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ID PMID Title PublicationDate abstract
15751075 Magnetic resonance imaging evidence of tendinopathy in early rheumatoid arthritis predicts 2005 Mar OBJECTIVE: To determine whether magnetic resonance imaging (MRI) evidence of tendinopathy in early rheumatoid arthritis (RA) could be used to predict the course of tendon involvement in later disease and specifically the risk of tendon rupture. METHODS: The occurrence, pattern, and progression of tendinopathy were studied prospectively over 6 years in a cohort of patients who had presented with RA. Of 42 patients enrolled, full MRI and clinical data were available for 31 at 6 years. MRI scans of the dominant wrist were scored for tendinopathy by 2 radiologists using a validated system. These data were compared with MRI synovitis, erosion scores, and disease activity measures. Prognostic factors for tendon inflammation and rupture were sought. RESULTS: Thirty-four patients (81%) had MRI evidence of tendinopathy at baseline, falling to 59% at 1 year and 68% at 6 years. The most commonly affected site was the extensor carpi ulnaris. MRI tendinopathy and synovitis scores were correlated at baseline (r = 0.37, P = 0.01) and 1 year (r = 0.45, P = 0.003) but not at 6 years (r = 0.11, P = 0.5). The strongest predictor of the 6-year tendinopathy score was the 1-year tendinopathy score (R(2) = 0.36, P = 0.0003 [beta = 1.28, SE = 0.31]). In 4 patients, extensor tendon rupture had occurred by 6 years. Their baseline and 1-year tendinopathy scores were higher than in the nonrupture group (medians 2.8 versus 1.0 [P = 0.04] and 4.3 versus 0.8 [P = 0.03], respectively), as were their Health Assessment Questionnaire scores (1.33 versus 0.54 [P = 0.02], 1.18 versus 0.25 [P = 0.03], and 0.98 versus 0.37 [P = 0.01] at 0, 1, and 6 years, respectively). For the group as a whole, the baseline tendinopathy score was predictive of rupture at 6 years (odds ratio [OR] 1.52, 95% confidence interval [95% CI] 1.02-2.32, P = 0.03), as was the 1-year score (OR 1.57, 95% CI 1.03-2.04, P = 0.02). CONCLUSION: MRI can be used to quantify tendinopathy at the wrist in RA patients. High scores in early disease were predictive of tendon rupture in a small group of patients, but further studies are required to determine whether this has clinical relevance.
16868999 Rates of serious infection, including site-specific and bacterial intracellular infection, 2006 Aug OBJECTIVE: To determine whether the rate of serious infection is higher in anti-tumor necrosis factor (anti-TNF)-treated rheumatoid arthritis (RA) patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs (DMARDs). METHODS: This was a national prospective observational study of 7,664 anti-TNF-treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register. All serious infections, stratified by site and organism, were included in the analysis. RESULTS: Between December 2001 and September 2005, there were 525 serious infections in the anti-TNF-treated cohort and 56 in the comparison cohort (9,868 and 1,352 person-years of followup, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, for the anti-TNF-treated cohort compared with the comparison cohort was 1.03 (95% confidence interval 0.68-1.57). However, the frequency of serious skin and soft tissue infections was increased in anti-TNF-treated patients, with an adjusted IRR of 4.28 (95% confidence interval 1.06-17.17). There was no difference in infection risk between the 3 main anti-TNF drugs. Nineteen serious bacterial intracellular infections occurred, exclusively in patients in the anti-TNF-treated cohort. CONCLUSION: In patients with active RA, anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues.
16274448 Coping in context: the role of stress, social support, and personality in coping. 2005 Dec Personality and social relationships play an important role in almost every aspect of stress and coping. Daily process methods are particularly useful in elucidating how these factors might influence both responses to and outcomes of stress. Our work has linked both dimensions of personality, particularly the Big Five, and aspects of social relationships, particularly social support, to the likelihood of engaging in certain coping strategies and the effectiveness or outcomes of these coping strategies. In addition, we have found the effect of personality on coping and stress outcomes to vary by the situational context in which stress occurs. We review findings from our recent daily process studies of stress, coping, and social support. Further, we discuss the costs and benefits of the daily process methodology for addressing these questions, highlighting the clinical utility of findings gleaned with the use of this approach. Finally, we discuss future directions and applications of daily process methods to the study of stress and coping.
16375587 Measurement of serum amyloid A1 (SAA1), a major isotype of acute phase SAA. 2006 Serum amyloid A (SAA), a plasma precursor of reactive amyloid deposits, is a multigene product. SAA1 and SAA2, with primary structures that are 93% identical (98 of 104 amino acids), behave as acute phase proteins, as demonstrated by their increasing levels in plasma. Heretofore, it has been understood that SAA1 predominates and functions as an isotype in plasma. However, accurate measurements differentiating the two isotypes have not been reported. In this study, using monoclonal antibodies specific for SAA1, we developed an enzyme-linked immunosorbent assay (ELISA) for SAA1. The levels and ratios of SAA1 in total SAA (TSAA) were investigated in healthy subjects and patients with rheumatoid arthritis (RA). The SAA1/TSAA ratio was 74 +/- 12% and 77 +/- 12% in healthy subjects and RA patients, respectively. In RA patients, the ratios were not influenced by SAA1 genotype, which has been proposed to affect plasma SAA values. The kinetics of SAA1 in inflamed patients undergoing hemodialysis was found to be parallel with total SAA and C-reactive protein. Finally, this study confirmed that SAA1 is a major isotype of acute phase SAA and may determine total SAA values. This specific assay could be used in the evaluation of SAA behavior in several clinical conditions.
16916345 Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthriti 2006 Sep Pulmonary alveolar proteinosis is an uncommon disorder marked by the abnormal accumulation of surfactant within the alveoli. Secondary pulmonary alveolar proteinosis develops in patients who are immunosuppressed, usually with corticosteroids. We present a case of biopsy-proven pulmonary alveolar proteinosis in a patient undergoing therapy with the disease-modifying antirheumatoid arthritis drug leflunomide (Arava; Aventis Pharmaceuticals, Bridgewater, NJ). He was treated with whole lung lavage and discontinuation of leflunomide with good results. This is the first reported association of secondary pulmonary alveolar proteinosis with leflunomide therapy. Pulmonary alveolar proteinosis should be considered in patients with diffuse lung disease that develops while on disease-modifying antirheumatoid arthritis drug therapy.
15868609 Reproducibility and sensitivity to change of 5 methods for scoring hand radiographic damag 2005 May OBJECTIVE: To compare intrarater and interrater reproducibility and sensitivity to change of 5 scoring methods for radiographic damage on hand radiographs in patients with rheumatoid arthritis (RA). METHODS: Radiographs of 22 patients from Norway and France with average 2 years' disease duration at baseline and mean 30 months' followup were assessed by 2 readers according to Larsen, Larsen/Rau, Sharp, Sharp/van der Heijde, and Simple Erosion Narrowing Score (SENS) methods. Reproducibility at baseline and on progression was assessed using intraclass correlation coefficients (ICC) and Bland-Altman graphs. Sensitivity to change was compared across methods by computing the country-adjusted standardized response means (SRM) ratio. RESULTS: Intrarater reproducibility varied with the reader (ICC ranging from 0.90 to 0.97), with Larsen and Larsen/Rau ranking highest. Interrater reproducibility was highest with Sharp and Sharp/van der Heijde (ICC 0.76 to 0.93). Bland-Altman graphs showed a decrease of concordance in cases of more severe damage. Sensitivity to change was higher with Sharp and Sharp/van der Heijde modified for erosions (SRM ratio 1.44 and 1.70), than with Larsen/Rau and SENS. The differences between Sharp, Sharp/van der Heijde, and Larsen were less for joint space narrowing. There was a significant reader effect (p < 0.05) in all but the Sharp method. Expressed as percentage of the maximum score, the smallest detectable difference varied between 3.5% (Sharp/van der Heijde) and 14.2% (SENS erosion). CONCLUSION: All methods have high intraobserver and interobserver reliability. The interrater reproducibility decreases with disease severity. Recent modified methods perform best to detect changes, but the advantages of SENS seemed to be lost when applied on hand radiographs alone. Training the readers appears to be essential.
16014683 Blockade of tumour necrosis factor {alpha} significantly alters the serum level of IgG- an 2005 Aug OBJECTIVE: To determine the effect on the humoral immune system of long term treatment of patients with RA with etanercept. METHODS: 12 consecutive patients with seropositive RA treated with etanercept were studied and followed up for 9 months. Clinical efficacy of treatment was evaluated using the 28 joint count Disease Activity Score (DAS28). Serum samples were collected at baseline and after 9 months and serum immunoglobulin, RF isotypes, and anti-cyclic citrullinated peptide (aCCP), antinuclear, nucleosome, and dsDNA antibodies determined. For comparison 7 patients with seropositive RA treated with adalimumab were studied. RESULTS: DAS28 decreased significantly after the first month and then was constant for the whole study (5.7 (0.3) v 3.8 (0.2), p< or=0.000). Serum IgA-RF and IgG-RF increased significantly after 9 months' etanercept treatment (mean (SEM) IgA-RF rose from 19.5 (4.8) to 30.5 (5.9) IU/ml, p< or=0.01; IgG-RF from 20.6 (8.1) to 33.8 (11.5) IU/ml, p< or=0.04). Serum levels of total immunoglobulin and specific autoantibodies remained unchanged during the study. In patients treated with adalimumab, no significant changes in serum levels of RF isotypes and aCCP antibodies were seen. CONCLUSION: Etanercept, although effective in treating the clinical symptoms of RA, seems to have a pivotal effect on RF-producing B cells either directly or indirectly.
17288969 Epidemiology of osteoporosis in rheumatic diseases. 2006 Nov Much work has been directed at establishing the impact of osteoporosis and related fragility fractures in rheumatic diseases. Several cross-sectional studies reported that disability and reduced motility that are due to functional impairment are among the most important determinants of bone loss in different rheumatic diseases. At the same time, longitudinal studies have confirmed the detrimental effect of uncontrolled disease activity on bone density. In this perspective, the suppression of inflammation probably remains the main concern when considering treatment options. Besides these variables, pharmacologic agents that are used commonly in the treatment of these conditions probably have an adjunctive effect on bone loss in rheumatic patients. Large epidemiologic studies have demonstrated clearly that patients who have RA, SLE, or AS are at an increased risk for fragility fractures. Further studies are required to investigate the effective impact of osteoporosis and fragility fractures in other rheumatic diseases, and to define the relationship between OA and osteoporosis. A better appreciation of the impact and mechanisms of osteoporosis in rheumatic diseases by rheumatologists represents a clinical challenge; however, a greater understanding of this frequent complication will improve the quality of health care and the lives of patients who have rheumatic diseases.
16466833 Influenza vaccine administration in patients with systemic lupus erythematosus and rheumat 2006 Apr 12 OBJECTIVE: To evaluate immunological safety and immunogenicity of influenza vaccine administration in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). PATIENTS AND METHODS: Twenty-four patients with low and/or stable disease activity 14 with SLE (mean age 43.42+/-12.18 years; 13 women) and 10 with RA (mean age 51+/-14.57 years; 9 women), diagnosed on the basis of the American College of Rheumatology criteria, have been immunized with trivalent split influenza vaccine without adjuvant. Further 24 non-vaccinated patients, 14 with SLE and 10 with RA, and 10 vaccinated healthy subjects, all age- and sex-matched, were used as controls. The patients underwent clinical and laboratory (specific anti-influenzavirus antibodies, auto-antibodies, peripheral blood lymphocyte subpopulations) evaluation before and 30 days after vaccination; auto-antibodies were also assessed at 90 days and disease activity at 90 and 180 days. RESULTS: The specific antibody response towards the three used antigens (A/New Caledonia/20/99, A/Moscow/10/99, and B/Shangdong/7/97) significantly increased in both patients and healthy controls, without any significant difference between them. No significant difference could instead be observed on the clinical activity, auto-antibodies, and peripheral blood lymphocyte subpopulations before and after vaccination, and between patients and controls. CONCLUSIONS: Trivalent split influenza vaccine without adjuvant seems to be safe and immunogenic in patients with SLE and RA, provided that only patients with low and/or stable disease activity are selected.
16269423 Anti-inflammatory effects of leflunomide in combination with methotrexate on co-culture of 2006 Jun OBJECTIVES: To investigate the anti-inflammatory effects of the active leflunomide metabolite A771726 (Lef-M) in combination with methotrexate (MTX) on synovial macrophages (SM) from rheumatoid arthritis (RA) patients co-cultured with an activated T cell line (Jurkat cell line). METHODS: Pro-inflammatory cytokines (TNFalpha, IL1beta, IL6), adhesion molecule ICAM-1, cyclooxygenase isoenzymes (COX1, COX2), and the nuclear factor kappaB (NF-kappaB) complex were analysed on SM co-cultured with a T cell line, as intracellular protein expression by immunocytochemistry (ICC) and western blot analysis, as extracellular protein expression by ELISA assay, and as mRNA expression by reverse transcriptase-multiplex PCR (RT-MPCR) after treatment with Lef-M (1, 10, 30 micromol/l) alone or in combination with MTX (50 ng/ml). RESULTS: The most significant intracellular decrease in cytokines was observed by ICC in SM treated with the combination of Lef-M (1, 10, 30 micromol/l) and MTX (50 ng/ml) versus untreated SM (TNFalpha 29%, 37%, 49%, IL1beta 56%, 43%, 50%, and IL6 59%, 62%, 71%, respectively). Furthermore, a significant decrease was confirmed concerning cytokine levels evaluated by ELISA in the medium of SM treated with the combination Lef-M+MTX (TNFalpha 40%, 41%, 44%; IL1beta 10%, 20%, 60%; IL6 37%, 41%, 49%, respectively). Western blot and RT-PCR analysis confirmed these results. Concordant decreased expression was observed for ICAM-1, COX1, COX2, and the NF-kappaB complex after Lef-M+MTX treatment. CONCLUSIONS: The combination of MTX and Lef-M shows additive inhibitory effects on the production of inflammatory mediators from SM co-cultured with a T cell line. These observations might support the positive results obtained in RA clinical studies by combination therapy.
15829424 Leflunomide reduces nitric oxide production in patients with active rheumatoid arthritis. 2005 Jun OBJECTIVES: Leflunomide is an immunomodulatory agent that was recently approved for the treatment of rheumatoid arthritis (RA). The mechanism of action is not fully understood. Nitric oxide (NO) plays an important role in the pathogenesis of RA. Leflunomide has been shown to cause cell specific inhibition of inducible nitric oxide synthase (iNOS) activation in animal models. We carried out this study to determine if there was alteration in NO production in patients with RA. METHODS: An 8-week open label study was carried out on patients with adult onset active RA. We measured levels of nitrite and citrulline spectrophotometrically as surrogate markers of NO production. Within-patient serum levels of nitrite and citrulline were compared with leflunomide therapy at three points of time (at 0, 4 and 8 weeks of therapy). RESULTS: Thirty-three patients with active RA were enrolled for this study. These patients were a subset of 63 individuals who are studied for clinical efficacy of leflunomide. Three patients were lost to follow-up. Median nitrite levels were 817.2 (nmol/ml) at the start of therapy and this declined to 440.9 nmol/ml and 301.1 nmol/ml at 4 and 8 weeks of therapy. Median citrulline levels were 649.3 nmol/ml at the start of the study, which declined to 549.2 nmol/ml and 485.4 nmol/ml at 4 and 8 weeks, respectively. Statistically significant decrease in median values for serum nitrite and citrulline levels was documented after 4 weeks of leflunomide therapy (p<0.01), which was sustained at 8 weeks (p<0.01), although there was no further fall between 4 and 8 weeks (p>0.1). CONCLUSIONS: Leflunomide inhibits nitric oxide production in patients with active RA. Inhibition of NO synthesis may be one of the mechanisms responsible for the immunomodulatory activity of leflunomide.
15286007 Effect of treatment of rheumatoid arthritis with infliximab on IFN gamma, IL4, T-bet, and 2005 Mar OBJECTIVE: To study interferon gamma (IFN gamma) production and the expression of T-bet and GATA-3, the transcription factors associated with Th1 and Th2, in peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis before and during infliximab treatment, so as to distinguish between a disease specific and a disease activity dependent defect. METHODS: Rheumatoid PBMC were obtained at weeks 0 and 6 of infliximab treatment and cultured for seven days with or without interleukin (IL)12 or the combination of IL12 and IL18. IFN gamma concentrations in supernatants were determined by ELISA. mRNA expression of IFN gamma, IL4, T-bet, and GATA-3 was determined by real time RT-PCR in whole blood at weeks 0 and 22. RESULTS: A reduction in spontaneous IFN gamma production and in the response to Th1 inducing cytokines occurred in rheumatoid PBMC. Reduction of systemic inflammation with infliximab treatment increased IFN gamma production in response to IL12 or IL12+IL18. The IFN gamma/IL4 expression ratio of rheumatoid blood before treatment was lower than in healthy controls but was increased by infliximab treatment. T-bet expression or T-bet/GATA-3 ratio of rheumatoid blood was less than in controls. The T-bet/GATA-3 ratio was not influenced by infliximab treatment. CONCLUSIONS: Regulation of T-bet and GATA-3 or IFN gamma and IL4 expression appeared different. The IFN gamma/IL4 ratio might express the blood Th1/Th2 balance better than the T-bet/GATA-3 ratio. Reduced IFN gamma production by rheumatoid PBMC and levels of IFN gamma and IL4 mRNA expression in blood were linked to disease improvement, indicating an association between this systemic Th1 feature and disease activity.
15322813 Pulmonary abscess due to leflunomide use in rheumatoid arthritis: a case report. 2005 Mar A 43-year-old woman had rheumatoid arthritis (RA) for 5 years and complained of fever, arthralgia/myalgia, and night sweating for a month. She had been receiving only leflunomide (20 mg/day) for 5 months. On admission, there was no evidence of active arthritis or vasculitic lesion. Laboratory evaluation showed an erythrocyte sedimentation rate of 145 mm/h and C-reactive protein of 160 mg/dl. All cultures were negative. Chest radiograph and computed tomography (CT) revealed a pulmonary abscess. Staphylococcus aureus multiplied in the culture of a purulent sample obtained from the abscess under ultrasonography. The leflunomide was stopped, and sultamicillin (IV 4x2 g/day) was started for a further 6 weeks. Four weeks later, the patient had completely recovered and CT showed significant improvement of the pulmonary abscess. Ten milligrams/day of prednisolone and 7.5 mg/week of methotrexate were started for RA treatment. The patient has been under control for 5 months without any further abscess or RA activation.
16881382 Soft tissue composition, axial bone mineral density, and grip strength in postmenopausal T 2006 Mar OBJECTIVE: To study bone mineral density and body composition in patients with early rheumatoid arthritis to determine the relationship of lean mass, fat mass and hand grip strength to bone mineral density. METHODS: Fifty-one female patients who fulfilled the American College of Rheumatology (ACR) for RA were recruited. Fifty-one (51) female RA patients, age matched female control subjects and 53 osteoporotic patients (WHO criteria) were included in the study. All subjects were at postmenopausal period. Early RA is defined as the disease duration <10 years. Whole body composition and BMD were estimated by DEXA (Norland XR-46). Hand grip strength was measured by JAMAR hand dynamometer. Body mass index (BMI) and anthropometric measures (skinfold thickness and waist-hip ratio) were also assessed. RESULTS: The mean age of patients and controls was 55.4 +/- 9.5, 56.9 +/- 7.4, and 55.2 +/- 7.6, respectively. There was no statistically significant difference in age, BMI, and years since menopause between RA patients, OP patients, and controls (p < 0.05). Bone mineral density of lumbar and femoral neck regions, total bone mineral density, and bone mineral content in RA patients were significantly lower than in controls but not in osteoporotic patients. Lean body mass was also significantly lower in RA patients than controls but not in osteoporotic patients. However, hand grip strength was significantly lower in RA patients than in osteoporotic patients and controls (p < 0.05). Total lean mass was correlated with body mass index, waist-hip ratio, femoral neck BMD, and total bone mineral content, total BMD in RA patients (p < 0.05). Grip strength was correlated with duration of disease (RA) and age negatively, and also correlated with total BMD in RA patients. CONCLUSION: These results indicate that lean mass was associated with BMD. To preserve BMD, maintaining or increasing lean mass would appear to be an appropriate strategy for avoiding hip fracture and its complications.
16463409 Prescription opioid use among older adults with arthritis or low back pain. 2006 Feb 15 OBJECTIVE: To examine patterns of chronic opioid use in selected groups with arthritis and low back pain and compare them with patterns among persons with ischemic heart disease. METHODS: The study database consisted of Medicare beneficiaries who were enrolled in a drug benefit program for low-to-moderate income Pennsylvania residents. We identified selected patients who had a diagnosis of rheumatoid arthritis, osteoarthritis, chronic low back pain, or ischemic heart disease since 1995. Chronic opioid use, defined as at least six 30-day prescriptions in a year, was the endpoint of interest. We examined the proportion of patients meeting this definition during the period 1996-2001 and determined predictors based on multivariable Cox proportional hazards models. RESULTS: Four percent of subjects with rheumatoid arthritis used opioids chronically in 2001, compared with <1% in each of the other groups. There was no increase in the chronic use of opioids over the 6-year study period. Low-potency opioids were the most commonly prescribed preparations for chronic users from all patient groups. The prior use of medicines for psychiatric illness, including benzodiazepines or barbiturates, was associated with chronic prescription opioid use across all diagnoses. However, subjects with a prior diagnosis of psychiatric illness were less likely to receive chronic opioids. CONCLUSION: Chronic opioid use is relatively uncommon, even among older individuals with arthritis or low back pain. The proportion of these individuals receiving such medicines has not increased in the late 1990s. There seems to be a complex relationship between psychiatric medication use, psychiatric diagnoses, and the use of chronic opioids among these individuals.
16014673 Macrophages from patients with SLE and rheumatoid arthritis have defective adhesion in vit 2006 Feb BACKGROUND: It has been suggested that defective handling of apoptotic cells by macrophages plays a key role in the development of systemic lupus erythematosus (SLE). The relative contribution of intrinsic defects and serum factors remains controversial. OBJECTIVE: To compare monocytes from SLE patients, patients with rheumatoid arthritis, and healthy controls for their ability to differentiate in vitro into macrophages and to bind/engulf apoptotic cells. METHODS: Peripheral blood derived monocytes from healthy donors or from patients with SLE or rheumatoid arthritis were allowed to differentiate into macrophages. The in vitro uptake of apoptotic cells by macrophages was evaluated by a flow cytometry assay that allowed discrimination between binding and internalisation. RESULTS: Monocytes from SLE and rheumatoid patients showed a striking defect in adherence to plastic compared with healthy donors. Absence or heat inactivation of serum resulted in a reduction in the binding and engulfment of apoptotic cells by macrophages. Macrophages from rheumatoid and SLE patients had similar percentages of apoptotic cells bound to their surface compared with normal controls. However, macrophages from SLE patients showed a significant defect in the internalisation of apoptotic cells compared with those from healthy controls, even in the presence of normal human serum. CONCLUSIONS: Monocytes from patients with SLE and rheumatoid arthritis have a similar defect in their capacity to adhere to plastic. However, only macrophages from SLE patients showed an impaired ability to engulf apoptotic cells, which indicates that an intrinsic cellular defect may be responsible for this phenomenon.
17012290 Role of the MHC2TA gene in autoimmune diseases. 2007 Mar OBJECTIVES: Expression of major histocompatibility complex (MHC) class II genes is almost exclusively regulated by the class II transactivator. A promoter polymorphism (-168A/G, rs3087456) in the MHC2TA gene was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction in a northern European population. However, no evidence of association of this MHC2TA variant with the two autoimmune diseases could be subsequently detected in independent cohorts. AIM: To test the aforementioned single nucleotide polymorphism and another G-->C change (nt1614 from coding sequence, rs4774) to analyse the haplotype pattern in this MHC2TA gene. METHODS: A case-control study was performed with 350 patients with rheumatoid arthritis, 396 patients with multiple sclerosis, 663 patients with inflammatory bowel disease (IBD) and 519 healthy controls from Madrid. Genotyping was ascertained by using TaqMan assays-on-demand on a 7900HT analyser, following the manufacturer's suggestions (Applied Biosystems, Foster City, California, USA). Haplotypes were inferred with the expectation-maximisation algorithm implemented by the Arlequin software. RESULTS: No independent association with these autoimmune diseases was found for either polymorphism in the Spanish cohorts tested. However, when haplotypes were compared between patients with rheumatoid arthritis and controls, a significant difference in their overall frequency distribution was observed, evidencing a protective haplotype (-168A/1614C, p = 0.006; odds ratio (OR) 0.7) and a risk haplotype (-168G/1614C, p = 0.019; OR 1.6). Patients with multiple sclerosis mirrored these results, but no effect on IBD was identified. CONCLUSIONS: The MHC2TA gene influences predisposition to rheumatoid arthritis and multiple sclerosis, but not to IBD. The -168G allele is not an aetiological variant in itself, but a genetic marker of susceptibility/protection haplotypes.
16540076 Specific modification of peptide-bound citrulline residues. 2006 May 1 Immune reactions to citrulline-containing proteins appear to be central in the immunopathogenesis of rheumatoid arthritis. Citrulline residues are introduced into proteins by deimination of arginine residues, likely by an enzymatic process. There is a need to characterize which proteins in the inflamed joints of rheumatoid patients contain citrulline in situ. The characterization of deiminated proteins will be greatly facilitated by specific modification of peptide-bound citrulline residues that will enable specific enrichment and detection of citrulline-containing peptides. This study presents the details of such a modification method. The chemistry behind the reaction of the ureido group of citrulline with 2,3-butanedione in the presence of antipyrine is unraveled. Parameters for optimization of the reaction with respect to specificity and completeness, including the testing of different acids, reactant concentrations, and reaction time, are presented. This modification reaction is specific for citrulline residues. The modified product shows a characteristic mass shift of +238Da, as demonstrated by mass spectrometry. The product absorbs UV-Vis radiation at 464nm, and it is demonstrated that this can be used to selectively monitor citrulline-containing peptides during the separation of protein digests. Finally, the structure of the product of modified citrulline is solved by nuclear magnetic resonance spectroscopy using N-butylurea as a model substance. The results presented should facilitate the development of tags that can be used for the enrichment and subsequent detection of citrulline-containing protein fragments by mass spectrometry.
15702237 Analysis of abnormally expressed genes in synovium from patients with rheumatoid arthritis 2005 Mar Rheumatoid arthritis (RA) is a chronic disease of unknown pathogenesis. To identify abnormally expressed genes in synovium from RA patients, we performed column gel electrophoresis-coupled subtractive hybridization (CGESH). CGESH is a newly developed subtractive hybridization technique to achieve sufficient enrichment of DNA sequences. CGESH was performed using restricted enzyme digested cDNA synthesized from mRNA of synovial tissues from one RA patient and one osteoarthritis (OA) patient. The obtained subtraction libraries (RA-OA) were screened by dot blot hybridization. The clones showing higher hybridization with the RA-OA probe were identified by sequence analysis and homology search. Their DNA sequencing revealed that the genes of HLA-DRB1, sequestosome 1, elongation factor 1alpha were included. Furthermore, a functionally unknown gene (FLJ00133) was also identified. It is reported that sequestosome 1 is a scaffold in the signal transduction of TNFalpha and interleukin 1, which are the important cytokines involved in the pathogenesis of RA. It is possible that other genes identified by the CGESH technique would be associated with the pathogenesis of RA, although there is no direct evidence yet. Our results imply that the CGESH technique is a useful tool to detect genes involved in the pathogenesis of RA. Further investigation of the functional roles of candidate genes should shed light on the pathogenesis of RA.
16258412 [Peroxisome proliferator-activated receptors-gamma (PPAR-gamma) and their role in immunore 2005 Peroxisome proliferator-activated receptors-gamma (PPAR-gamma) are members of the nuclear receptor superfamily containing transcription factors regulating gene expression. PPAR-gamma have attracted attention so far as key factors in adipogenesis, lipid metabolism, insulin sensitivity, and apoptosis. Recently, growing evidence points to their implication in the regulation of the immune response, particularly in inflammation control. Not only are PPAR-gamma found in various structures of the immune system, but many inflammatory mediators, such as arachidonic acid and its metabolites, also act as potent and specific ligands of them. Inflammation is the basis of the pathogeneses of such chronic diseases as bronchial asthma, atherosclerosis, rheumatoid arthritis, and chronic inflammatory bowel diseases. The causative relationship between PPAR-gamma activity and the pathogeneses of these inflammatory disorders has been found in specific animal models. Moreover, PPAR-gamma agonists have been shown to act as potent anti-inflammatory agents. Thus, PPAR-gamma can serve as potential therapeutic targets in the treatment of inflammation. The aim of this paper is to present the characteristics of PPAR-gamma regarding their gene and protein structures, ligand selectivity, mechanisms of action, and target genes. The review highlights the roles that PPAR-gamma play in inflammation and immune responses. Particular emphasis is focused on their roles in asthma, atheroclerosis, rheumatoid arthritis and chronic inflammatory bowel diseases.