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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
15573872 SCIO-469 Scios Inc. 2004 Nov SCIO-469 is a small-molecule p38 mitogen-activated protein (MAP) kinase inhibitor under development by Scios Inc as a potential oral therapy for inflammatory disorders. By July 2004, SCIO-469 was in phase lib clinical trials for rheumatoid arthritis.
11824146 [Safety aspects of folic acid for the general population]. 2002 Jan 9 Periconceptional use of folic acid reduces the risk of neural tube defects considerably. In Switzerland, implementation of these findings could be improved through fortification of a staple food with folic acid. The present paper reviews possible hazards associated with high intake of folic acid in the general population. Among the potential safety issues are interaction between folic acid and zinc, interaction between folic acid and drugs (phenytoin, methotrexate etc.) and hypersensitivity to folic acid. Of main concern are adverse effects of folic acid in cobalamin deficiency. Solutions are discussed.
14670825 Parallel detection of autoantibodies with microarrays in rheumatoid diseases. 2004 Feb BACKGROUND: Clinical needs often dictate testing for several autoantibodies in a single patient with evidence of autoimmune disease. We developed a microarray containing 15 autoantigens for the detection of autoantibodies in rheumatoid autoimmune diseases. METHODS: We synthesized recombinant centromere protein B, cytokeratin 19, SSA 52-kDa antigen, SSA 60-kDa antigen, SSB antigen, and Jo-1 antigen and prepared anti-nuclear antibody antigens. Cyclic citrullinated peptide, histone, goat IgG for detection of rheumatoid factor, double-stranded DNA, and single-stranded DNA were purchased, as were recombinant small nuclear ribonucleoprotein U1, topoisomerase I, and Smith antigen (Sm). All 15 antigens were of human origin except calf thymus Sm. Proteins were printed on polystyrene. The arrays were incubated with serum samples and then with horseradish peroxidase-conjugated secondary antibodies and chemiluminescent substrates, and light signals were captured by a charge-coupled device camera-based chip reader. Antibodies were quantified by use of calibration curves. Positive samples were confirmed by commercially available methods. RESULTS: The detection limit of the microarray system was 20 pg of IgG printed on the polystyrene support. More than 85% of the confirmed positive sera were detected as positive with the microarray system based on cutoff values established with the microarray system. The imprecision (CV) of the microarrays was <15% for all 15 autoantibody assays, with the exception of single-stranded DNA (18% and 23%) within and between batches. Characteristic autoantibody patterns were seen in patients with clinical diagnoses of rheumatoid arthritis (n = 83), systemic lupus erythematosus (n = 71), systemic sclerosis (n = 36), polymyositis (n = 38), and Sjogren syndrome (n = 20). CONCLUSIONS: This microarray system provides results similar to those by conventional methods. Assessment of the diagnostic accuracy of the system remains to be done.
16228686 Anterior dislocation after total knee arthroplasty: a case report. 2004 We report a case of anterior dislocation of an 11-year-old total knee arthroplasty in a 52-year-old woman with severe rheumatoid arthritis and osteoporosis. It was noteworthy that the mechanism of dislocation was unique in that massive wear of ultra-high-molecular-weight polyethylene, avulsion injuries of the medial collateral ligament and patellar tendon, and a stress fracture of the fibula secondary to the increased posterior tilt angle eventually caused anterior dislocation of the left knee without obvious trauma or infection.
15059263 Measuring effectiveness of drugs in observational databanks: promises and perils. 2004 Observational databanks have inherent strengths and shortcomings. As in randomized controlled trials, poor design of these databanks can either exaggerate or reduce estimates of drug effectiveness and can limit generalizability. This commentary highlights selected aspects of study design, data collection and statistical analysis that can help overcome many of these inadequacies. An international metaRegister and a formal mechanism for standardizing and sharing drug data could help improve the utility of databanks. Medical journals have a vital role in enforcing a quality checklist that improves reporting.
15513676 Risk assessment for coronary heart disease in rheumatoid arthritis and osteoarthritis. 2004 BACKGROUND: The risk of coronary heart disease (CHD) is increased in rheumatoid arthritis (RA). The reasons for this remain unknown, but traditional risk factors for CHD identified in the general population may be important contributors. OBJECTIVE: To assess comparatively the prevalence of traditional CHD risk factors and the absolute 10-year CHD risk in patients with RA or osteoarthritis (OA) without known cardiovascular co-morbidity. METHODS: Consecutive Caucasian hospital outpatients with RA (n = 150) or OA (n = 100) aged 40-75 years were assessed for known cardiovascular co-morbidity, age, sex, smoking status, presence of diabetes mellitus (DM), height, weight, systolic blood pressure (BP), total cholesterol (TC) and HDL cholesterol. Absolute 10-year CHD risk for each individual was calculated using the Joint British Societies CHD risk calculator. RESULTS: Prevalence and distribution of known cardiovascular co-morbid conditions were similar in RA (56/150, 37%) and OA (34/100, 34%). The resulting subgroups of patients without known co-morbidity (RA: n = 94; OA: n = 66) were not significantly different for age, sex, DM, smoking, systolic BP or TC: HDL cholesterol ratio. There was no significant difference in the absolute 10-year CHD risk between RA and OA (15.6+/-11.0 versus 14.8+/-9.3, p = 0.63). However, a significant proportion of patients without known cardiovascular disease in both the RA and OA subgroups had a 10-year CHD risk above the 15% or 30% risk levels, indicating the need for possible or definite intervention respectively. Over 80% of RA patients had at least 1 CHD risk factor that could be modified. CONCLUSION: Absolute 10-year CHD risk was not different between RA and OA patients in this study. Substantial numbers of RA and OA patients have potentially modifiable CHD risk factors present. We suggest that CHD risk should be assessed and modifiable risk factors addressed in the routine rheumatology clinic setting.
15479887 A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mono 2004 Nov BACKGROUND: In previous studies the presence of a distinct gene expression pattern has been shown in peripheral blood cells from patients with autoimmune disease. OBJECTIVE: To determine whether other specific signatures might be used to identify subsets of these autoimmune diseases and whether gene expression patterns in early disease might identify pathogenetic factors. METHODS: Peripheral blood mononuclear cells were acquired from patients with rheumatoid arthritis (RA) and analysed by microarrays containing over 4300 named human genes. Patients with RA for <2 years were compared with subjects with longstanding RA (average duration 10 years) and with patients with other immune or autoimmune diagnoses. RESULTS: Cluster analyses permitted separation of the patients with early RA (ERA) from those with longstanding disease. Comparison with other patient groups suggested that the ERA signature showed some overlap with that seen in the normal immune response to viral antigen as well as with a subset of patients with systemic lupus erythematosus. CONCLUSIONS: The ERA signature may reflect, in part, a response to an unknown infectious agent. Furthermore, shared features with some lupus patients suggest that common aetiological factors and pathogenetic pathways may be involved in these two autoimmune disorders.
12375256 Factors affecting patellar tracking after total knee arthroplasty. 2002 Oct This study examined factors that influence patellar tracking after total knee arthroplasty. A total of 62 knees were evaluated radiographically for postoperative patellar tracking. Six factors were examined regarding their influence on postoperative patellar tracking. This study showed the effects of patellar component position, patellar resection angle, and lateral retinacular release on postoperative patellar tracking. There was no significant effect of the remaining 3 factors: the thickness of the patellar resection, preoperative patellar tilt, and rotational alignment of the femoral component. A medialized patellar component and obliquity of resection of the patella are effective for obtaining proper patellar tracking, whereas the evaluation of the influence of the external rotation of the femoral component requires more clinical studies.
12913930 Evidence for immunostimulatory effects of intramuscular gold in patients with rheumatoid a 2003 Aug OBJECTIVE: Intramuscular gold is a well documented treatment in rheumatoid arthritis (RA), but its mechanism of action is still poorly understood. From an observation that gold sodium thiomalate (GSTM) induces monocyte-derived interleukin 6 (IL-6) and IL-10 production in vitro, a hypothesis has been proposed that gold exerts its action mainly as a selective immunostimulator rather than as a general immunosuppressant. In this prospective study we investigated cytokine production in peripheral blood from patients with RA during treatment with GSTM. METHODS: A total of 20 patients with RA were treated with GSTM for at least 3 months. Disease activity was recorded at baseline, 12, 20, and 28 weeks. The ELISPOT method was used to measure spontaneous production of IL-6, IL-10, and interferon-g (IFN-g) from peripheral blood mononuclear cells (PBMC) at baseline and 4 and 12 weeks and production after incubation with GSTM in vitro, at different concentrations (0, 3, 12.5, 40 micro g/ml) at baseline. IL-6 and IL-10 concentrations in serum were measured with ELISA. RESULTS: The numbers of IL-10-producing cells were increased after 4 weeks' treatment with GSTM (p < 0.01). The numbers of cells spontaneously producing IL-6 were increased after 4 weeks (p < 0.01) and 12 weeks (p < 0.01). The numbers of IFN-g-producing cells were increased after 4 weeks (p < 0.01). Serum concentrations of IL-10 were increased after 4 weeks (p < 0.01). Serum concentrations of IL-6 were not changed at any timepoint. The in vitro effect of GSTM on IL-10 production from PBMC at baseline predicted development of skin reactions during GSTM treatment, with lack of skin reactions being associated with high gold induced IL-10 production (p < 0.05). There was no correlation between clinical response and cytokine production. CONCLUSION: This study indicates an immunostimulatory effect of GSTM treatment in patients with RA. The increase in IL-10 production during GSTM treatment may contribute to the positive effects of gold in RA.
12934466 [Prospects of the anti-cytokine therapy in rheumatoid arthritis]. 2003 The development and introduction of the anti-cytokine therapy applicable to rheumatoid arthritis (RA) is a most significant achievement in RA therapy. A high degree of purpose-orientation and selectivity of the mentioned method ensuring a high therapeutic effect and providing, simultaneously, for defining a number of important chains in RA pathogenesis is an essential advantage of the discussed approach. The clinical use of neutralization of key cytokines TNF-alpha, IL-1 and IF-gamma is a serious progress within this trend. Possibilities of developing new directions of the cytokines therapy are preconditioned, to a great extent, by the role of new, including little-studied cytokines, in the evolution of immune inflammation. A search for more simple low-molecular inhibitors of cytokines, which do not cause any tolerance-related problems, is another important trend. Hopefully, a further study of anti-cytokines and of their application in combination with other antirheumatic drugs will improve the general treatment results and outline new opportunities in antirheumatic therapy.
12379522 Mortality risk associated with rheumatoid arthritis in a prospective cohort of older women 2002 Nov OBJECTIVE: To determine whether rheumatoid arthritis (RA) is associated with excess mortality among older women. METHODS: RA associated mortality was examined in a prospective cohort study that was started in 1986, and included 31 336 women aged 55-69 years without a history of RA at baseline. Up to 1997, 158 cases of RA were identified and validated against medical records. The relative risk (RR) and 95% confidence interval (CI) were calculated as measures of association between RA onset and subsequent mortality (overall and cause-specific) using Cox proportional hazards regression. RESULTS: Compared with non-cases, women developing RA during follow up had a significantly increased mortality risk (RR=1.52; 95% CI 1.05 to 2.20). Mortality was higher among rheumatoid factor (RF) positive cases (RR=1.90; 95% CI 1.24 to 2.92) than among RF negative cases (RR=1.00; 95% CI 0.45 to 1.99). There were trends towards increased proportions of RA related deaths from infection (RR=3.61; 95% CI 0.89-14.69) and circulatory disease (RR=1.46; 95% CI 0.76 to 2.81) but not malignancy (RR=0.97; 95% CI 0.46 to 2.04). CONCLUSIONS: RA was associated with significantly increased mortality in a cohort of older women, and the association appeared to be restricted to those with RF positive disease.
11935470 [Skin nodules and ulcers of the limbs in a patient with rheumatoid arthritis]. 2002 Apr 5 CASE HISTORY: While being treated with corticosteroids and methotrexate for rheumatoid arthritis, a 63-year-old man developed livid nodules on his lower arms, hands and feet, as well as fever, necrotizing skin ulcers and rupture of a finger extensor tendon. INVESTIGATIONS: No vasculitis was found in a biopsy of one of the nodules on the lower arm. Fast growing mycobacteria, classified as M. marinum by PCR, were cultured from wound swabs. TREATMENT AND COURSE: The lesions healed on administration of ciprofloxacin, ethambutol and clarithromycin as well as local treatment. CONCLUSION: Cutaneous lesions of an atypical mycobacterial infection are often misdiagnosed. This is especially so in immunocompromised patients and in the differential diagnosis of vasculitis.
11899747 Advances in anti-inflammatory therapy. 2002 Our goal was to evaluate the state of nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of rheumatoid arthritis (RA), before the introduction of the coxibs. The prerequisite for inclusion was the presence of RA (ACR criteria) plus therapy with an NSAID with or without a disease modifying antirheumatic drug (DMARD). A total of 368 consecutive RA patients (81% women) from the outpatient clinic at the Vienna General Hospital were included. Rheumatoid factor was positive in 62%, the patients' mean age was 60 +/- 14 years. The period of observation was 1972-1998. Seventy-seven per cent of the patients had DMARD and NSAID therapy. NSAID therapy was dominated by diclofenac, accounting for 60% of all therapies. Eighteen other substances were applied more rarely. All NSAIDs together were given for 768 patient years (with a mean duration of therapy of 17 years +/- 21 months). Seventy-two per cent of the patients received GI-protective therapy mainly with histamine antagonists and sucralfate while on nonsteroidal therapy. NSAID toxicity mostly affected the GI tract. There was a similar incidence of GI-related adverse events between patients with and patients without GI protection, mainly dyspepsia and nausea. NSAIDs have the potential to cause adverse events in the GI tract. Therapy with histamine antagonists or sucralfate did not reduce the patients' rate of gastrointestinal adverse events.
15611293 Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. 2004 Dec 20 Cadherins are integral membrane proteins expressed in tissue-restricted patterns that mediate homophilic intercellular adhesion. During development, they orchestrate tissue morphogenesis and, in the adult, they determine tissue integrity and architecture. The synovial lining is a condensation of fibroblast-like synoviocytes (FLS) and macrophages one to three cells thick. These cells are embedded within the extracellular matrix, but the structure is neither an epithelium nor an endothelium. Previously, the basis for organization of the synovium into a tissue was unknown. Here, we cloned cadherin-11 from human rheumatoid arthritis (RA)-derived FLS. We developed L cell transfectants expressing cadherin-11, cadherin-11 fusion proteins, and anti-cadherin-11 mAb. Cadherin-11 was found to be expressed mainly in the synovial lining by immunohistologic staining of human synovium. FLS adhered to cadherin-11-Fc, and transfection of cadherin-11 conferred the formation of tissue-like sheets and lining-like structures upon fibroblasts in vitro. These findings support a key role for cadherin-11 in the specific adhesion of FLS and in synovial tissue organization and behavior in health and RA.
15228616 Does safety make a difference in selecting the right TNF antagonist? 2004 Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved the outcomes in patients with rheumatoid arthritis (RA). At this report, safety data were collected on approximately 271,000 patients administered infliximab (as of February 2002), 121,000 patients administered etanercept (as of December 2001), and on 2400 patients who received adalimumab in trials in connection with the regulatory approval process (approval granted December 2002 in the US and September 2003 in European Union). Infliximab and etanercept have predictable and manageable safety profiles, and preliminary data suggest that the profile of adalimumab is comparable. Safety issues involving the anti-TNF agents as a class include the risk of injection-site reactions or infusion-related reactions, infection (for example, serious, opportunistic, or tubercular), malignancy, autoimmunity, and demyelinating and neurologic disorders. Injection-site and infusion-related reactions are most often easily managed and rarely lead to discontinuation of therapy. Infections can be minimized or prevented by screening and careful monitoring and follow-up; most infections respond to appropriate medical treatment. More studies are needed to evaluate the occurrence of malignancies in patients with RA to determine the potential risk posed by therapy. Antibody formation can follow the administration of any biologic agent. Although demyelinating disease has been reported with anti-TNF agents, it is not clear whether a causal relationship exists. Overall, the anti-TNF agents are well tolerated and have demonstrated a favorable benefit-to-risk profile in patients with RA.
14742795 Listeria meningitis associated with infliximab. 2004 Jan OBJECTIVE: To report a case of Listeria monocytogenes meningitis in a 73-year-old man receiving infliximab for rheumatoid arthritis. CASE SUMMARY: A 73-year-old white man taking infliximab for rheumatoid arthritis developed listeria meningitis following his second dose. He was receiving other immunosuppressants; however, these remained constant immediately prior to the infection. Diagnosis was confirmed with L. monocytogenes isolated in the cerebrospinal fluid. The patient received 21 days of antibiotic therapy and recovered without any complications. DISCUSSION: L. monocytogenes is a gram-positive, non-spore-forming rod that has been associated with the ingestion of undercooked foods. This organism can cause sepsis or meningitis; however, immunocompromised patients, elderly patients, pregnant women, and neonates appear to be at greater risk for this type of infection. Tumor-necrosis factor-alpha (TNF-alpha) plays an important role in resistance to this type of infection, and listeria infections have been reported in 26 patients receiving TNF-alpha inhibitors. In our patient, the listeria infection occurred following his second course of infliximab, which provides a temporal relationship between the listeria infection and infliximab. However, his underlying rheumatoid arthritis and chronic steroid therapy would also increase his risk for a listeria infection. CONCLUSIONS: The listeria infection in our patient was a possible adverse event of infliximab according to the Naranjo probability scale. Because the majority of listeria infections occur in patients who are immunosuppressed, it would be reasonable to provide education for healthcare professionals on preventing these infections in all patients receiving immunosuppressants, including anti-TNF-alpha therapy. Those at risk due to their underlying health conditions should also be monitored closely.
15306993 Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. 2004 Aug 1 Infliximab, a tumor necrosis factor (TNF) antagonist, is associated with tuberculosis (TB), but it is unknown whether this phenomenon is true of all TNF antagonists. We reviewed 25 cases of TB due to another TNF antagonist, etanercept, that were reported to the US Food and Drug Administration (FDA) between November 1998 and March 2002. Such cases are sometimes incomplete and are subject to underreporting. Fifteen patients received other immunosuppressive medications. The median interval between the receipt of the first dose of etanercept and the diagnosis of TB was 11.5 months. Thirteen patients had extrapulmonary TB at the time of diagnosis. Diagnosis was made on the basis of culture results for 12 patients, biopsy findings for 9, and sputum staining for 4. There were 2 deaths, 1 of which was directly attributed to TB. The estimated number of TB cases reported to the FDA for each person-year of treatment with etanercept (i.e., the "reporting rate") among patients with rheumatoid arthritis (RA) was ~10 cases/100,000 patient-years of exposure. Clinicians considering etanercept for patients with RA should be alert to the possibility of the occurrence of TB, sometimes with an unusual extrapulmonary presentation. It is unclear whether etanercept therapy increases the risk of TB beyond the elevated TB rates already documented for patients with RA.
15476202 The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate 2004 Oct OBJECTIVE: To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5-aminoimidazole-4-carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism. METHODS: Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24-hour urinary AICA and adenosine excretion levels, respectively. RESULTS: At the end of 6 weeks, 24-hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels. CONCLUSION: The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase-catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.
14730600 Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients show 2004 Jan OBJECTIVE: To examine the entire HLA region for loci (other than the DRB1 locus) associated with rheumatoid arthritis (RA) susceptibility, by typing HLA-DRB1 alleles and multiple single-nucleotide polymorphisms (SNPs) in the Japanese population. METHODS: The HLA-DRB1 alleles and 88 SNPs distributed over the HLA gene complex were genotyped, for 828 patients with RA and 1,032 control subjects. The data were evaluated for linkage disequilibrium, and case-control associations were analyzed in 2 ways, in the presence or absence of the disease-susceptibility DRB1 allele, to detect loci independent of the DRB1 allele. RESULTS: HLA-DRB1 alleles *0405, *0401, *0901, *0101, *1401, *1602, *0403, and *1405 were significantly associated with RA in the Japanese population. The smallest P value (P = 1.4 x 10(-27)) was observed in association with an intronic SNP of the NOTCH4 gene, which was due to strong linkage disequilibrium with the HLA-DRB1 allele. A strong association that was independent of HLA-DRB1 shared epitope alleles was observed in 2 SNPs: one in the intron of the MICA gene, the other in the intron of the HLA-DQB2 gene. Their association with RA, independent of HLA-DRB1 shared epitope alleles, was suggestive (P = 0.0024 [corrected P (P(corr)) = 0.068, and P = 0.00037 [P(corr) = 0.012], respectively). CONCLUSION: These findings suggest that 1 or more other loci besides the HLA-DRB1 or other DRB1 (non-shared epitope, non-*0901) alleles are involved in RA susceptibility/protection.
12832715 Michael Mason prize essay 2003. Why do leucocytes accumulate within chronically inflamed j 2003 Dec Chronic inflammation is characterized by the accumulation of leucocytes within tissues. In rheumatoid arthritis the inflammatory infiltrate shares many architectural features with lymphoid tissue. For example, CD4 T cells and B cells accumulate in perivascular lymphoid structures within synovial tissue. CD8 T cells and neutrophils are found predominantly within synovial fluid. What drives these distinctive lymphoid microstructures and the relative contribution of lymphocytes and stromal cells such as fibroblasts to this process is the subject of this review. Cellular interactions between leucocytes and stromal cells such as macrophages and fibroblasts are important in generating tumour necrosis factor-alpha within the inflamed synovium. Therefore understanding how leucocytes accumulate within the inflamed synovium is likely to provide new therapeutic approaches to modify the inflammatory process. We have found that fibroblasts play a dominant role in defining the disordered synovial microenvironment in rheumatoid arthritis. Through their production of a variety of cytokines (interferon-beta, transforming growth factor-beta) and constitutive chemokines (stromal cell-derived factor-1, CXCL12) they directly alter the behaviour of lymphocytes that accumulate within chronically inflamed joints leading to their inappropriate survival and retention. We have extended these observations to another chronic persistent rheumatic disease, Sjögren's syndrome, and found that ectopic production of the constitutive B cell-attracting chemokine BCA-1 (CXCL13) is associated with lymphocyte accumulation and lymphoid tissue formation. These findings suggest that stromal cells such as fibroblasts play an important role in the switch from acute resolving to chronic persistent arthritis by allowing lymphocytes to accumulate in the wrong place at the wrong time.