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ID PMID Title PublicationDate abstract
11896888 Mizoribine in the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. 2002 Apr BACKGROUND: Mizoribine (MZR), isolated from culture medium of the mold, is a novel immunosuppressant developed in Japan. It has been used in patients with renal transplantation, lupus nephritis, nephrotic syndrome and rheumatoid arthritis (RA). OBJECTIVES: To review MZR in regards to mechanism of action, pharmacokinetics, efficacy and safety in the treatment of rheumatoid RA and juvenile idiopathic arthritis (JIA). RESULTS: The drug MZR inhibits both humoral and cellular immunity in RA patients. It is completely excreted in the urine within 24 h, which contributes to the safety of MZR. A series of multicenter studies indicated that MZR was effective and safe in the treatment of RA. In JIA, however, there are only a few case reports reporting its efficacy and safety. CONCLUSION: A double-blinded multicenter study is needed to establish the efficacy, safety and indication of MZR in the treatment of JIA.
12832707 Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic a 2003 Nov OBJECTIVES: Infiltration of synovial tissue by neutrophils is crucial in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and seronegative arthritis (SA). Altered vascular function and endothelial activation are important in PsA. S100A12 (EN-RAGE) is secreted by activated granulocytes and binds to the receptor for advanced glycation end products, which induces nuclear factor (NF)-kappaB-dependent activation of endothelium. METHODS: Immunohistochemical studies were performed to detect synovial S100A12 expression. We analysed serum and synovial fluid of 42 patients for S100A12 levels. RESULTS: S100A12 was strongly expressed in inflamed synovial tissue whereas it was nearly undetectable in synovia of controls or patients after successful treatment. Serum levels of S100A12 correlated with disease activity. CONCLUSIONS: Local expression of S100A12 in inflamed tissue suggests a role in synovitis, especially in PsA. High serum concentrations of S100A12 in patients with active arthritis compared with healthy controls or patients in remission point to its usefulness as a serum marker.
14616545 Allergic manifestations in patients with rheumatoid arthritis. 2003 Oct A functional dichotomy between Th1- and Th2-type immune responses has been suggested. This study was performed to investigate whether rheumatoid arthritis (RA), a disease with indications of Th1-deviated immune activation, is inversly related to atopic conditions which are Th2-mediated. Two hundred and sixty-three adult cases of RA, fulfilling the American Rheumatism Association (ARA) 1987 Revised Classification Criteria for RA, were identified in 1995 and compared with 541 randomly selected population referents. The presence of atopic manifestations was established through a postal questionnaire and by demonstrating circulating IgE antibodies to common allergens. RA was inversely associated with certain manifestations of rhinitis, which were regarded as the most reliable indicators of atopic disease in the present study. However, no negative association was seen between RA and asthma and eczema, respectively. The main results give some support for an inverse relationship between RA and rhinitis. The prevalence of circulating IgE antibodies was however similar in cases and controls, suggesting that the T-cell commitment mainly occurs in the affected organs.
14671726 Cyclooxygenase-2 and prostaglandins in articular tissues. 2003 Dec OBJECTIVES: To provide an overview on: 1) the expression of cyclooxygenase (COX)-2 in articular tissues; 2) the role of prostaglandin E2 (PGE2) in these tissue functions; and 3) clinical trials with COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) (coxibs). METHODS: MEDLINE search was performed using the key words "cyclooxygenase," "prostaglandin," "osteoarthritis" (OA), and "rheumatoid arthritis" (RA). Selected publications related to clinical trials with coxibs also are included. RESULTS: COX-2 is upregulated in inflamed joint tissues and is responsible for elevated PGE2 production. The overexpression of COX-2 is likely induced by proinflammatory mediators such as interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF) alpha. However, the exact molecular mechanisms through which the expression of COX-2 is regulated remain to be elucidated. Several studies suggest that PGE2 is involved in inflammation, apoptosis, angiogenesis, and possibly structural changes that characterize arthritic diseases. NSAIDs are prescribed for the treatment of OA and RA and provide effective relief from symptoms; however, serious gastrointestinal complications occur with their use. The clinical efficacy of NSAIDs is primarily related to the inhibition of COX-2, whereas much of the toxicity is related to COX-1 inhibition. Selective COX-2 inhibitors (coxibs) that spare COX-1 at therapeutic doses are more effective than placebo and as effective as other NSAIDs for relief of symptoms of OA and RA, and have significantly improved gastrointestinal safety and tolerability. However, some studies showed that COX-2-selective inhibitors still have classic NSAID complications. CONCLUSIONS: Overexpression of COX-2 protein in articular tissues is a characteristic feature of arthritic diseases. However, the molecular mechanisms involved in the regulation of COX-2 expression and activity are still unclear. Elucidating the mechanisms of COX-2 expression and PGE2 production and action will help identify novel and more selective potential drug targets in the treatment of arthritic diseases.
12920653 Erosive osteoarthritis. 2003 Jun Erosive osteoarthritis (EOA) is a progressive disorder affecting the interphalangeal joints of the hands. Severe synovitis is superimposed on the typical changes seen in conventional interphalangeal osteoarthritis (OA), which includes formation of Heberden's and Bouchard's nodes. Imaging studies show a combination of bony proliferation (osteophytosis), periosteal reaction, and articular erosions, which assume "gull-wing" configuration. Differential diagnosis includes classic "degenerative" OA, rheumatoid arthritis, and psoriatic arthritis.
12236617 The mode of action of cytokine inhibitors. 2002 Sep Tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) are important mediators of inflammation and tissue damage in animal models of inflammatory arthritis and in patients with active rheumatoid arthritis (RA). Several inhibitors of these cytokines are now available for RA treatment, each having a different mode of action. Etanercept is a recombinant fusion protein of the soluble type II TNF receptor on a human IgG1 backbone, whereas infliximab is a chimeric anti-TNF-alpha monoclonal antibody containing a murine TNF-alpha binding region and human IgG1 backbone. Both agents potently and selectively bind TNF-alpha in the cellular microenvironment, thereby preventing TNF-alpha from interacting with membrane-bound TNF receptors on target cells. In comparison, anakinra is a recombinant human IL-1 receptor antagonist (IL-1Ra) that binds avidly to type 1 IL-1 receptors but does not stimulate any intracellular responses. Studies of these agents in animal models of inflammatory arthritis suggest that TNF-alpha plays a more important role in promoting inflammation, whereas IL-1 is more important in causing cartilage and bone destruction. However, these differential actions have not been borne out in clinical trials, where TNF-alpha blockers and anakinra similarly reduce clinical signs and symptoms of RA as well as slow radiographic evidence of disease progression.
12847675 Doppler sonographic findings in the long bicipital tendon sheath in patients with rheumato 2003 Jul OBJECTIVE: To compare power Doppler sonography (PDS) findings inside the bicipital tendon sheath in patients with rheumatoid arthritis (RA) and degenerative disorders of the shoulder, in order to evaluate the diagnostic value of PDS in distinguishing between inflammatory and noninflammatory shoulder pain. METHODS: The glenohumeral joints of 41 consecutive patients with shoulder pain were examined by ultrasound. Using ventral transverse and longitudinal scanning, the vascularity near and/or inside the bicipital tendon sheath was visualized by PDS. One fully trained and experienced examiner performed the sonography. Representative images were digitally stored and were read, under blinded conditions, by 2 independent investigators, who categorized the Doppler signals as being either inside or outside the tendon sheath. RESULTS: Biceps tendon sheath effusion, represented by the typical hypoechoic rim, was found in 95.8% of the RA patients (23 of 24) and in 58.8% of the patients with degenerative disorders (10 of 17). PDS signals were localized to inside the tendon sheath in 22 of the RA patients (91.7%) and in none of the patients with degenerative disorders. Although no PDS signal was found inside the tendon sheath in patients with degenerative disorders, in 9 of these patients (52.9%), signals could be localized to the environment of the tendon sheath. CONCLUSION: PDS demonstrates vascularity in the long bicipital tendon sheath of patients with RA, but not in those with degenerative shoulder disorders.
12721704 [Multiple joint replacement of the lower limbs in rheumatoid arthritis]. 2003 Apr INTRODUCTION: Erosive-destructive changes in rheumatoid arthritis particularly in the large joints of the lower limbs often result in the patient's immobility. The aim of this retrospective study was to weigh the benefits of multiple joint replacement in rheumatoid arthritis against the specific complications. MATERIALS AND METHODS: From January 1977 until 31 December 1998, 215 patients with proven rheumatoid arthritis (according to the ACR classification) received three or four endoprostheses in the lover limbs. In a retrospective study with a standard questionnaire and evaluation of the patient record, we were able to assess 201 rheumatoid patients (93.5%) who received 688 endoprostheses (93.7%), with 347 total hip prostheses (THR) and 341 total knee prostheses (TKR). RESULTS: There was a significant improvement of the patient's ability to walk and in 16.9% of the cases even a remobilization of the rheumatoid patients who had been unable to walk before surgery. On the other hand, there were significant complications--in the majority of the cases (appr. 60%) with total knee replacement. Together the complications per implant had an extremely high complication rate of 43.8% (n=88) per rheumatoid patient. DISCUSSION: Due to the long-term follow-up of 22 years (1977 through 1998), we were able to demonstrate that with a new implant generation and a more a careful indication this unacceptable complication rate can be reduced considerably. However, the multiple joint replacement of the lower limbs remains a difficult method with a high complication rate and should therefore only be performed at orthopedic rheumatological centers.
12886966 Methotrexate pneumonitis in a patient with rheumatoid arthritis. 2003 Jun Methotrexate pneumonitis is an unpredictable and life-threatening side effect of methotrexate therapy. Early diagnosis, cessation of methotrexate, and treatment with corticosteroids and/or cyclophosphamide are important in the management of patients with methotrexate pneumonitis. Methotrexate pneumonitis has not been reported in patients of Chinese ethnicity. We report a case of methotrexate pneumonitis in a Taiwan patient with rheumatoid arthritis who presented with acute nonproductive cough, dyspnea, fever, severe hypoxemia, and rapid progression to respiratory failure. Chest roentgenogram demonstrated bilateral diffuse interstitial and alveolar infiltration. Thoracoscopic biopsy with wedge resection of the upper lobe of the right lung was performed and the histologic findings of the biopsy specimen were consistent with bronchiolitis obliterans with organizing pneumonia. Rapid improvement of methotrexate pneumonitis was achieved after pulse therapies of methylprednisolone and cyclophosphamide and daily use of prednisolone.
12180725 Infusion of epinephrine decreases serum levels of cortisol and 17-hydroxyprogesterone in p 2002 Aug OBJECTIVE: To investigate the pituitary and adrenal hormone response after an intravenous epinephrine challenge in patients with rheumatoid arthritis (RA) and controls. METHODS: Fifteen untreated female patients with RA (age 51.5 +/- 3.2 yrs) and 7 healthy female controls (48.0 +/- 4.3 yrs) were infused with epinephrine (0.05 microg/kg/min) for about 20 min. Plasma levels of adrenocorticotropic hormone (ACTH), and serum levels of cortisol, 17-hydroxyprogesterone (17OHP), and dehydroepiandrosterone sulfate (DHEAS) were analyzed at baseline and shortly after cessation of epinephrine infusion (20 min). RESULTS: At baseline and after epinephrine infusion, serum levels of cortisol (p = 0.045) and 17OHP (p = 0.021) were higher in controls compared to patients with RA. In contrast, at baseline and after epinephrine infusion, plasma levels of ACTH and serum levels of DHEAS were similar in controls and patients. After epinephrine infusion, only the patients with RA had a significant decrease of serum cortisol (p = 0.026) and serum 17OHP (p = 0.026). Plasma levels of ACTH (p = 0.073) and serum levels of DHEAS (p = 0.055) tended to decrease. CONCLUSION: Serum cortisol and 17OHP (cortisol precursor) were lower in patients with RA compared to controls despite similar ACTH levels. Simulation of an adrenomedullary stress response by epinephrine infusion decreased serum cortisol and 17OHP in patients but not in controls. Such a response may play an unfavorable role during a typical stress reaction in patients with RA that may lead to a more proinflammatory situation.
12865407 Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheu 2003 Jul It has been shown that osteopontin (OPN) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). However, the molecular mechanism of OPN action is yet to be elucidated. Splenic monocytes obtained from arthritic mice exhibited a significant capacity for cell migration toward thrombin-cleaved OPN but not toward full-length OPN. Migratory monocytes expressed alpha9 and alpha4 integrins. Since cleavage of OPN by thrombin exposes the cryptic epitope recognized by alpha9 and alpha4 integrins, we investigated the role of the cryptic epitope SLAYGLR in a murine RA model by using a specific antibody (M5) reacting to SLAYGLR sequence. The M5 antibody could abrogate monocyte migration toward the thrombin-cleaved form of OPN. Importantly, M5 antibody could inhibit the proliferation of synovium, bone erosion, and inflammatory cell infiltration in arthritic joints. Thus, we demonstrated that a cryptic epitope, the SLAYGLR sequence of murine OPN, is critically involved in the pathogenesis of a murine model of RA.
12233873 HLA-DR/DQ haplotype in rheumatoid arthritis: novel allelic associations in UK Caucasians. 2002 Sep OBJECTIVE: To elucidate the relative importance of the HLA-DR and HLA-DQ loci in conferring genetic predisposition to rheumatoid arthritis (RA). METHODS: HLA-DRB1 and HLA-DQB1 alleles were typed in a set of 685 patients with RA using sequence-specific polymerase chain reaction. Allele and phenotype frequencies were compared with those in 2 large sets of historical, ethnically matched healthy controls, using the relative predispositional effect method. RESULTS: Positive association was confirmed with the shared epitope positive HLA-DRB1 alleles associated with RA in Caucasians. A significant susceptibility effect was observed with HLA-DRB1*09, described in other ethnically diverse populations but not in Caucasians. A significant underrepresentation of the HLA-DRB1*0103 variant was noted among the RA cases, supporting the proposed protective role of the DERAA motif at residues 70-74 of the DRbeta molecule. No HLA-DRB1 independent association of the HLA-DQB1 alleles, implicated in predisposing to RA, was evident. CONCLUSION: These data corroborate the shared epitope hypothesis of susceptibility to RA and provide strong evidence for the DRB1 locus as the primary RA susceptibility factor in the HLA region.
12058436 [A case of airway obstruction after posterior occipito-cervical fusion]. 2002 May A 62-year-old female with rheumatoid arthritis underwent posterior occipito-cervical fusion. Although the operation was successfully performed, airway obstruction developed immediately after the extubation. We succeed in fiberoptic intubation. We consider that airway obstruction was caused by the preexisting reduction of the pharyngeal space and the occipito-cervical fusion malalignment. On the extubation after occipito-cervical fusion, we should always consider the possibility of re-intubation and its difficulty.
15292528 Detection of differentially expressed genes in synovial fibroblasts by restriction fragmen 2004 Nov OBJECTIVE: To identify differentially expressed genes in synovial fibroblasts and examine the effect on gene expression of exposure to TNF-alpha and IL-1beta. METHODS: Restriction fragment differential display was used to isolate genes using degenerate primers complementary to the lysophosphatidic acid acyl transferase gene family. Differential gene expression was confirmed by reverse transcription-polymerase chain reaction and immunohistochemistry using a variety of synovial fibroblasts, including cells from patients with osteoarthritis and self-limiting parvovirus arthritis. RESULTS: Irrespective of disease process, synovial fibroblasts constitutively produced higher levels of IL-6 and monocyte chemoattractant protein 1 (MCP-1) (CCL2) than skin fibroblasts. Seven genes were differentially expressed in synovial fibroblasts compared with skin fibroblasts. Of these genes, four [tissue factor pathway inhibitor 2 (TFPI2), growth regulatory oncogene beta (GRObeta), manganese superoxide dismutase (MnSOD) and granulocyte chemotactic protein 2 (GCP-2)] were all found to be constitutively overexpressed in synoviocytes derived from patients with osteoarthritis. These four genes were only weakly expressed in other synovial fibroblasts (rheumatoid and self-limiting parvovirus infection). However, expression in all types of fibroblasts was increased after stimulation with TNF-alpha and IL-1beta. Three other genes (aggrecan, biglycan and caldesmon) were expressed at higher levels in all types of synovial fibroblasts compared with skin fibroblasts even after stimulation with TNF-alpha and IL-1. CONCLUSIONS: Seven genes have been identified with differential expression patterns in terms of disease process (osteoarthritis vs rheumatoid arthritis), state of activation (resting vs cytokine activation) and anatomical location (synovium vs skin). Four of these genes, TFPI2, GRObeta (CXCL2), MnSOD and GCP-2 (CXCL6), were selectively overexpressed in osteoarthritis fibroblasts rather than rheumatoid fibroblasts. While these differences may represent differential behaviour of synovial fibroblasts in in vitro culture, these observations suggest that TFPI2, GRObeta (CXCL2), MnSOD and GCP-2 (CXCL6) may represent new targets for treatments specifically tailored to osteoarthritis.
12690629 [Pathological roles of oxidative stress in autoimmune diseases]. 2003 Feb Autoimmune diseases are complex diseases in which both genetic and environmental factors are involved. Excessive oxidative stress is thought to have an important role in the pathogenesis of autoimmune diseases by enhancing the inflammation, inducing apoptotic cell death, and breaking down the immunological tolerance. When the state of oxidative stress was investigated in patients with rheumatoid arthritis(RA), systemic lupus erythematosus(SLE), and Sjögren's syndrome(SS) by oxidative stress profile(OSP), most subjects were in excessive oxidative stress or in defective antioxidant potentials. The thioredoxin(TRX) level in peripheral blood was significantly higher in these patients than in healthy subjects. Urinary excretion of 8-hydroxy-guanosine was also significantly increased in these patients compared with healthy subjects. We have proven that oxidative stress as well as UV irradiation induced the expression of SS-A/Ro52 autoantigen on the cell surface of keratinocytes. Oxidative stress not only injures the cellular components but also induces cellular responses, including apoptosis and gene activation. We also identified that GSTM1 null genotype was a candidate gene for susceptibility to SS and was associated with SS-A/Ro autoantibody production. In the synovial fluid of RA patients, TRX was abundantly detected and was produced in the lining layer of synovial tissue, indicating that TRX might protect synovial tissue from oxidative stress. Infections, UV irradiation, coldness, and emotional stress have been clinically well known as developing and exacerbating factors for autoimmune diseases. These environmental factors are closely related to oxidative stress. It is very important to develop reliable test methods to detect the state of oxidative stress and antioxidants.
11795718 Extreme lateral-transatlas approach for resection of the dens of the axis. 2002 Jan OBJECT: Various approaches have been described for resection of the dens of the axis, each of which has potential advantages and disadvantages. Anterior approaches such as the transoral route or its modifications are the most commonly used for resection of this structure. The transcondylar approach, however, which allows the surgeon to view the craniovertebral junction (CVJ) from a lateral perspective, has been introduced by Al-Mefty, et al., as an alternative approach. In this report, the authors describe the surgical technique of the extreme lateral-transatlas approach and their clinical experiences. METHODS: The authors first examined the surgical approach to the dens from a lateral perspective in five cadaveric heads. They found that removal of the lateral mass of the atlas provided adequate exposure for resection of the dens. Following this cadaveric study, the extreme lateral-transatlas approach was successfully performed at the authors' institution over a 1-year period (September 1998-August 1999) in five patients with basilar invagination due to congenital anomaly of the CVJ and rheumatoid arthritis. Furthermore, during the same procedure, unilateral occipitocervical fusion was performed following resection of the dens. In all cases complete resection of the dens was achieved using the extreme-lateral transatlas approach. This procedure provides a sterile operative field and the ability to perform occipitocervical fusion immediately following the resection. No postoperative complications or craniocervical instability were observed. The mean follow-up period was 17.2 months (range 13-24 months). CONCLUSIONS: The extreme lateral-transatlas approach for resection of the dens was found to be safe and effective. Knowledge of the anatomy of this region, especially of the V3 segment of the vertebral artery, is essential for the success of this procedure.
12114267 Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthr 2002 Jun Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti-inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune-suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases.
11860615 Rheumatoid arthritis, gold therapy, contact allergy and blood cytokines. 2002 OBJECTIVE: To study the clinical and biochemical effects of a low starting dose for gold therapy in rheumatoid arthritis patients with a contact allergy to gold. METHODS: Serum cytokines were assayed before and 24 h after the first injection of gold sodium thiomalate (GSTM). RESULTS: Contact allergy to gold was found in 4 of 19 patients. Compared to gold-negative patients (starting dose: 10 mg GSTM), there was a larger increase in serum TNFalpha (p < 0.05), sTNF-R1 (NS), and IL-1 ra (p < 0.05) in gold-allergic patients. CONCLUSIONS: Cytokines are released in blood by GSTM in RA patients with gold allergy. To minimize the risk of acute adverse reactions the starting dose of GSTM should be lowered to 5 mg. Alternatively, patients should be patch-tested before gold therapy; in test-positive cases, 5 mg is recommended as the first dose.
15642132 p53 tumor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium 2005 Abnormalities in the p53 tumor suppressor gene have been detected in rheumatoid arthritis (RA) and could contribute to the pathogenesis of chronic disease. To determine whether synoviocytes from invasive synovium in RA have an increased number of mutations compared with non-erosion synoviocytes, p53 cDNA subclones from fibroblast-like synoviocytes (FLS) derived from erosion and non-erosion sites of the same synovium were examined in patients requiring total joint replacement. Ten erosion FLS lines and nine non-erosion FLS lines were established from nine patients with RA. Exons 5-10 from 209 p53 subclones were sequenced (114 from erosion FLS, 95 from non-erosion FLS). Sixty percent of RA FLS cell lines and 8.6% of the p53 subclones isolated from FLS contained p53 mutations. No significant differences were observed between the erosion and non-erosion FLS with regard to the frequency or type of p53 mutation. The majority of the mutations were missense transition mutations, which are characteristic of oxidative damage. In addition, paired intact RA synovium and cultured FLS from the same joints were evaluated for p53 mutations. Matched synovium and cultured synoviocytes contained p53 mutations, although there was no overlap in the specific mutations identified in the paired samples. Clusters of p53 mutations in subclones were detected in some FLS, including one in codon 249, which is a well-recognized 'hot spot' associated with cancer. Our data are consistent with the hypothesis that p53 mutations are randomly induced by genotoxic exposure in small numbers of RA synoviocytes localized to erosion and non-erosion regions of RA synovium. The determining factor for invasiveness might be proximity to bone or cartilage rather than the presence of a p53 mutation.
15172041 Overview of radiologic efficacy of new treatments. 2004 May Randomized, double-blind trials on new treatments, including anakinra, etanercept, infliximab, and leflunomide, show convincing reduction in radiographic progression. The relative efficacy of these new treatments is unknown. Head-to-head comparisons have not been performed and comparing treatment arms across trials has several pitfalls. These possible pitfalls are discussed.