenia and renal failure (serum creatinine 316 micromol/l). Proteinuria was moderate and ultrasonography of the kidneys was normal. Silver concentration in blood was 1818 nmol/l (N < 92 nmol/l) and 1381 nmol/l (N < 9 nmol/l) in urine. Sulfadiazine concentration in blood was undetectable. All the signs regressed after withdrawal of silver sulfadiazine and after several sessions of hemodialysis. DISCUSSION: Various causes of renal failure are discussed in our patient. However, direct silver-induced renal toxicity is the most likely and is confirmed by the high concentration of silver in blood and urine and the improvement on withdrawal of the topical cream, without modification in the oral treatment. The absence of red corpuscles and crystals in the urine and undetectable concentrations of sulfadiazine in blood are not in favor of sulphonamide renal toxicity. Furthermore, the autoimmune diseases of our patient were well-controlled. Leukopenia could be secondary to silver sulfadiazine medullar toxicity. This observation confirms that this topical cream should not be used for long periods on extensive wounds.
16901957 Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline aut 2007 Jun OBJECTIVES: To identify peripheral blood autoantibody and cytokine profiles that characterise clinically relevant subgroups of patients with early rheumatoid arthritis using arthritis antigen microarrays and a multiplex cytokine assay. METHODS: Serum samples from 56 patients with a diagnosis of rheumatoid arthritis of <6 months' duration were tested. Cytokine profiles were also determined in samples from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (n = 21), and from healthy individuals (n = 19). Data were analysed using Kruskal-Wallis test with Dunn's adjustment for multiple comparisons, linear correlation tests, significance analysis of microarrays (SAM) and hierarchical clustering software. RESULTS: Distinct antibody profiles were associated with subgroups of patients who exhibited high serum levels of tumour necrosis factor (TNF)alpha, interleukin (IL)1beta, IL6, IL13, IL15 and granulocyte macrophage colony-stimulating factor. Significantly increased autoantibody reactivity against citrullinated epitopes was observed in patients within the cytokine "high" subgroup. Increased levels of TNFalpha, IL1alpha, IL12p40 and IL13, and the chemokines eotaxin/CCL11, monocyte chemoattractant protein-1 and interferon-inducible protein 10, were present in early rheumatoid arthritis as compared with controls (p<0.001). Chemokines showed some of the most impressive differences. Only IL8/CXCL8 concentrations were higher in patients with PsA/ankylosing spondylitis (p = 0.02). CONCLUSIONS: Increased blood levels of proinflammatory cytokines are associated with autoantibody targeting of citrullinated antigens and surrogate markers of disease activity in patients with early rheumatoid arthritis. Proteomic analysis of serum autoantibodies, cytokines and chemokines enables stratification of patients with early rheumatoid arthritis into molecular subgroups.
15576336 Macrophage migration inhibitory factor in rheumatoid arthritis. 2005 Jan 1 Rheumatoid arthritis is characterised by the interaction of multiple mediators, among the most important of which are cytokines. In recent years, extensive data demonstrates a pivotal role for one cytokine, macrophage migration inhibitory factor (MIF), in fundamental events in innate and adaptive immunity. MIF has now been demonstrated to be involved in the pathogenesis of many diseases, but in the case of RA the evidence for a role of MIF is very strong. MIF is abundantly expressed in the serum of RA patients, and in RA synovial tissue where it correlates with disease activity. MIF induces synoviocyte expression of key proinflammatory genes including TNF, IL-1, IL-6, IL-8, cPLA2, COX2 and MMPs. MIF also regulates the function of endothelial cells and B cells. Moreover, MIF is implicated in the control of synoviocyte proliferation and apoptosis via direct effects on the expression of the tumor suppressor protein p53. In multiple rat and mouse models of RA, anti-MIF antibodies or genetic MIF deficiency are associated with significant inhibition of disease. MIF -/- mice further demonstrate increases in synovial apoptosis. That the human Mif gene is encoded by different functional alleles in subjects with inflammatory disease also provides evidence for the role of MIF in RA. The mechanism of action of MIF is becoming better understood. MIF appears to interact with cell surface CD74, with consequent activation of MAP kinases but possibly not NFkappaB intracellular signal transduction. This apparent selectivity may be implicated in the ability of MIF to antagonise the effects of glucocorticoids. As MIF expression is induced by glucocorticoids, inhibition of its antagonistic effects may permit enhanced therapeutic effect of glucocorticoids, or "steroid sparing". To date there are no clinical trials of MIF antagonism in any disease, but exploitation of antibody, soluble receptor, or small molecule approaches enabled by the unique crystal structure of MIF, may soon lead to the ability to test in the clinic the importance of this cytokine in human RA.
16150434 Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme 2005 Nov OBJECTIVES: The metabolism of cells in inflammatory and noninflammatory arthritic joint diseases is subject to complex environmental controls. The aim of the present study was to investigate the total antioxidant capacity (TAC), levels of lipid peroxidation (LPO), and antioxidant enzyme activities in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). DESIGN AND METHODS: Plasma levels of TAC, malondialdehyde (MDA), the activities of some erythrocyte antioxidant enzymes, as well as erythrocyte sedimentation rates (ESR) were estimated in patients with RA and OA and compared with controls. RESULTS: The plasma TAC levels were significantly lower in the RA group than the OA and control group (P < 0.05). Plasma MDA concentrations were significantly higher in patients with RA than those with OA and healthy subjects (P < 0.05). Erythrocyte GSH-Px and CAT activities were found to be significantly lower in patients with RA than those with OA and healthy subjects (P < 0.05, P < 0.05, respectively). However, there were no significant differences in erythrocyte SOD activities between the groups (P > 0.05). ESR were significantly higher in RA patients than in healthy subjects and patients with OA (P < 0.01). Moreover, there were significant negative correlations between TAC vs. MDA, ESR vs. TAC, and a positive correlation between ESR vs. MDA in the RA group (r = -0.398, P < 0.05; r = -0.422, P < 0.05; r = 0.530, P < 0.05, respectively). CONCLUSIONS: Our results demonstrated that levels of LPO are increased in patients with RA compared to patients with OA. In addition, plasma TAC levels are decreased in RA due to its inflammatory character. We conclude that detecting plasma TAC levels with this novel method may be used as a routine and rapid test to verify the levels of oxidative stress in RA. Furthermore, correlating TAC and LPO levels with acute phase reactants such as ESR may give some clues about disease activity in RA.
16192646 Trypsin-2 degrades human type II collagen and is expressed and activated in mesenchymally 2005 Oct It has traditionally been believed that only the human collagenases (matrix metalloproteinase-1, -8, and -13) are capable of initiating the degradation of collagens. Here, we show that human trypsin-2 is also capable of cleaving the triple helix of human cartilage collagen type II. We purified human trypsin-2 and tumor-associated trypsin inhibitor by affinity chromatography whereas collagen type II was purified from cartilage extracts using pepsin digestion and salt precipitation. Degradation of type II collagen and gelatin by trypsin-2 was demonstrated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis, zymography, and mass spectrometry, and tumor-associated trypsin inhibitor specifically inhibited this degradation. Although human trypsin-2 efficiently digested type II collagen, bovine trypsin did not. Furthermore, immunohistochemical staining detected trypsin-2 in the fibroblast-like synovial lining and in stromal cells of human rheumatoid arthritis synovial membrane. These findings were confirmed by reverse transcriptase-polymerase chain reaction and nucleotide sequencing. Trypsin-2 alone and complexed with alpha(1)-proteinase inhibitor were also detected in the synovial fluid of affected joints by time-resolved immunofluorometric assay, suggesting that trypsin-2 is activated locally. These results are the first to assess the ability of human trypsin to cleave human type II collagen. Thus, trypsin-2 and its regulators should be further studied for use as markers of prognosis and disease activity in rheumatoid arthritis.
15564310 Soluble TRAIL concentrations are raised in patients with systemic lupus erythematosus. 2005 Jun BACKGROUND: Increased apoptosis may induce autoimmune conditions. Apoptosis is induced by binding of death receptor ligands, members of the tumour necrosis factor (TNF) superfamily, to their cognate receptors. The Fas-Fas ligand pathway has been studied extensively in relation to systemic lupus erythematosus (SLE). However, other death pathways are also considered important. TNF related apoptosis inducing ligand (TRAIL), another ligand of the TNF superfamily, induces apoptosis in sensitive cells. OBJECTIVE: To assess soluble (s) TRAIL concentrations in sera of SLE patients. METHODS: 40 SLE patients were studied (20 with active and 20 with inactive disease). Serum sTRAIL concentrations were measured by a solid phase sandwich enzyme linked immunosorbent assay. Levels in SLE patients were compared with those in patients with rheumatoid arthritis (n = 20), Wegener's granulomatosis (n = 20), and healthy controls (n = 20). RESULTS: Mean (SEM) serum sTRAIL concentration in SLE patients (936.0 (108.2) pg/ml) was higher than in healthy controls (509.4 (33.8) pg/ml; p<0.01) or in disease control patients with rheumatoid arthritis (443.8 (36.1) pg/ml, p<0.001) or Wegener's granulomatosis (357.1 (32.2) pg/ml; p<0.001). The mean serum sTRAIL concentration was 1010.2 (168.0) pg/ml for patients with inactive disease and 861.8 (138.7) pg/ml for those with active disease. sTRAIL values were not correlated with specific manifestations of the disease, such as leucopenia or lymphopenia, or with SLE disease activity index. CONCLUSIONS: Serum sTRAIL concentrations are increased SLE patients. This seems to be disease specific and could indicate a role for TRAIL in SLE pathophysiology.
16278818 Synovial fluid macrophages are capable of osteoclast formation and resorption. 2006 Jan To determine whether synovial fluid (SF) macrophages isolated from the SF of osteoarthritis (OA), rheumatoid arthritis (RA) and pyrophosphate arthropathy (PPA) joints are capable of osteoclast formation, and to investigate the cellular and humoral factors required for this to occur, SF macrophages (CD14+) were isolated from the knee joint SF from patients with OA, RA and PPA and cultured for up to 14 days with macrophage-colony stimulating factor (M-CSF) and soluble receptor activator for nuclear factor-kappaB ligand (RANKL) or tumour-necrosis factor-alpha (TNFalpha) and interleukin-1alpha (IL-1alpha). Osteoclast differentiation was assessed by expression of tartrate-resistant acid phosphatase (TRAP) and vitronectin receptor (VNR), F-actin ring formation and lacunar resorption. Osteoclast formation and lacunar resorption was seen in RANKL-treated cultures of SF macrophages isolated from OA, RA and PPA joints with the largest amount of resorption noted in RA and PPA SF macrophage cultures. In TNFalpha/IL-1alpha-treated RA and PPA SF macrophage cultures, osteoclasts capable of lacunar resorption were also formed. Lacunar resorption was more extensive in RANKL than TNFalpha/IL-1alpha-treated cultures. These findings indicate that SF macrophages are capable of differentiating into mature osteoclasts capable of lacunar resorption. M-CSF in combination with RANKL or TNFalpha/IL-1alpha was required for osteoclast formation. As inflammatory synovial fluids contain an increase in the number of macrophages and an increase in the amounts of RANKL, TNFalpha and IL-1alpha, these findings suggest that one means whereby bone erosions may form in rheumatoid or crystal arthritis is by differentiation of synovial fluid macrophages into osteoclasts.
15930538 Uncemented glenoid component in total shoulder arthroplasty. Survivorship and outcomes. 2005 Jun BACKGROUND: Glenoid component loosening continues to be a major factor affecting the long-term survivorship of total shoulder replacements. Radiolucent lines, cement fracture, migration, and loosening requiring revision are common problems with cemented glenoid components. The purpose of this study was to evaluate the results of total shoulder arthroplasty with an uncemented glenoid component and to identify predictors of glenoid component failure. METHODS: One hundred and forty-seven consecutive total shoulder arthroplasties were performed in 132 patients (mean age, 63.3 years) with use of an uncemented glenoid component fixed with screws between 1988 and 1996. One hundred and forty shoulders in 124 patients were available for follow-up at an average of 7.5 years. One shoulder in which the arthroplasty had failed at 2.4 years and for which the duration of follow-up was four years was also included for completeness. The preoperative diagnoses included osteoarthritis in seventy-two shoulders and rheumatoid arthritis in fifty-five. RESULTS: Radiolucency was noted around the glenoid component and/or screws in fifty-three of the 140 shoulders. The mean modified ASES (American Shoulder and Elbow Surgeons) score (and standard deviation) improved from 15.6 +/- 11.8 points preoperatively to 75.8 +/- 17.5 points at the time of follow-up. Eighty-five shoulders were not painful, forty-two were slightly or mildly painful, ten were moderately painful, and three were severely painful. Fifteen (11%) of the glenoid components failed clinically, and ten of them also had radiographic signs of failure. Eleven other shoulders had radiographic signs of failure but no symptoms at the time of writing. Three factors had a significant independent association with clinical failure: male gender (p = 0.02), pain (p < 0.01), and radiolucency adjacent to the flat tray (p < 0.001). In addition, the annual risk of implant revision was nearly seven times higher for patients with radiographic signs of failure. Clinical survivorship was 95% at five years and 85% at ten years. CONCLUSIONS: The failure rates of the total shoulder arthroplasties in this study were higher than those in previously reported studies of cemented polyethylene components with similar durations of follow-up. Screw breakage and excessive polyethylene wear were common problems that may lead to additional failures of these uncemented glenoid components in the future.
15954248 Cervical lymphadenopathy in the dental patient: a review of clinical approach. 2005 Jun Lymph node enlargement may be an incidental finding on examination, or may be associated with a patient complaint. It is likely that over half of all patients examined each day may have enlarged lymph nodes in the head and neck region. There are no written guidelines specifying when further evaluation of lymphadenopathy is necessary. With such a high frequency of occurrence, oral health care providers need to be able to determine when lymphadenopathy should be investigated further. Although most cervical lymphadenopathy is the result of a benign infectious etiology, clinicians should search for a precipitating cause and examine other nodal locations to exclude generalized lymphadenopathy. Lymph nodes larger than 1 cm in diameter are generally considered abnormal. Malignancy should be considered when palpable lymph nodes are identified in the supraclavicular region, or when nodes are rock hard, rubbery, or fixed in consistency. Patients with unexplained localized cervical lymphadenopathy presenting with a benign clinical picture should be observed for a 2- to 4-week period. Generalized lymphadenopathy should prompt further clinical investigation. This article reviews common causes of lymphadenopathy, and presents a methodical clinical approach to a patient with cervical lymphadenopathy.
15934080 Class II major histocompatibility complex-peptide tetramer staining in relation to functio 2005 Jun OBJECTIVE: Although studies have suggested that human cartilage (HC) gp-39 may be an antigen recognized by autoreactive CD4(+) T cells in rheumatoid arthritis, we previously failed to identify specific CD4(+) T cells in patients' synovial fluid or blood using a class II major histocompatibility complex-peptide tetramer composed of the immunodominant HC gp-39(263-275) epitope covalently linked to DR4. We undertook this study to better understand the parameters for specific binding of this tetramer. METHODS: DR4-transgenic mice were immunized with the HC gp-39 peptide, and a set of peptide-responsive hybridomas was derived. Hybridomas were stained with the DR4-gp-39 tetramer and cultured with increasing amounts of peptide in the presence of DR4-expressing antigen-presenting cells to determine functional avidity. RESULTS: Great variability was apparent in the ability of the tetramer to stain the hybridomas, and there was a strong correlation between the intensity of tetramer staining and functional avidity. Importantly, nearly 30% of the hybridomas did not stain with tetramer, and these cells exhibited relatively low functional avidity. Although the addition of an anti-T cell receptor (anti-TCR) monoclonal antibody during the staining procedure enhanced binding of the tetramer to a number of the hybridomas, a significant percentage remained unstainable. Analysis of TCR expression showed that >90% of the hybridomas expressed the same TCR beta-chain variable region (V(beta)10), and sequencing of the TCR junctional regions showed diversity in the third complementarity-determining region. CONCLUSION: These results suggest that immune responses dominated by relatively low-affinity TCR interactions, such as those that may occur in autoimmune disease, will be difficult to detect using standard tetramer techniques.
16575713 [Evaluation of the Extra Short Musculoskeletal Function Assessment questionnaire XSMFA-D i 2006 Apr AIM: The present study had the objective of evaluating the psychometric characteristics of the shortened 16-item version of the German Short Musculoskeletal Function Assessment questionnaire (XSMFA-D), which was designed for routine assessment of functional capacity in patients with various orthopaedic disorders treated either surgically or medically. METHODS: A total of 382 patients from seven different samples with either osteoarthritis of the knee, osteoarthritis of the hip, rheumatoid arthritis or rotator cuff tear treated either in surgical hospitals or rehabilitation settings were assessed both before and after treatment. The XSMFA-D was compared with both questionnaires measuring similar constructs and widely accepted indicators of health status in musculoskeletal disorders. Psychometric characteristics were computed. RESULTS: The internal consistency (Cronbach's alpha) exceeded 0.90 in most cases for the function index and was between 0.80 and 0.90 in most cases for the bother index of the XSMFA-D. Retest-reliability was between 0.80 and 0.95 for the function index and between 0.60 and 0.92 for the bother index. Correlations between the XSMFA-D subscales and the other questionnaires were substantial, showing construct validity. Criterion validity was also demonstrated as significant relationships with accepted external parameters such as function tests, judgements by physicians, pain self-ratings by patients and disease severity scores were found. Sensitivity to change was as high as for the other assessment instruments used in this study. CONCLUSIONS: The XSMFA-D, a very short assessment instrument, proved to be practical, reliable, valid and sensitive to change among the various patient samples studied. It may be recommended for the assessment of patients' state as well as the evaluation of treatments.
16645969 The effect of therapeutic glucocorticoids on the adrenal response in a randomized controll 2006 May OBJECTIVE: To measure the effect of low-dose systemic glucocorticoid treatment on the adrenal response to adrenocorticotropic hormone (ACTH) in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who took part in a randomized double-blind placebo-controlled trial of budesonide (3 mg/day and 9 mg/day) and prednisolone (7.5 mg/day) underwent a short (60-minute) test with injection of ACTH (tetracosactide hexaacetate) at baseline and the day after completing the 3-month treatment program. Plasma cortisol measurements at baseline and 3 months were compared within and between the treatment groups. Individual patients were classified as normal responders to ACTH or as abnormal responders if changes were >2 SD below the pretreatment value in the entire group of study patients. RESULTS: Short tests with ACTH injection were performed on 139 patients before beginning the study medication and on 134 patients after cessation of the medication. There were no changes in the placebo group. Mean plasma cortisol levels following treatment were reduced in all active treatment groups. In addition, mean values were significantly reduced for the 30-minute and 60-minute responses to ACTH. The maximum reduction (35%) occurred in the prednisolone group at 60 minutes. Following treatment, 34% of patients taking budesonide 9 mg and 46% of those taking prednisolone 7.5 mg failed to reach the normal maximum cortisol response to ACTH. Four patients failed to achieve the normal percentage increase in cortisol levels, but only 1 patient failed to meet both criteria. CONCLUSION: Low doses of a glucocorticoid resulted in depression of baseline and ACTH-stimulated cortisol levels after 12 weeks of therapy. Although the responsiveness of the hypothalamic-pituitary-adrenal axis in individual patients generally remained within the normal range, these changes should be investigated further.
15642131 MMP-3 expression and release by rheumatoid arthritis fibroblast-like synoviocytes induced 2005 Fibroblast-like synoviocytes (FLSs) play a major role in the pathogenesis of rheumatoid arthritis (RA) by secreting effector molecules that promote inflammation and joint destruction. How these cells become and remain activated is still elusive. Both genetic and environmental factors probably play a role in transforming FLSs into inflammatory matrix-degrading cells. As bacterial products have been detected in the joint and shown to trigger joint inflammation, this study was undertaken to investigate whether a bacterial ligand of integrin alpha5beta1, protein I/II, could contribute to the aggressive behavior of RA FLSs. Protein I/II is a pathogen-associated molecular pattern (PAMP) isolated from oral streptococci that have been identified in the joints of RA patients. The response of RA and osteoarthritis FLSs to protein I/II was analyzed using human cancer cDNA expression arrays. RT-PCR and pro-MMP-3 (pro-matrix metalloproteinase) assays were then performed to confirm the up-regulation of gene expression. Protein I/II modulated about 6% of all profiled genes. Three of these, those encoding IL-6, leukemia inhibitory factor, and MMP-3, showed a high expression level in all RA FLSs tested, whereas the expression of genes encoding other members of the cytokine or MMP-family was not affected. Furthermore, the up-regulation of MMP-3 gene expression was followed by an increase of pro-MMP-3 release. The expression of interferon regulatory factor 1 and fibroblast growth factor-5 was also up-regulated, although the expression levels were lower. Only one gene, that for insulin-like growth factor binding protein-4, was down-regulated in all RA FLSs. In contrast, in osteoarthritis FLSs only one gene, that for IL-6, was modulated. These results suggest that a bacterial ligand of integrin alpha5beta1 may contribute to the aggressive behavior of RA FLSs by inducing the release of pro-inflammatory cytokines and a cartilage-degrading enzyme, such as IL-6 and MMP-3, respectively.
16531560 It takes nerve to tell T and B cells what to do. 2006 Jun The existence of an association between the brain and immunity has been documented. Data show that the nervous and immune systems communicate with one another to maintain immune homeostasis. Activated immune cells secrete cytokines that influence central nervous system activity, which in turn, activates output through the peripheral nervous system to regulate the level of immune cell activity and the subsequent magnitude of an immune response. In this review, we will focus our presentation and discussion on the findings that indicate a regulatory role for the peripheral sympathetic nervous system in modulating the level of cytokine and antibody produced during an immune response. Data will be discussed from studies involving the stimulation of the beta2 adrenergic receptor expressed on CD4+ T cells and B cells by norepinephrine or selective agonists. We will also discuss how dysregulation of this line of communication between the nervous and immune systems might contribute to disease development and progression.
15880821 T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. 2005 May OBJECTIVE: Patients with rheumatoid arthritis (RA) accumulate prematurely aged T cells that have acquired a new profile of regulatory receptors. Many of the de novo-expressed receptors are typically found on natural killer cells, including CX(3)CR1, the receptor for the chemokine fractalkine (FKN). This study explored whether interactions between CX(3)CR1 and FKN are relevant for T cell functions in rheumatoid synovitis. METHODS: FKN expression was examined by real-time polymerase chain reaction and immunohistochemistry. CX(3)CR1 expression on peripheral blood T cells was analyzed by flow cytometry. T cell activation was quantified by determining proliferative responses, interferon-gamma (IFNgamma) secretion, and granule release. Fibroblast-like synoviocyte (FLS)/T cell adhesion was measured by the retention of 5-carboxyfluorescein diacetate succinimidyl ester-labeled T cells on FLS monolayers. RESULTS: FKN was expressed on cultured synovial fibroblasts and hyperplastic synoviocytes in the rheumatoid tissue. Among CD4+ T cells, only senescent CD28- T cells were positive for CX(3)CR1 (P < 0.001). Such CD4+,CD28-,CX(3)CR1+ T cells strongly adhered to FLS, with soluble FKN blocking the interaction. FKN expressed on FLS costimulated T cell-activating signals and amplified proliferation, IFNgamma production, and expulsion of cytoplasmic granules. CONCLUSION: Senescent CD4+ T cells that accumulate in rheumatoid arthritis aberrantly express CX(3)CR1. FKN, which is membrane-anchored on synoviocytes, enhances CD4+ T cell adhesion, provides survival signals, and costimulates the production of proinflammatory cytokines as well as the release of granules. By virtue of their altered receptor profile, senescent CD4+ T cells receive strong stimulatory signals from nonprofessional antigen-presenting cells in the synovial microenvironment.
15663617 Intracranial hypertension induced by rofecoxib. 2005 Jan Several secondary causes are implicated in the etiology of idiopathic intracranial hypertension. Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor, now being increasingly used in place of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). We report a case of intracranial hypertension in a 69-year-old man 3 weeks after the commencement of rofecoxib therapy with reversal of clinical findings on drug withdrawal.