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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
16627149 Outcome assessment in the elderly after total hip arthroplasty. 2006 Apr An analysis of the Short-Form 36 (SF-36) and Oxford Hip questionnaires, were used to assess 2 randomized groups, by either mail or interview, at a minimum 10-year follow up after total hip arthroplasty. Ninety-nine patients (median age 77 years) were reviewed at a median 11 years after total hip arthroplasty. There was a 91% response rate to participation in the study. There was no significant difference between the groups for missing values. The mode of administration did not affect the mean Oxford scores (P > .1), but significant differences were noted in SF-36 health scales Role Emotional and Role Physical (P = .01). Analysis of other demographic variables revealed unexpectedly that comorbidity affected the Pain score in the Oxford questionnaire (P = .002) and that age had no effect on scores obtained in either questionnaire (P > .05). The uses of both general health and disease-specific questionnaires complement each other in the assessment of such groups. The SF-36 and Oxford questionnaires give a more accurate reflection of health status when self-completed while accepting higher missing values in an elderly population.
15971415 Hormone concentrations in synovial fluid of patients with rheumatoid arthritis. 2005 May OBJECTIVE: Alterations in local concentrations of hormones, affecting directly synovial cells, could be involved in the modulation of the rheumatic inflammatory processes. The aim of present study was to investigate the levels of selected hormones (steroids, peptide and thyroid hormones) in synovial fluid of knee joint of patients with rheumatoid arthritis (RA) and control individuals with non-rheumatic exudate (with osteoarthrosis, OA). METHODS: Thirty-eight patients, 22 female and 16 males, with rheumatoid arthritis (RA) and 12 subjects with osteoarthrosis (OA, control group, 6 females and 6 males) participated in the study. Concentrations of cortisol (CS), 17-beta-estradiol (ES), dehydroepiandrosterone (DHEA), progesterone (PRG), aldosterone ALD), prolactin (PRL), insulin (INS), and C-peptide were determined by radioimmunoassay in synovial fluid. Insulin binding to isolated cell membrane of cells from synovial sediment was estimated by using radioiodine labeled insulin. In a group of patients (10 with RA and 4 with OS), the levels of free threeiodothyronine (FT3), TSH and growth hormone (GH) were also determined in synovial fluid. RESULTS: Increased levels of ES in synovial fluid of RA patients were observed, and higher differences were noted in men. TE concentrations were moderately elevated in synovial fluid of RA patients, however the ratio of ES/TE was significantly higher in male RA compared to OA patients. Higher levels of PRG, ALD and growth hormone were noted in synovial fluid of RA patients. Besides the steroid hormones the presence of insulin and C-peptide was noted in synovial fluid and the correlation between the levels of these two peptides was highly significant. The concentrations of INS and C-peptide in synovial fluid of patients from RA and OA group were not significantly different, however, highly significant increase of insulin binding to isolated membrane of synovial cells was found. Concentrations of cortisol, dehydroepiandosterone, prolactin, TSH and FT3 in synovial fluid were not significantly different in RA and OA groups. CONCLUSIONS: Besides the steroids also insulin, c-peptide, GH and FT3 were found in synovial fluid. The elevated ALD and GH levels in synovial fluid of RA patients and the presence of INS in synovial fluid with increase of INS binding to plasma membranes of cells from synovial fluid of RA patients suggest that besides the gonadal steroids also these hormones may affect the local inflammatory processes.
15843907 Involvement of mitochondria in myasthenia gravis complicated with dermatomyositis and rheu 2005 May We report a 57-year-old male with myasthenia gravis complicated with dermatomyositis and rheumatoid arthritis without evidence of thymoma. He showed prominent muscle wasting and weakness in the four extremities and trunk in addition to swallowing disturbance. He showed intolerance to exercise on a bicycle ergometer, and muscle biopsy specimens demonstrated ragged-red fibers. An anti-acetylcholine receptor (AChR) antibody was detected in his serum but no anti-mitochondrial M2 component antibody was found. In contrast, results of immunohistochemical study indicated that his serum sample reacted to muscle mitochondria as well as AChR. These results indicate the presence of an unidentified anti-mitochondrial antibody that may be involved in the development of mitochondrial dysfunction in skeletal muscle of the present patient.
15878904 Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. 2005 Dec BACKGROUND: Early treatment prevents progression of joint damage in rheumatoid arthritis (RA), but diagnosis in early disease is impeded by lack of appropriate diagnostic criteria. OBJECTIVE: To study the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide autoantibodies (anti-CCP), and anti-RA33 autoantibodies for diagnosis of RA and prediction of outcome in patients with very early arthritis. METHODS: The prospective follow up inception cohort included 200 patients with very early (<3 months) inflammatory joint disease. Autoantibodies were measured at baseline and analysed in a tree based model which aimed at determining the added diagnostic value of testing for anti-CCP and anti-RA33 as compared with RF alone. RESULTS: RA was diagnosed in 102 patients, while 98 developed other inflammatory arthropathies. Receiver operator curve analysis showed an optimum cut off level for RF at 50 U/ml, above which anti-CCP and anti-RA33 had no additional diagnostic value. Remarkably, RF >or=50 U/ml and anti-CCP showed similar sensitivity and high specificity for RA, but overlapped considerably. Anti-RA33 was less specific and did not correlate with RF or anti-CCP. Among patients with RA, 72% showed at least one of these three autoantibodies, compared with 15% of non-RA patients. RF >or=50 U/ml and anti-CCP were predictors of erosive disease, whereas anti-RA33 was associated with mild disease. CONCLUSIONS: Stepwise autoantibody testing in early inflammatory joint disease, starting with RF, followed by anti-CCP (in patients with RF <50 U/ml), and finally anti-RA33, should be used as a sensitive and effective strategy for distinguishing patients with RA at high risk for poor outcome.
16848700 Fatty acids as modulators of the immune response. 2006 Research describing fatty acids as modulators of inflammation and immune responses abounds. Many of these studies have focused on one particular group of fatty acids, omega-3. The data from animal studies have shown that these fatty acids can have powerful anti-inflammatory and immunomodulatory activities in a wide array of diseases (e.g., autoimmunity, arthritis, and infection). However, the evidence from human trials is more equivocal. In this review, a historical framework for understanding how and why fatty acids may affect the immune system is provided. Second, highlights of two recent landmark reports from the Agency for Healthcare Research and Quality are presented. These reports critically evaluate the evidence from human clinical trials of omega-3 fatty acids and rheumatoid arthritis, asthma, and a few other immune-mediated diseases. Third, the data from human clinical trials investigating the impact of various bioactive fatty acids on ex vivo and in vivo immune response are reviewed. Limitations in experimental design and immune assays commonly used are discussed. The discordance between expectation and evidence in this field has been a disappointment. Recommendations for improving both animal-based and human studies are provided.
16308647 Semi-constrained total elbow arthroplasty for the treatment of rheumatoid arthritis of the 2005 Dec INTRODUCTION: We retrospectively reviewed the results of total elbow arthroplasty in patients with rheumatoid arthritis of the elbow followed for a minimum of two years. METHODS: Between September 1999 and March 2001, seven patients with rheumatoid arthritis of the elbow were treated with total elbow arthroplasty using the semi-constrained Coonrad-Morrey elbow replacement prostheses. One patient died 19 months after her surgery and was excluded from the study. Two patients had bilateral total elbow replacements. Eight elbows were thus available for review. The mean age of our patients at the time of surgery was 55.5 years. The indication for surgery was severe pain and stiffness in six elbows, and distal humerus fractures in two elbows. RESULTS: The mean duration of postoperative hospitalisation stay was 6.6 days. The average length of follow-up was 39.4 months. Six elbows had no pain, while two elbows had mild pain. The mean arc of flexion was 101.3 degrees. The mean Mayo elbow performance score was 93.1 points. Excellent results were achieved in six elbows, while two elbows had good outcome. There was one case of intraoperative lateral condylar fracture treated with internal fixation. One patient developed blisters postoperatively but resolved with dressings and antibiotics. CONCLUSION: Our small study revealed good to excellent short-term outcome with the use of semi-constrained total elbow arthroplasty for the treatment of rheumatoid arthritis of the elbow in Asian patients.
16984661 Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascula 2006 Rheumatoid arthritis (RA) is characterized by inflammation and an increased risk for cardiovascular disease (CVD). This study investigates possible associations between CVD and the use of conventional disease-modifying antirheumatic drugs (DMARDs) in RA. Using a case control design, 613 RA patients (5,649 patient-years) were studied, 72 with CVD and 541 without CVD. Data on RA, CVD and drug treatment were evaluated from time of RA diagnosis up to the first cardiovascular event or the end of the follow-up period. The dataset was categorized according to DMARD use: sulfasalazine (SSZ), hydroxychloroquine (HCQ) or methotrexate (MTX). Odds ratios (ORs) for CVD, corrected for age, gender, smoking and RA duration, were calculated per DMARD group. Patients who never used SSZ, HCQ or MTX were used as a reference group. MTX treatment was associated with a significant CVD risk reduction, with ORs (95% CI): 'MTX only', 0.16 (0.04 to 0.66); 'MTX and SSZ ever', 0.20 (0.08 to 0.51); and 'MTX, SSZ and HCQ ever', 0.20 (0.08 to 0.54). The risk reductions remained significant after additional correction for the presence of rheumatoid factor and erosions. After correction for hypertension, diabetes and hypercholesterolemia, 'MTX or SSZ ever' and 'MTX, SSZ and HCQ ever' showed significant CVD risk reduction. Rheumatoid factor positivity and erosions both increased CVD risk, with ORs of 2.04 (1.02 to 4.07) and 2.36 (0.92 to 6.08), respectively. MTX and, to a lesser extent, SSZ were associated with significantly lower CVD risk compared to RA patients who never used SSZ, HCQ or MTX. We hypothesize that DMARD use, in particular MTX use, results in powerful suppression of inflammation, thereby reducing the development of atherosclerosis and subsequently clinically overt CVD.
16511938 Parvovirus B19 infection in patients with rheumatoid arthritis in Taiwan. 2006 May OBJECTIVE: To investigate the role of human parvovirus B19 infection in the pathogenesis of rheumatoid arthritis (RA) in Taiwan. METHODS: Seventy-eight patients with RA and 55 unrelated controls (51 trauma and 4 osteoarthritis) were enrolled. Anti-parvovirus B19 IgG and IgM antibodies were detected in plasma of patients with RA and controls by the enzyme immunoassay method. These antibodies were also detected in the synovial fluid of 18 RA patients and 52 controls. B19 DNA was measured in the plasma of 72 patients with RA and 45 controls by nested polymerase chain reaction (PCR). It was also measured in the synovial fluid of 14 RA patients and 39 controls. Immunohistochemistry was performed to detect viral capsid protein VP1 of B19 in the synovial membrane of 7 RA patients and 32 controls. HLA-DR genotyping was performed by the sequence-specific primer PCR method. The interactions between B19 infection and HLA-DR genotype and susceptibility to RA were also analyzed. RESULTS: The prevalence of B19 infection was significantly increased in patients with RA compared with controls. The positive rates of B19 DNA in plasma and synovial fluid were significantly higher in RA patients than in controls. The odds ratio of DR4(+) B19 infection(+) was higher than that in DR4(+) B19 infection(-) or DR4(-) B19 infection(+) in comparison with DR4(-) B19 infection(-). A significant association was found between RA and DR4(+) B19 infection(+) in comparison with DR4(+) B19 infection(-). The odds ratio of DR4(+) plasma B19 DNA(+) was also higher than that of DR4(+) plasma B19 DNA(-) or DR4(-) plasma B19 DNA(+) in comparison with DR4(-) plasma B19 DNA(-). RA tended to be associated with DR4(+) plasma B19 DNA(+) compared with DR4(+) plasma B19 DNA(-). CONCLUSION: The prevalence of parvovirus B19 infection was significantly higher in patients with RA than in controls. Synergistic effects were present between HLA-DR4 and parvovirus B19 infection or plasma B19 DNA for susceptibility to RA. Parvovirus B19 infection may play a role in susceptibility to RA.
16508926 Predictors of joint damage in patients with early rheumatoid arthritis treated with high-d 2006 Mar OBJECTIVE: To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. METHODS: Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. RESULTS: C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (> or = 3 mg/dl) and ESR (> or = 52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS > or = 10.5) showed less progression with infliximab plus MTX compared with MTX alone (-0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. CONCLUSION: High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.
15642152 Interleukin-18: a therapeutic target in rheumatoid arthritis? 2005 Interleukin 18 (IL-18), a member of the IL-1 superfamily of cytokines has been demonstrated to be an important mediator of both innate and adaptive immune responses. Several reports have implicated its role in the pathogenesis of rheumatoid arthritis (RA). Although biologic therapy is firmly established in the treatment of a number of inflammatory diseases including RA, partial and non-responder patients constitute residual unmet clinical need. The aim of this article is to briefly review the biology of, and experimental approaches to IL-18 neutralisation, together with speculation as to the relative merits of IL-18 as an alternative to existing targets.
16308339 Methotrexate modulates the kinetics of adenosine in humans in vivo. 2006 Apr BACKGROUND: Animal studies suggest that the anti-inflammatory effect of methotrexate (MTX) is mediated by increased adenosine concentrations. OBJECTIVE: To assess the effect of MTX on the vasodilator effects of adenosine and the nucleoside uptake inhibitor, dipyridamole, in humans in vivo as a marker for changes in adenosine kinetics. METHODS: Ten patients with active arthritis were treated with MTX (15 mg/week). Measurements were performed before and after 12 weeks of treatment. At these time points, the activity of adenosine deaminase was measured in isolated lymphocytes, and forearm blood flow (FBF) was determined by venous occlusion plethysmography during administration of adenosine and dipyridamole into the brachial artery. RESULTS: The Vmax of adenosine deaminase in lymphocytes was reduced by MTX treatment (p<0.05). MTX significantly enhanced vasodilator response to adenosine (0.5 and 1.5 microg/min/dl of forearm tissue; mean (SE) FBF ratio increased from 1.2 (0.2) to 1.4 (0.2) and 2.2 (0.2) ml/dl/min, respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 3.2 (0.5) ml/dl/min during MTX treatment; p<0.05). Also, dipyridamole-induced vasodilatation (30 and 100 microg/min/dl) was enhanced by MTX (FBF ratio increased from 1.2 (0.2) to 1.5 (0.3) and 1.8 (0.2), respectively, before and from 1.3 (0.1) to 1.8 (0.2) and 2.4 (0.4) during MTX treatment; p<0.05). CONCLUSIONS: MTX treatment inhibits deamination of adenosine and potentiates adenosine-induced vasodilatation. Also dipyridamole-induced vasodilatation is enhanced by MTX treatment, suggesting an increased extracellular formation of adenosine. These effects on the adenosine kinetics in humans may contribute to the therapeutic efficacy of MTX.
15842630 Rheumatoid arthritis and pigmented villonodular synovitis: comparative analysis of cell po 2005 May AIMS: Rheumatoid arthritis (RA) and pigmented villonodular synovitis (PVNS) are aggressive diseases with progressive joint destruction. The present study aims to define cell cycle phases, polyploidy and the immunophenotype of proliferating synovial cells in both diseases. METHODS AND RESULTS: Synovial tissues from patients with proliferative-active RA, localized and diffuse PVNS were analysed by DNA flow cytometry, immunohistochemistry and double immunofluorescence with confocal laser scan microscopy. Expression of macrophage markers (CD68/CD163), fibroblast markers (h4Ph/CD55) and Ki67 antigen was examined. Synovial cells positive for either macrophage or fibroblast markers as well as double-labelled cells were found in both RA and PVNS. In RA, CD68/CD163+ synoviocytes were preferentially located in the vicinity of the synovial lining layer, while they were more randomly distributed in PVNS. Of cases with diffuse PVNS, 20% showed an aneuploid cell pattern. All samples of localized PVNS and RA were diploid. Proliferative activity was significantly higher in aneuploid PVNS. CONCLUSIONS: In spite of their histologically homogeneous appearance, proliferating synovial cells display a heterogeneous immunophenotype in both RA and PVNS, indicating functional properties of both macrophages and fibroblasts. Aneuploidy seems to be a special feature of diffuse PVNS.
16868816 Rapid improvement in rheumatoid arthritis patients on combination of methotrexate and infl 2007 Jun The objectives of this study was to assess, using clinical and magnetic resonance imaging (MRI) criteria, the efficacy of combination infliximab therapy in patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX) treatment and to ascertain whether the changes in MRI parameters correlate with the clinical response. Four infusions of infliximab (3 mg/kg) at weeks 0, 2, 6, and 14 were added to a stable background dose of MTX in 19 patients with active disease. Clinical parameters were assessed before each infusion and at week 14. Dynamic contrast-enhanced MRI examination of the most severely affected wrist was performed at baseline and week 14. Synovitis severity, volume of synovitis, and synovial perfusion indices were evaluated. Significant improvement in all clinical disease activity parameters was seen at week 14 with reduction in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and DAS28. Sixty-eight percent of patients achieved ACR20. MRI disease activity parameters also significantly decreased after treatment with reduction in grading of synovitis, volume of active synovitis, and perfusion enhancement slope. Significant positive correlations were seen between the baseline volume of synovitis and the pain score (r=0.65), patient global score (r=0.68), and health assessment questionnaire (HAQ) score (r=0.46). In conclusion, addition of infliximab to methotrexate rapidly reduces inflammation in longstanding patients with RA. Assessment of enhancing synovial volume and perfusion indices on serial MRI examination was helpful in documenting the effect of treatment over this short period.
15999273 Anti-TNF-alpha antibody Infliximab and glucocorticoids reduce serum vascular endothelial g 2006 Jan To compare the effect of oral glucocorticoid (GC) therapy with the effect of intravenous anti-TNF-alpha-therapy on serum VEGF levels of patients with rheumatoid arthritis (RA). Five RA patients (5/8) who had no prior treatment with DMARDs (Disease modifying antirheumatic drugs) or GCs were administered 20 mg prednisolone daily. Three patients who failed more than one DMARD therapy received infusion with Infliximab (200 mg). VEGF-serum levels were measured by enzyme-linked immunosorbent assay before treatment,and at day 10 or 13 during prednisolone therapy, or 14 days after the first Infliximab infusion. Serum VEGF levels in therapy naive RA patients (GC group) were higher than those in pretreated patients who received Infliximab (median serum VEGF level: 1106 vs 320 pg/ml; P=0.1). Treatment with Infliximab as well as GCs significantly decreased serum VEGF levels after 10-14 days in RA patients (median serum VEGF level after treatment: GC group 559 pg/ml, Infliximab group 92 pg/ml; P=0.01 vs without treatment or preinfusion). CONCLUSIONS: Anti-TNF-alpha antibody Infliximab as well as GC are able to decrease serum VEGF levels in patients with active RA. Whether therapeutic reduction of serum VEGF levels is associated with inhibition of angiogenesis should be evaluated in future by imaging of synovial vasculature.
16273807 Rheumatoid arthritis registries in Sweden. 2005 Sep Patient registries provide valuable contributions to the field of rheumatology for both quality control and scientific purposes. With respect to the latter, patient registries are among the most important datasets used for longitudinal observational studies in rheumatic diseases, which are in turn an essential complement to data obtained from randomized, controlled trials. In Sweden a number of registries are available for such studies, ranging from general medical registries such as the in-patient registry, to rheumatoid arthritis (RA)-specific inception cohorts and biologics registries focusing on a specific patient population defined by a group of treatments. In recent years it has become particularly clear that questions regarding new therapies, their use in practice and their long-term safety, as well as aspects such as pharmacoeconomics, cannot fully be assessed using the data from clinical trials, and that registries are indispensible to obtain accurate answers to such questions. In this review we describe the Swedish rheumatology registries, including the Swedish RA registry and the Swedish biologics registries ARTIS (Antirheumatic Therapies Iin Sweden), SSATG (Southern Sweden Antirheumatic Therapy Group), and STURE (Stockholm Tumor Necrosis Factor-a Follow-up Registry). Data obtained from analyses based on these registries are reviewed. It is concluded that rheumatology registries are excellent tools for improving our knowledge base regarding rheumatic diseases.
15804598 Cytokine production of stimulated whole blood cultures in rheumatoid arthritis patients re 2005 Apr 21 Patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) strategies have an increased susceptibility to infections, especially those caused by intracellular pathogens. In this study we assessed the cytokine production capacity in patients with RA and we further investigated whether anti-TNF therapy modulates the production of pro-inflammatory cytokines involved in the resistance against infections. Whole blood cultures from 10 RA patients and 10 healthy controls were stimulated with heat-killed Candida albicans, Salmonella typhimurium, Staphyloccocus aureus, Aspergillus fumigatus or Mycobacterium tuberculosis and production of interleukin (IL)-1beta, IL-6, IL-10, interferon (IFN)-gamma and TNF-alpha was measured. Before anti-TNF therapy, whole blood cultures from RA patients released significantly less IFN-gamma than healthy controls after stimulation with all tested microorganisms. Short-term anti-TNF therapy did not have an inhibitory effect on the release of the cytokines tested. We conclude that cells of patients with RA have a strongly reduced production capacity of IFN-gamma after bacterial challenge. Although short-term therapy with anti-TNF agents did not further decrease the release of other proinflammatory cytokines, the combination of defective IFN-gamma production in basal conditions and TNF neutralization during anti-TNF therapy is likely to be responsible for the higher susceptibility to infections in patients with RA.
16127437 Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumato 2005 Sep Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.
17143328 Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complicat 2006 Dec Bronchus-associated lymphoid tissue (BALT) was originally described as a mucosal lymphoid organ in the lungs of some species. However, while the lungs of naive mice and humans typically lack BALT, pulmonary infection in mice leads to the development of inducible BALT (iBALT), which is located in peribronchial, perivascular, and interstitial areas throughout the lung. Here we investigated whether iBALT forms in patients with a variety of interstitial lung diseases. We show that while iBALT can be found in the lungs of patients suffering from multiple diseases, well-developed iBALT is most prevalent in patients with pulmonary complications of RA and Sjögren syndrome. In these patients, iBALT consisted of numerous B cell follicles containing germinal centers and follicular dendritic cells. A loosely defined T cell area surrounded the B cell follicles while lymphatics and high endothelial venules were found at the B cell/T cell interface. Increased expression of lymphoid-organizing chemokines, such as CXCL13 and CCL21, as well as molecules involved in the immunopathology of RA, such as B cell-activating factor of the TNF family (BAFF), ICOS ligand, and lymphotoxin, correlated with more well-developed iBALT. Finally, the presence of iBALT correlated with tissue damage in the lungs of RA patients, suggesting that iBALT participates in local RA pathogenesis.
17133559 Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthrit 2006 Dec OBJECTIVE: Infliximab, an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial. This study was undertaken to investigate whether serologic monitoring of infliximab bioavailability and immunogenicity in individual patients would be useful in optimizing treatment regimens to improve efficacy and tolerability. METHODS: To avoid the use of solid-phase assays, two radioimmunoassays were developed: one for measurement of levels of anti-infliximab antibody, and a functional one for measurement of TNFalpha binding due to infliximab. Sera from 106 randomly selected rheumatoid arthritis patients were tested within 6 months of therapy initiation, and associations between findings of serum assays and disease activity, infusion reactions, and treatment failure occurring within 18 months were assessed. RESULTS: Trough serum infliximab levels after the first 2 intravenous infusions of infliximab at 3 mg/kg varied considerably between patients (range 0-22 microg/ml). At this stage, only 13% of the patients were anti-infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of infliximab. Indeed, low infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. High baseline disease activity, judged by C-reactive protein level and Disease Activity Score, was associated with low levels of infliximab at the early stage of treatment and later development of anti-infliximab antibodies. Cotreatment with methotrexate resulted in slightly reduced antibody levels after 6 months; other disease-modifying antirheumatic drugs and prednisolone had no effect. CONCLUSION: Development of anti-infliximab antibodies, heralded by low preinfusion serum infliximab levels, is associated with increased risk of infusion reaction and treatment failure. Early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent prolonged use of inadequate infliximab therapy.
16568505 Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly i 2006 Apr OBJECTIVE: This study examined the effect of abatacept, a costimulation modulator, on the health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA). METHODS: Three hundred thirty-nine patients with RA on a background of methotrexate (MTX), who participated in a multicenter, double-blind, placebo-controlled trial, were randomized to abatacept 2 mg/kg, abatacept 10 mg/kg, or placebo. HRQOL was assessed at pretreatment, and at 3, 6, and 12 months posttreatment using the SF-36 Health Survey (SF-36). Changes in SF-36 scores from baseline to 12 months were compared across treatment and placebo groups to examine HRQOL benefits of abatacept. A link between American College of Rheumatology improvement and changes in SF-36 scores was established to demonstrate the association between HRQOL outcomes and clinical response. RESULTS: After 12 months of treatment, patients randomized to abatacept 10 mg/kg showed significantly better HRQOL outcomes overall versus patients randomized to placebo (MANOVA F = 4.71, p < 0.001) or to abatacept 2 mg/kg (MANOVA F = 1.97, p = 0.05). Differences in SF-36 change scores between abatacept 10 mg/kg and placebo groups reached statistical significance on all 8 domain scales, the 2 summary measures, and the SF-36 utility index (SF-6D). Differences in SF-36 change scores between abatacept 10 mg/kg and abatacept 2 mg/kg reached statistical significance on 5 of the 8 domain scales, the physical summary measure, and the SF-6D. Improvement in HRQOL was highly related to clinical response. CONCLUSION Abatacept 10 mg/kg plus MTX demonstrated a stronger HRQOL response than placebo plus MTX. The abatacept 2 mg/kg arm showed a very weak and transient response.