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ID PMID Title PublicationDate abstract
18830906 Glucocorticoid receptor variants may predispose to rheumatoid arthritis susceptibility. 2009 Jan OBJECTIVES: Deregulation of glucocorticoid (GC) secretion could be associated with rheumatoid arthritis (RA). The GC receptor (GR) has two isoforms. In the present study, we explored the role of GR-alpha polymorphisms rs33388, rs33389, and Bcl I, and the GR-beta variant rs6198 in RA susceptibility. METHODS: One hundred and thirty-six RA patients and 148 ethnic matching controls were studied. Polymorphisms rs33388 and Bcl I were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and variants rs33389 and rs6198 by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) coupled with sequencing. Arlequin and SPSS softwares were used in the statistical analysis. RESULTS: The polymorphisms studied were in Hardy-Weinberg equilibrium in both groups. A marginally statistical significant difference was observed in the distribution of rs33388 genotypes between RA patients and controls (p = 0.053). When the A and T alleles were compared, the statistical significance was p = 0.025. Specific complex genotypes were also differentially distributed: the GR-alpha complex genotypes (a) [homozygote (homo) wild-type (wt) rs33388-homo wt rs33389] (11% RA vs. 21% controls; p = 0.023), (b) [homo wt rs33388-homo wt rs33389-homo non-wt Bcl I] (0.7% RA vs. 4.7% controls; p = 0.042), and (c) the GR-beta complex genotype [homo wt rs33388-homo wt rs33389-homo non-wt Bcl I-homo wt rs6198] (0.7% RA vs. 4.7% controls; p = 0.042). CONCLUSIONS: GR-alpha and GR-beta polymorphisms are potentially associated with RA susceptibility. However, additional studies in larger and other ethnic groups of patients are needed to confirm the results of the present study.
19844717 Pseudo-pseudo Meigs syndrome developed under the leflunomide therapy. 2011 Apr Pseudo-pseudo Meigs syndrome or Tjalma syndrome is characterized by increased CA-125 level, pleural effusion and ascites in systemic lupus erythematosus (SLE) patients without over tumor. The disorder is relatively rare and it has been reported usually in SLE patients with impaired renal functions. Herein, we present a case of a 47-year-old female patient who developed Tjalma syndrome after administration of leflunomide for rheumatoid arthritis. Surprisingly renal functions of our patient were found in normal limits. This is the first case of Tjalma syndrome that is developed in normal renal functions and the probable role of leflunomide therapy is discussed.
19289382 Does anti-mutated citrullinated vimentin have additional value as a serological marker in 2010 Feb OBJECTIVE: To review the diagnostic and prognostic value of anti-mutated citrullinated vimentin (MCV) in rheumatoid arthritis, taking into account the already available serology. METHODS: Medline was searched via PubMed (1966 to May 2008) for anti-MCV and related terms, arthritis and arthropathies. Studies with anti-MCV, arthritis/arthropathy, and primary data on diagnosis and/or prognosis were included. Their methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) instrument for diagnostic studies and the modified Hayden list for prognostic studies. RESULTS: Of 14 eligible studies, 11 included diagnostic data and 3 included prognostic data. No study evaluated anti-MCV as an added diagnostic test to the already available anti-cyclic citrullinated peptide (CCP) and rheumatoid factor serology. One study included the optimal patient spectrum resulting in a sensitivity of 0.59 and specificity of 0.98. A total of 10 diagnostic case-control studies using the same anti-MCV kit showed a sensitivity of 0.64-0.84 and a specificity of 0.79-0.96. This almost equalled the performance of anti-CCP in the same studies. The prognostic evaluation of anti-MCV was limited by differences in study methodology, outcome and statistical modelling. Individual studies showed moderate associations for anti-MCV and radiological progression with the strength of the association comparable to that of anti-CCP. CONCLUSIONS: Study heterogeneity, choice of study population and methodological limitations limited overall conclusions about the true diagnostic and prognostic test performance of anti-MCV. Evidence from the diagnostic case-control studies suggests that anti-MCV may be used as an alternative for anti-CCP.
19343596 The R620W polymorphism of the protein tyrosine phosphatase 22 gene in autoimmune thyroid d 2009 May BACKGROUND: Protein tyrosine phosphatase (PTPN22) is involved in the negative regulation of T-cell responsiveness. The association of a coding variant of the PTPN22 gene (R620W) with a number of autoimmune diseases has been described. AIM: The present study investigated whether PTPN22 gene polymorphism was also involved in the genetic predisposition to autoimmune thyroid diseases (AITDs) and rheumatoid arthritis (RA) in a Tunisian case control study. SUBJECTS AND METHODS: DNA samples from 150 patients affected with RA, 204 patients affected with AITDs and 236 healthy controls were genotyped for PTPN22 R620W polymorphism (1858C/T). Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No significant differences in T allele frequency (2.3% in RA patients and 1% in AITDs patients vs 2.6% in controls; p=0.85 and p=0.08, respectively) and in genotype frequencies were detected between RA patients and controls (p=0.15) and between AITDs patients (p=0.11). Stratifying patients affected with AITDs according to their phenotype (Graves' disease and Hashimoto's thyroiditis) and RA patients according to the presence of rheumatoid factor (RF) and antibodies against cyclic citrullinated peptides (ACPA) did not show any significant association with PTPN22 R620W allele (p>0.05). CONCLUSION: Our data suggest that the PTPN22 C1858T single nucleotide polymorphism has no or minor effect on RA and AITDs susceptibility in the Tunisian population.
18336873 Bone marrow edema in the cervical spine of symptomatic rheumatoid arthritis patients. 2009 Feb OBJECTIVE: To investigate the frequency and clinical significance of bone marrow edema (BME) in a series of patients with rheumatoid arthritis (RA) and symptomatic involvement of the cervical spine. METHODS: We studied 19 consecutive RA patients with cervical spine magnetic resonance imaging (MRI) according to a specifically designed protocol that included short inversion time inversion recovery sequences. All cases had neck pain unresponsive to conventional treatment, neurological symptoms, or signs suggestive of cervical myelopathy, or cervical pain with evidence of atlantoaxial subluxation on radiographs. RESULTS: The mean age of the 19 patients (15 women and 4 men) at time of the study was 59 +/- 12 years (range, 23-82) and the median disease duration was 14 +/- 7.4 years (range, 4-30). BME was observed in 74% (14/19) of the patients: at the atlantoaxial level alone in 16% of the patients; subaxially alone in 16%; and at both levels in 42% of the patients. At the atlantoaxial level, BME was usually observed involving the odontoid process, whereas subaxially BME was limited to the vertebral plates and the interapophyseal joints. Patients with BME had higher erythrocyte sedimentation rate (ESR) values at the time of MRI examination (P = 0.014) and more severe atlantoaxial joint MRI synovitis scores (P = 0.05) compared with the remaining patients; the frequency of odontoid erosions was also greater in this group, but the difference did not reach statistical significance. Altogether, these data suggest a more severe inflammatory response in these patients. In this group a significant correlation was found between BME scores at atlantoaxial level and (1) ESR values (r = 0.854; P = 0.001) and (2) atlantoaxial joint MRI synovitis scores (r = 0.691; P = 0.001). CONCLUSION: BME is frequently observed in patients with established RA and symptomatic cervical spine involvement. Both atlantoaxial and subaxial levels are equally affected. The presence of BME seems related to the intensity of the inflammatory response and to the severity of the atlantoaxial joint synovitis.
19847432 The effects of adalimumab and methotrexate treatment on peripheral Th17 cells and IL-17/IL 2010 Nov Objective of the study is to assess the effects of adalimumab and MTX therapy on peripheral Th17 cells and IL-17/IL-6 secretion in RA patients. Twenty active RA patients were treated with oral MTX 15 mg per week (MTX group, n = 10), or hypodermal adalimumab 40 or 80 mg every other week (ADA group, n = 10). Peripheral blood samples were taken for laboratory evaluation at week 0 and week 12 of treatment, including flowcytometric detection of peripheral CD4(+) IL-17(+) cells, RT-PCR detection of mRNA expressions of IL-17, RORc and FoxP3, and ELISA determination of serum IL-17 and IL-6. Ten age and sex marched healthy volunteers were included as normal controls. Results showed that (1) DAS28 in both groups improved at week 12 compared to week 0 (3.9 ± 1.3 vs. 6.4 ± 1.4 and 3.2 ± 0.9 vs. 5.2 ± 0.9, respectively). (2) The percentage and MFI of peripheral CD4(+) IL-17(+) cells in RA patients were significantly higher comparing to normal controls (1.64 ± 0.97% vs. 0.75 ± 0.20%, p < 0.01; and 29.8 ± 9.7 vs. 19.8 ± 4.6, p < 0.05, respectively), and positively correlated with ESR and DAS28. Peripheral Th17 cells and serum IL-6 in RA patients decreased after treatment (from 1.60 ± 0.78% to 1.28 ± 0.41%, and from 17.15 ± 14.53 pg/ml to 6.97 ± 5.51 pg/ml, p < 0.05, respectively). Peripheral FoxP3 mRNA expression in active RA patients was significantly lower comparing to normal controls, and negatively correlated with ESR. Baseline Th17 percentage of RA patients negatively correlated with DAS28 improvement after treatment. In conclusion, adalimumab and MTX treatment down regulates peripheral Th17 cells and serum IL-6 level in RA patients. Baseline Th17 level negatively predicts the effect of adalimumb/MTX treatment.
19895906 Rheumatoid arthritis, Proteus, anti-CCP antibodies and Karl Popper. 2010 Feb Rheumatoid arthritis (RA) is a crippling joint disease affecting over 20 million people worldwide. The cause of RA is most probably linked to the triad of microbial trigger, genetic association and autoimmunity and can be explained using the philosophical method of Karl Popper or Popperian sequences. Ten "Popper sequences" have been identified which point to the urinary microbe Proteus mirabilis as the cause of RA: Popper sequence 1 establishes that HLA-DR4 lymphocytes injected into a rabbit evoke specific antibodies against Proteus bacteria. Popper sequence 2 establishes that antibodies to Proteus bacteria are present in RA patients from 14 different countries. Popper sequence 3 establishes that antibodies to Proteus bacteria in RA patients are disease specific since no such antibodies are found in other conditions. Popper sequence 4 establishes that when RA patients have high titres of antibodies to Proteus such bacteria are found in urinary cultures. Popper sequence 5 establishes that only Proteus bacteria and no other microbes evoke significantly elevated antibodies in RA patients. Popper sequence 6 establishes that the "shared epitope" EQR(K)RAA shows "molecular mimicry" with the sequence ESRRAL found in Proteus haemolysin. Popper sequence 7 establishes that Proteus urease contains a sequence IRRET which has "molecular mimicry" with LRREI found in collagen XI of hyaline cartilage. Popper sequence 8 establishes that sera obtained from RA patients have cytopathic properties against sheep red cells coated with the cross-reacting EQR(K)RAA and LRREI self-antigen peptides. Popper sequence 9 establishes that Proteus sequences in haemolysin and urease as well as the self antigens, HLA-DR1/4 and collagen XI, each contain an arginine doublet, thereby providing a substrate for peptidyl arginine deiminase (PAD) to give rise to citrulline, which is the main antigenic component of CCP, antibodies to which are found in early cases of RA. Popper sequence 10 establishes that antibodies to Proteus come not only from sequences crossreacting to self antigens but also from non-crossreacting sequences, thereby indicating that active RA patients have been exposed to infection by Proteus. The ten Popper sequences establish that RA is most probably caused by Proteus upper urinary tract infections, which can possibly be treated with anti-Proteus therapy.
20506214 Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen an 2010 Sep OBJECTIVE: To investigate protein citrullination by the periodontal pathogen Porphyromonas gingivalis as a potential mechanism for breaking tolerance to citrullinated proteins in rheumatoid arthritis (RA). METHODS: The expression of endogenous citrullinated proteins was analyzed by immunoblotting of cell extracts from P gingivalis and 10 other oral bacteria. P gingivalis-knockout strains lacking the bacterial peptidylarginine deiminases (PADs) or gingipains were created to assess the role of these enzymes in citrullination. Citrullination of human fibrinogen and α-enolase by P gingivalis was studied by incubating live wild-type and knockout strains with the proteins and analyzing the products by immunoblotting and mass spectrometry. RESULTS: Endogenous protein citrullination was abundant in P gingivalis but lacking in the other oral bacteria. Deletion of the bacterial PAD gene resulted in complete abrogation of protein citrullination. Inactivation of arginine gingipains, but not lysine gingipains, led to decreased citrullination. Incubation of wild-type P gingivalis with fibrinogen or α-enolase caused degradation of the proteins and citrullination of the resulting peptides at carboxy-terminal arginine residues, which were identified by mass spectrometry. CONCLUSION: Our findings demonstrate that among the oral bacterial pathogens tested, P gingivalis is unique in its ability to citrullinate proteins. We further show that P gingivalis rapidly generates citrullinated host peptides by proteolytic cleavage at Arg-X peptide bonds by arginine gingipains, followed by citrullination of carboxy-terminal arginines by bacterial PAD. Our results suggest a novel model where P gingivalis-mediated citrullination of bacterial and host proteins provides a molecular mechanism for generating antigens that drive the autoimmune response in RA.
21302486 [Efficacy of integrative medicine for the treatment of rheumatoid arthritis and its effect 2010 Dec OBJECTIVE: To investigate the efficacy and mechanism of Fengshikang (FSK) in treating rheumatoid arthritis (RA). METHODS: Thirty-eight patients with RA of damp-heat block syndrome type in Chinese medicine (CM), were randomized into two groups. They all received glucocorticoid therapy for 1 month, but FSK was administered to the 20 patients in the CM group in addition, while to the 18 in the WM group, MTX was given. Besides, a normal control group with 20 healthy subjects was set up. Blood levels of RA related indices were measured and compared. RESULTS: After treatment, the levels of rheumatoid factor (RF) and C-reactive protein (CRP) were significantly reduced in both groups (P<0.05), but the reduction was more significant in the CM group (P<0.05). No significant change was found in the level of ESR after treatment and showed no significant difference between groups (P>0.05). Both hGRalpha mRNA and hGRbeta mRNA expressions were significantly higher in the patients than in the normal controls (P<0.01), they were lowered after treatment in the CM group (P<0.01), but significant reduction could only be found in level of hGRbeta mRNA in the control group (P<0.01). CONCLUSION: FSK combined with glucocorticoid can effectively control the inflammatory reaction, decrease the level of hGRalpha and hGRbeta expressions and enhance the clinical efficacy in treating RA.
20039396 Humoral responses after influenza vaccination are severely reduced in patients with rheuma 2010 Jan OBJECTIVE: For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab is unknown. The objectives of this study were to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. We also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination. METHODS: Trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4-8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6-10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity. RESULTS: Following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX-treated group and in healthy controls, but for no strains in the rituximab-treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab-treated group than in the MTX-treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab-treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab-treated group, previously vaccinated patients in the rituximab-treated group had higher pre- and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination. CONCLUSION: Rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6-10 months after rituximab administration. Previous influenza vaccination in rituximab-treated patients increases pre- and postvaccination titers. RA activity was not influenced.
20819596 Circulating Dickkopf-1 and osteoprotegerin in patients with early and longstanding rheumat 2010 Jun BACKGROUND: Rheumatoid arthritis (RA) is characterized by inflammation of the synovial membrane, leading to invasion of synovial tissue into the adjacent cartilage matrix with degradation of articular cartilage and bone as a consequence. Dickkopf-1 (DKK-1) and osteoprotegerin (OPG) have been demonstrated to be key molecules involved in bone erosion and bone remodeling. The aim of this study was to explore the potential role of DKK-1 and OPG in different stage of RA. METHODS: The protein levels of DKK-1 and OPG were detected by ELISA. The serum samples were collected from 300 patients with RA and 60 healthy controls. Of which, 150 RA patients were defined as early RA (disease duration < or = 1 year), and other 150 RA patients were defined as longlasting RA (disease duration > or = 5 years). At the time of serum sampling, various clinical and laboratory parameters were assessed. The correlations of DKK-1 or OPG and clinical/laboratory parameters were analyzed. RESULTS: The serum level of DKK-1 was elevated in patients with longstanding RA compared with healthy controls, while no significant difference was observed between the two groups in the level of OPG. In contrast, in early RA patients, the circulating OPG was elevated, while there was no significant difference between the two groups in expression of DKK-1. The serum DKK-1 was correlated with Sharp score and DAS28 in longstanding RA patients. In early RA, age was the only parameter that was significantly related to serum OPG. CONCLUSIONS: There was a cross-talk between DKK-1 and OPG, which involved in bone destruction in RA. In different stage of RA, DKK-1 and OPG may play different roles in the pathogenesis of RA.
20345251 Access and perceived need for physical and occupational therapy in chronic arthritis. 2010 PURPOSE: Physical and occupational therapy are beneficial for persons with chronic arthritis; however, access is problematic. The goal was to examine issues related to access to these services for patients with chronic arthritis. METHODS: We used two data sources: 1) questionnaires sent to a random sample of 600 family physicians and to all 85 rheumatologists in the province of Quebec; and 2) interviews of 211 patients with physician-confirmed chronic arthritis recruited from 34 primary care settings in Quebec. RESULTS: Only 11.5% of family physicians and 31.7% of rheumatologists referred patients with rheumatoid arthritis (RA) to rehabilitation, whereas 60.4% of family doctors referred patients with osteoarthritis. Only 26.1% of patients felt that they required rehabilitation and this was associated with lower self-efficacy (OR: 0.84, 95% CI: 0.72, 0.99) and higher educational level (OR: 2.10, 95% CI: 1.01, 4.36). CONCLUSION: Family physicians are less likely to refer patients with RA to therapy. Only about a quarter of patients with chronic arthritis treated in primary care perceived the need for these services. Efforts to improve arthritis care should address education of physicians and patients regarding the benefits of rehabilitation and there should be efforts to increase therapy resources in order to enhance access.
20533542 Role of osteopontin in synovial Th17 differentiation in rheumatoid arthritis. 2010 Oct OBJECTIVE: Osteopontin (OPN) that is aberrantly produced in rheumatoid synovium is thought to play an important role in rheumatoid arthritis (RA). This study was undertaken to investigate the role of OPN in the differentiation and accumulation of Th17 cells in rheumatoid synovium. METHODS: Peripheral blood mononuclear cells and purified CD4+ T cells derived from patients with RA or healthy controls were used to test the effect of OPN in vitro. Cytokine expression was determined by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Intracellular staining and flow cytometry were used to detect the percentages of Th17 cells and OPN receptors. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation. RESULTS: The levels of OPN correlated significantly with interleukin-17 (IL-17) production and the frequency of Th17 cells in the synovial fluid (SF) of RA patients. Endogenous OPN produced in RA SF was responsible for markedly increased production of IL-17 in T cells, which was blocked by OPN antibody. The effect of OPN in Th17 differentiation was mediated through a mechanism independent of the IL-6/STAT-3 pathway or other cytokines and specifically involved the OPN receptors CD44 and CD29 and the transcription factor retinoic acid-related orphan receptor (ROR). Furthermore, OPN was found to induce H3 acetylation of the IL17A gene promoter, mainly through the CD44 binding domain in CD4+ T cells, allowing the interaction of the IL17A gene locus with ROR. CONCLUSION: This study reveals new evidence of the critical role of OPN in Th17 differentiation in rheumatoid synovitis.
19652024 Periodic, partial inhibition of IkappaB Kinase beta-mediated signaling yields therapeutic 2009 Nov We have previously shown that inhibitors of IkappaB kinase beta (IKKbeta), including 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline (BMS-345541), are efficacious against experimental arthritis in rodents. In our efforts to identify an analog as a clinical candidate for the treatment of autoimmune and inflammatory disorders, we have discovered the potent and highly selective IKKbeta inhibitor 2-methoxy-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)acetamide (BMS-066). Investigations of its pharmacology in rodent models of experimental arthritis showed that BMS-066 at doses of 5 and 10 mg/kg once daily was effective at protecting rats against adjuvant-induced arthritis, despite showing only weak inhibition at 10 mg/kg against a pharmacodymanic model of tumor necrosis factor alpha production in rats challenged with lipopolysaccharide. The duration of exposure in rats indicated that just 6 to 9 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50% in vivo was necessary for protection against arthritis. Similar findings were observed in the mouse collagen-induced arthritis model, with efficacy observed at a dose providing only 6 h of coverage per day of the concentration necessary to inhibit IKKbeta by 50%. This finding probably results from the cumulative effect on multiple cellular mechanisms that contribute to autoimmunity and joint destruction, because BMS-066 was shown to inhibit a broad spectrum of activities such as T cell proliferation, B cell function, cytokine and interleukin secretion from monocytes, T(H)17 cell function and regulation, and osteoclastogenesis. Thus, only partial and transient inhibition of IKKbeta is sufficient to yield dramatic benefit in vivo, and this understanding will be important in the clinical development of IKKbeta inhibitors.
20156944 Thrombin-cleaved osteopontin is increased in urine of patients with rheumatoid arthritis. 2010 Apr OBJECTIVE: To measure concentrations of the thrombin-cleaved isoform of osteopontin (OPN) in urine and plasma of patients with rheumatoid arthritis (RA), and to assess whether levels of thrombin-cleaved OPN are associated with measures of RA. METHODS: Subjects comprised 70 patients with RA, 20 patients with osteoarthritis (OA), and 46 healthy controls. RA disease activity was evaluated by tender joint count, swollen joint count, patient's global assessment of disease activity, erythrocyte sedimentation rate (ESR), and levels of C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), and rheumatoid factor (RF), as well as 28-joint count Disease Activity Score (DAS28). OPN levels in plasma and urine were measured by ELISA. RESULTS: Median levels of thrombin-cleaved OPN in urine (U-half) were significantly higher in RA patients (143.5 pmol/mmol Cr) than in healthy controls (67.9 pmol/mmol Cr) or OA patients (69.8 pmol/mmol Cr). Thrombin-cleaved OPN was not detected in plasma. U-half levels correlated significantly with levels of CRP (r = 0.26, p = 0.03), ESR (r = 0.26, p = 0.03), and RF (r = 0.28, p = 0.03). Median U-half levels were significantly higher in patients with stage III (249.9 pmol/mmol Cr) and IV (251.6 pmol/mmol Cr) disease than in patients with stage I (98.6 pmol/mmol Cr) disease. CONCLUSION: Our results suggest that urine levels of the thrombin-cleaved isoform of OPN may reflect the severity of active inflammatory arthritis in patients with RA.
20714691 Adverse effects of low dose methotrexate in rheumatoid arthritis patients. A hospital-base 2010 Aug OBJECTIVE: To evaluate the side effects of methotrexate (MTX) in rheumatoid arthritis (RA) patients and to evaluate the possible predisposing variables. METHODS: A retrospective analysis conducted for all patients diagnosed with RA and treated with MTX over 3-years (January 2006 to December 2008) at King Abdul-Aziz University Hospital, Jeddah, Kingdom of Saudi Arabia. Frequency of MTX side effects and the predictive variables were recorded and analyzed statistically. RESULTS: Out of 116 RA patients, 71 patients used MTX. The most frequent side effect was gastrointestinal (GIT) disturbance in 31%, followed by central nervous system symptoms in 18%, hepatotoxicity in 14%, stomatitis and alopecia in 10% each, macrocytosis 7%, fever, malar rash and pancytopenia in 4%, and MTX-induced lung injury with increase in the size of rheumatoid nodule in 1% of patients. By Logistic regression analysis, renal impairment was the most significant variable increasing the risk of the side effects (OR=7.14, p<0.05). Other associated variables were male-gender, non-Saudi nationality, smoking, steroids use, hypoalbuminemia, and the presence of extra-articular manifestations. CONCLUSION: Methotrexate is the most commonly drug used in the treatment of RA. Gastrointestinal disturbances were the most common side effect while lung involvement was the least. The impact of each clinical variable on MTX side effects requires paying more attention on the disease management as not all variables can be considered as risk factors.
19404960 Down-regulation of myeloid cell leukemia 1 by epigallocatechin-3-gallate sensitizes rheuma 2009 May OBJECTIVE: Overexpression of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) in rheumatoid arthritis (RA) synovial fibroblasts is a major cause of their resistance to tumor necrosis factor alpha (TNFalpha)-induced apoptosis. This study was undertaken to evaluate the efficacy of epigallocatechin-3-gallate (EGCG) in down-regulating Mcl-1 expression and its mechanism of RA synovial fibroblast sensitization to TNFalpha-induced apoptosis. METHODS: EGCG effects on cultured RA synovial fibroblast cell morphology, proliferation, and viability over 72 hours were determined by microscopy and a fluorescent cell enumeration assay. Caspase 3 activity was determined by a colorimetric assay. Western blotting was used to evaluate the apoptosis mediators poly(ADP-ribose) polymerase (PARP), Mcl-1, Bcl-2, Akt, and nuclear translocation of NF-kappaB. RESULTS: In RA synovial fibroblasts, EGCG (5-50 microM) inhibited constitutive and TNFalpha-induced Mcl-1 protein expression in a concentration- and time-dependent manner (P<0.05). Importantly, EGCG specifically abrogated Mcl-1 expression in RA synovial fibroblasts and affected Mcl-1 expression to a lesser extent in osteoarthritis and normal synovial fibroblasts or endothelial cells. Inhibition of Mcl-1 by EGCG triggered caspase 3 activity in RA synovial fibroblasts, which was mediated via down-regulation of the TNFalpha-induced Akt and NF-kappaB pathways. Caspase 3 activation by EGCG also suppressed RA synovial fibroblast growth, and this effect was mimicked by Akt and NF-kappaB inhibitors. Interestingly, Mcl-1 degradation by EGCG sensitized RA synovial fibroblasts to TNFalpha-induced PARP cleavage and apoptotic cell death. CONCLUSION: Our findings indicate that EGCG itself induces apoptosis and further sensitizes RA synovial fibroblasts to TNFalpha-induced apoptosis by specifically blocking Mcl-1 expression and, hence, may be of promising adjunct therapeutic value in regulating the invasive growth of synovial fibroblasts in RA.
20112376 Methotrexate polyglutamate concentrations are not associated with disease control in rheum 2010 Feb OBJECTIVE: There are limited data suggesting that methotrexate polyglutamate (MTXGlu) concentrations can guide MTX dosing in patients with rheumatoid arthritis (RA). The aim of this study was to define a therapeutic range of red blood cell (RBC) MTXGlu(n) concentrations (where n refers to the number of glutamate groups), including threshold values for efficacy and adverse effects in patients receiving long-term oral MTX treatment. METHODS: A cross-sectional study of 192 patients receiving oral MTX was undertaken. Disease activity was assessed by the swollen and tender joint counts, the C-reactive protein level, and the Disease Activity Score in 28 joints (DAS28). High disease activity was defined as a DAS28 of >3.2. A standardized questionnaire regarding common MTX adverse effects was completed. RESULTS: The MTX dosage was significantly higher in patients in whom the swollen joint count and DAS28 were higher. The MTXGlu(4), MTXGlu(5), MTXGlu(3-5), and MTXGlu(1-5) concentrations were significantly higher in patients with high disease activity. After correction for age, the estimated glomerular filtration rate, and the MTX dosage, the association remained significant for MTXGlu(5). RBC folate concentrations were significantly higher in the group with high disease activity. There was no association between any MTXGlu(n) concentration and adverse effects. CONCLUSION: In contrast to other studies, the results of the present study did not show a relationship between the MTXGlu(n) concentration and reduced disease activity in patients with RA who were receiving long-term MTX therapy. However, disease activity was influenced by the RBC folate level, which may be a more important factor than MTXGlu(n) concentrations for disease control. In accordance with the findings of previous studies, we were unable to show a relationship between MTXGlu(n) concentrations and adverse effects. Prospective studies will be important to determine whether there is a role for measuring MTXGlu(n) concentrations in patients receiving long-term treatment with MTX.
19826823 Scoring evaluation for histopathological features of synovium in patients with rheumatoid 2010 Jan The present study was performed to evaluate the synovium in patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor alpha agents (anti-TNFalpha). Synovial tissue specimens were obtained during total knee arthroplasty (TKA) from 42 RA patients (12 men, 30 women). Twenty-one RA patients were given anti-TNFalpha agents (infliximab, n = 12; etanercept, n = 9), while the remaining 21 RA patients were given no such agents.The histopathological findings were compared between specimens from these groups using the histological scoring system reported by Rooney, which consists of six items:degree of synovial hyperplasia, fibrosis, number of blood vessels, perivascular lymphocyte infiltration, focal aggregates of lymphocytes, and diffuse infiltrates of lymphocytes.Clinical laboratory data including C-reactive protein(CRP), matrix metalloproteinase-3 (MMP-3), and disease activity scores including a 28-joint count (DAS28), disease duration, methotrexate (MTX) dose, and glucocorticoid dose were also assessed before surgery. There were no significant differences in total score between anti-TNFalpha and no anti-TNFalpha groups. However, significant differences were observed in scores of synoviocyte hyperplasia and perivascular infiltrates of lymphocytes between the groups. These results suggested that these agents have a suppressive effect on cell proliferation in the lining layer and on perivascular lymphocyte infiltration. However, further studies are necessary to elucidate the mechanisms of these effects.
20359956 CD161 receptor participates in both impairing NK cell cytotoxicity and the response to gly 2010 Jul We investigated the role of natural killer (NK) cells and CD161, their primary C-type-lectin-like receptor in rheumatoid arthritis (RA). Samples were compared with healthy donors (HD), dermatomyositic (DM), polymyositic (PM), and osteoarthritic (OA) patients. RA, PM, and DM NK cell cytotoxicities significantly decreased relative to the HD and OA NK cells (p<0.0001). These results correlated with an increased expression of NK cell inhibitory receptor CD161, in active disease RA patients. We demonstrated that NK cells are able to respond to mutated citrullinated vimentin (MCV), an RA-specific autoantigen, leading to increases in both PAD4 enzyme and CD161 mRNA expression. MGAT5 glycosidase involvement was detected in GlcNAc metabolism within the synoviocytes of RA patients. Our findings reveal a functional relationship between CD161 expression and NK cell cytotoxicity as well as reactivity to glycans and MCV, thus providing new insight into the pathogenesis of RA and confirming the involvement of surface glycosylation.