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ID PMID Title PublicationDate abstract
23728499 Imaging manifestations of autoimmune disease-associated lymphoproliferative disorders of t 2013 Oct Lymphoproliferative disorders (LPDs) may involve intrathoracic organs in patients with autoimmune disease, but little is known about the radiologic manifestations of autoimmune disease-associated LPDs (ALPDs) of the lungs. The purpose of our work was to identify the radiologic characteristics of pulmonary involvement in ALPDs. A comprehensive search for PubMed database was conducted with the combination of MeSH words. All articles which had original images or description on radiologic findings were included in this analysis. Also, CT images of eight patients with biopsy-proven lymphoproliferative disorder observed from our institution were added. Overall, 44 cases of ALPD were identified, and consisted of 24 cases of bronchus-associated lymphoid tissue lymphoma (BALToma), eight cases of non-Hodgkin's lymphoma (NHL), six cases of lymphoid interstitial pneumonia (LIP), two cases of nodular lymphoid hyperplasia, two cases of unclassified lymphoproliferative disorder, and one case each of lymphomatoid granulomatosis and hyperblastic BALT. Multiple nodules (n = 14, 32 %) and single mass (n = 8, 18 %) were the predominant radiologic manifestations. The imaging findings conformed to previously described findings of BALToma, NHL, or LIP. Data suggest that BALToma, NHL, and LIP are the predominant ALPDs of the lung, and ALPD generally shared common radiologic features with sporadic LPDs. Familiarity with ALPDs and their imaging findings may enable radiologists or clinicians to include the disease as a potential differential diagnosis and thus, to prompt early biopsy followed by appropriate treatment.
22586176 Childhood socioeconomic factors and perinatal characteristics influence development of rhe 2013 Mar BACKGROUND: Rheumatoid arthritis (RA) has been associated with lower socioeconomic status (SES), but the reasons for this are not known. OBJECTIVE: To examine childhood SES measures, SES trajectory and other perinatal factors in relation to RA. METHODS: The sample included 50 884 women, aged 35-74 (84% non-Hispanic white) enrolled 2004-9 in a US national cohort study. In baseline questionnaires, cases (N=424, 0.8%) reported RA diagnosis after age 16, ever use of disease-modifying antirheumatic drugs or steroids for RA and ≥6 weeks bilateral joint swelling. Childhood SES measures are presented as OR and 95% CI adjusted for age and race/ethnicity. Analyses of perinatal factors also adjusted for childhood SES, and joint effects of childhood and adult SES and smoking exposures were evaluated. RESULTS: Patients with RA reported lower childhood household education (<12 years vs college degree; OR=1.7; 95% CI 1.1 to 2.5), food insecurity (OR=1.5, 95% CI 1.1 to 2.0) and young maternal age (<20 vs 20-34 years; OR=1.7, 95% CI 1.2 to 2.5), with a trend (p<0.0001) for increasing number of adverse factors (OR=3.0; 95% CI 1.3 to 7.0; 4 vs 0 factors) compared with non-cases. Low birth weight (<2500 g) [corrected] and preconception paternal smoking were independently associated with RA. Together, lower childhood SES and adult education (
24599922 What drives the comparative effectiveness of biologics vs. methotrexate in rheumatoid arth 2014 Jul OBJECTIVE: The aim of this study was to explore which clinical factors and patient characteristics are associated with the magnitude of comparative efficacy between biologics vs. MTX in RA patients with inadequate response to MTX. METHODS: We included randomized controlled trials assessing the efficacy of a biologic plus MTX vs. MTX alone. We examined several clinical factors and patient characteristics potentially associated with magnitude of response, measured as ACR20 (20% improvement in ACR criteria) and ACR50 (16-26 weeks). We employed meta-regression for formal estimates and statistical significance of effect modification. We produced regression and forest plots to further inspect potential associations. RESULTS: For ACR50, a 1-year increment on the average patient disease duration was statistically significantly associated with a 16% relative increase in the pooled odds ratio (OR) estimate (P = 0.003). A 1-year increment in patient age and a 1 mg/week increment in MTX dose were marginally statistically significantly associated with a 9% (P = 0.056) and 22% (P = 0.092) relative increase in the OR. For ACR20, the average number of swollen and tender joints was marginally statistically associated with a 3% relative decrease. The associations for age and MTX dose appeared to be partly driven by significant negative associations between these two factors and the control group response. CONCLUSION: Our analyses identified key variables associated with the magnitude of comparative effects for ACR outcomes. Our findings provide valuable insights for future trial designs and systematic reviews as well as decision-making and clinical practice.
23940213 Variations in criteria regulating treatment with reimbursed biologic DMARDs across Europea 2014 Nov OBJECTIVES: To explore criteria regulating treatment with reimbursed biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) across Europe and to relate criteria to indicators of national socioeconomic welfare. METHODS: A cross-sectional study among 46 European countries. One expert from each country completed a questionnaire on criteria regulating the start, maintenance/stop and switch of reimbursed bDMARDs. A composite score was developed to evaluate the level of restrictions in prescription of a first bDMARD (0=highly restricted, 5=most liberal). The level of restrictiveness was correlated with national socioeconomic welfare indicators. RESULTS: In 10 countries (22%), no bDMARD was reimbursed. Among 36 countries with at least one biologic reimbursed, 23(64%) had no requirement for disease duration to initiate a biologic. Half of the countries required a failure of two synthetic DMARDs to qualify for therapy. 31 countries specified a minimum level of disease activity to be fulfilled and in 20 (56%) countries cut-off for disease activity score with 28-joint assessment was higher than 3.2. Four countries (11%) had the maximum composite score (most liberal) and 20 (56%) scored between 0 and 2 (more restrictive). Criteria for initiation of a bDMARD were negatively associated with countries' socioeconomic welfare (-0.34 to -0.64), and a moderate positive correlation was found between the composite score and welfare indicators (0.59-0.72). Only some countries had regulations for stopping (n=14(39%)) or switching (n=19(53%)). CONCLUSIONS: Clinical criteria regulating prescription of bDMARDs in RA differ significantly across Europe. Countries with lower socioeconomic welfare tend to have stricter eligibility criteria, pointing to inequities in access to treatment.
23315865 Gαq gene promoter polymorphisms and rheumatoid arthritis in the Han Chinese population ar 2013 Jun 11 Mice that lose Gαq from their immune system can spontaneously develop inflammatory arthritis. Gαq expression in the peripheral blood lymphocytes of rheumatoid arthritis (RA) patients is significantly decreased in comparison to that in healthy individuals, and reduced Gαq expression is closely correlated with RA disease activity. These indicate that Gαq plays critical roles in the pathogenesis of RA. To address whether single nucleotide polymorphism in the promoter region of the Gαq gene (GNAQ) influenced Gαq expression in RA patients and was a genetic risk factor for RA, we sequenced the promoter region of GNAQ in a Han Chinese population. A common dinucleotide polymorphism at position -695/-694, an exchange of 2 adjacent nucleotides (GC>TT), was revealed in 118 RA patients and 101 healthy adults. The proportions of genotypes observed for -695/-694 in the RA group were GC/GC (65.25%), GC/TT (33.05%), and TT/TT (1.70%), and those in the control group were GC/GC (62.38%), GC/TT (33.66%), and TT/TT (3.96%). No significant difference in the allele and genotype frequencies between RA patients and healthy controls for dinucleotide polymorphism was found in the Han Chinese population, neither in the whole data set nor in stratified subsets, i.e., rheumatoid factors, anti-cyclic citrullinated peptide antibody, and Gαq expression status (P > 0.05). We conclude that the GNAQ promoter polymorphism is not a genetic risk factor for RA in the Han Chinese population, and that decreased Gαq expression in peripheral blood lymphocytes of RA might potentially be due to other causes.
25228459 Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis 2015 Apr The association between inhibition of tumor necrosis factor-alpha (TNF-α) in patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) and the onset of inflammatory bowel disease (IBD) is unclear. We sought to evaluate this association by analyzing adverse events (AEs) reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) with a standardized scoring tool for drug-induced AEs. A search of the FAERS for RA or JRA (January 2003-December 2011) reported with adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab was performed. This dataset was then queried for cases indicating IBD. Full-length reports were accessed using the Freedom of Information Act and organized by age, sex, concomitant medications, co-morbidities, type of TNF-α inhibitor used, and diagnosis/treatment details. The Naranjo score was used to determine whether the drug-induced AEs were definite, probable, possible, or doubtful. There were 158 cases of IBD after TNF-α inhibitor exposure in RA or JRA patients. Use of the Naranjo score revealed that, in a majority of the cases (71.5 %), TNF-α inhibitor exposure was considered a 'possible' cause. A majority of the 'probable cases' in JRA were reported with etanercept (40 patients, 90.91 %). There were no 'definite' cases of anti-TNF-induced IBD. After applying the Naranjo scale, a weak association between new-onset IBD and TNF-α inhibitor therapy in RA patients and a moderately strong association especially with etanercept exposure in JRA patients was observed. However, causality cannot be determined due to limitations of the FAERS and the Naranjo score.
24817415 Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis 2015 Sep OBJECTIVES: Immunological events in the lungs might trigger production of anti-citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA. PATIENTS AND METHODS: Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA. RESULTS: Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA. CONCLUSIONS: Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.
23972290 Associations of interleukin-4 receptor gene polymorphisms (Q551R, I50V) with rheumatoid ar 2013 Oct BACKGROUND AND AIMS: Published data on the associations between interleukin-4 receptor (IL-4R) gene polymorphisms (Q551R, I50V) and rheumatoid arthritis (RA) risk are controversial. To quantitatively evaluate the relationships, a meta-analysis was performed. METHODS: Studies were identified from the databases of PubMed, MEDLINE, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure, with the last report up to June 2012. The effect summary odds ratio (OR) and 95% confidence interval (CI) were obtained. RESULTS: A total of six separate comparisons involving 2173 patients and 1892 controls were included to assess the association of IL-4R gene Q551R polymorphism and RA susceptibility. Overall, no significantly elevated RA risk was found in the meta-analysis. The pooled OR for the minor R allele was 0.942 (95% CI: 0.848-1.047, p=0.268) in patients with RA. After stratification by ethnicity, there was still no significant association detected in the European population (OR=0.979, 95% CI: 0.875-1.094). As for I50V polymorphism, there were four comparisons involving 1653 patients and 1584 controls in this meta-analysis. The pooled OR for the V allele was 1.104 (95% CI: 1.001-1.217) in RA, the V allele of the IL-4R gene I50V variant might be a risk factor for RA. However, the relationship between the V allele of IL-4R gene I50V polymorphism and rheumatoid factor positive in patients with RA was not identified through a minor meta-analysis, including four independent relevant comparisons. CONCLUSIONS: This meta-analysis indicates that the I50V polymorphism of IL-4R gene may confer susceptibility to RA; up to now, there is still not enough evidence to reveal the association of the IL-4R gene Q551R polymorphism with RA risk.
24465537 Increased HEV seroprevalence in patients with autoimmune hepatitis. 2014 BACKGROUND: Hepatitis E virus (HEV) infection takes a clinically silent, self-limited course in the far majority of cases. Chronic hepatitis E has been reported in some cohorts of immunocompromised individuals. The role of HEV infections in patients with autoimmune hepatitis (AIH) is unknown. METHODS: 969 individuals were tested for anti-HEV antibodies (MP-diagnostics) including 208 patients with AIH, 537 healthy controls, 114 patients with another autoimmune disease, rheumatoid arthritis (RA), and 109 patients with chronic HCV- or HBV-infection (HBV/HCV). Patients with AIH, RA and HBV/HCV were tested for HEV RNA. HEV-specific proliferative T cell responses were investigated using CFSE staining and in vitro stimulation of PBMC with overlapping HEV peptides. RESULTS: HEV-antibodies tested more frequently positive in patients with AIH (n = 16; 7.7%) than in healthy controls (n = 11; 2.0%; p = 0.0002), patients with RA (n = 4; 3.5%; p = 0.13) or patients with HBV/HCV infection (n = 2; 2.8%; p = 0.03). HEV-specific T cell responses could be detected in all anti-HEV-positive AIH patients. One AIH patient receiving immunosuppression with cyclosporin and prednisolone and elevated ALT levels had acute hepatitis E but HEV viremia resolved after reducing immunosuppressive medication. None of the RA or HBV/HCV patients tested HEV RNA positive. CONCLUSIONS: Patients with autoimmune hepatitis but not RA or HBV/HCV patients are more likely to test anti-HEV positive. HEV infection should been ruled out before the diagnosis of AIH is made. Testing for HEV RNA is also recommended in AIH patients not responding to immunosuppressive therapy.
23467774 Septic shock after seasonal influenza vaccination in an HIV-infected patient during treatm 2013 May Anti-tumor necrosis factor alpha (anti-TNF-α) is used in the treatment of rheumatic diseases not responsive to first-line regimens. Data on the safety of anti-TNF-α in HIV-infected patients are scarce and conflicting. We describe a case of septic shock and multiorgan failure that occurred after etanercept initiation and influenza vaccination in an HIV-infected woman with rheumatoid arthritis.
24889405 T cell ALL presenting as seropositive rheumatoid arthritis: case report and review of the 2015 Sep We present the case of a 61-year-old female with an acute onset of polyarthritis involving the wrists, hands, knees, and ankles. Associated systemic symptoms included fever, weight loss, and lymphadenopathy. Serologic workup revealed positive rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP) antibodies. Radiograph imaging of her bilateral hands and wrists showed erosive joint disease and lymph node, and bone marrow biopsy confirmed a diagnosis of T cell lymphoblastic leukemia. Our case demonstrates a unique clinical phenotype of paraneoplastic arthritis and is only the second reported case of RF, anti-CCP-positive arthritis related to a hematological malignancy. We review the only three published cases of seropositive paraneoplastic arthritis. In each case, systemic symptoms or a poor response to steroid treatment triggered additional workup. These cases highlight the importance of careful clinical assessment and vigilance to rule out secondary causes of inflammatory arthritis, even in patients with seropositive erosive arthritis.
23901134 HLA-C alleles confer risk for anti-citrullinated peptide antibody-positive rheumatoid arth 2013 Nov OBJECTIVE: The MHC exerts the greatest contribution to RA susceptibility, where certain HLA-DRB1 alleles confer the greatest risk. Interestingly, there is evidence for more risk factors in the MHC with regions surrounding the HLA class I loci, but whether these antigen-presenting loci could be causal risk variants has not been directly investigated. In this study we investigate the HLA association by direct genotyping of the HLA loci. METHODS: Nine hundred and fifty RA patients and 933 healthy controls were genotyped for HLA-A, -B and -C. Eleven single-nucleotide polymorphisms (SNPs) and one insertion/deletion in the MHC were also included. Conditional logistic regression analyses were performed separately in ACPA-positive and -negative RA to identify the strongest susceptibility locus and additional risk loci. RESULTS: In ACPA-positive RA, the most significantly associated locus was HLA-DRB1 (P = 1.58 × 10(-54)), with SE alleles being predisposing. After controlling for HLA-DRB1, the HLA-C locus was found to confer susceptibility (P = 2.32 × 10(-9)), particularly, the HLA-C*03 allele. Also, in ACPA-negative RA, HLA-DRB1 was the most significant locus (P = 7.22 × 10(-9)), but with other risk alleles (particularly DRB1*03). A possible independent involvement of HLA-C was also observed for ACPA-negative RA (P = 0.02). CONCLUSION: HLA-DRB1 was the major MHC risk locus in both ACPA-positive and ACPA-negative RA, but with allelic risk heterogeneity. Joint analyses of the HLA class I loci together with previously proposed SNP associations pointed at HLA-C as a second susceptibility locus in ACPA-positive RA.
24234752 Association between polymorphism in TRAF1/C5 gene and risk of rheumatoid arthritis: a meta 2014 Jan Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease. Single nucleotide polymorphisms of tumor necrosis factor-receptor associated factor 1/complement component 5 (TRAF1/C5) gene are suspected to be associated with the risk of RA. This meta-analysis was performed to study the relationship between the polymorphism rs10818488 in TRAF1/C5 gene with RA. We retrieved the relevant articles from PubMed, EMBASE and the China National Knowledge Infrastructure databases. Odd ratios were calculated to assess the association between TRAF1/C5 rs10818488 polymorphism and RA risk. Meta-analyses were performed on the total data set and separately for the major ethnic groups and RF and ACAP status. All analyses were performed using the Stata software. Eight articles were included in the present analysis. Meta-analysis showed a weak association between TRAF1/C5 rs10818488 polymorphism and RA in all subjects (OR = 1.13, 95 % CI = 1.01–1.27, P heterogeneity < 0.001). Stratified analyses indicated that the TRAF1/C5 rs10818488 A allele was significantly associated with RA in Caucasians (OR = 1.29, 95 %CI = 1.14–1.47, P heterogeneity = 0.026), Asians (OR = 0.92, 95 %CI = 0.86–0.99, P heterogeneity = 0.378) and Africans (OR = 1.56, 95 %CI = 1.23–1.98, P heterogeneity = 0.876), also significantly in positive ACPA and positive RF patients versus controls (ORs were 1.20 and 1.25, 95 %CIs were 1.08–1.33 and 1.14–1.37, P values for heterogeneity were 0.215 and 0.133, respectively). Genetic polymorphism rs10818488 in TRAF1/C5 gene might be associated with RA susceptibility.
23622819 Hand impairment and activity limitations in four chronic diseases. 2013 Jul STUDY DESIGN: Retrospective cohort. INTRODUCTION: Hand involvement in osteoarthritis (OA) and rheumatoid arthritis (RA) are well known to occupational and physical therapists; however, it is not known whether the impairments and activity limitations with diabetes (DMII) and systemic sclerosis (SSc) are as severe as those observed with OA and RA. PURPOSE: To compare the hand impairments and activity limitations in the 4 diseases. METHODS: A convenience sample of 156 participants received evaluations of hand impairments: strength, joint motion, and dexterity and completed a hand activity limitations questionnaire. RESULTS: The SSc and RA participants had weaker pinch, decreased joint motion and more activity limitations than the DMII and OA groups. There were no significant differences between the groups for right hand grip strength and pegboard dexterity, and applied dexterity. CONCLUSIONS: OA and DMII groups had significantly less impairments and activity limitations than the SSc and RA groups. LEVEL OF EVIDENCE: 2C.
24942081 Rank-based tests for identifying multiple genetic variants associated with quantitative tr 2014 Jul We consider the analysis of multiple genetic variants within a gene or a region that are expected to confer risks to human complex diseases with quantitative traits, where the trait values do not follow the normal distribution even after some transformations. We rank the phenotypic values, calculate a score to measure the trend effect of a particular allele for each marker, and then construct three statistics based on the quadratic frameworks of methods Hotelling T(2) , the summation of squared univariate statistic and the inverse of the square root weighted statistics to combine the scores for different marker loci. Simulation results show that the above three test statistics can control the type I error rate well and are more robust than standard tests constructed based on linear regression. Application to GAW16 data for rheumatoid arthritis successfully detects the association between the HLA-DRB1 gene and anticyclic citrullinated protein measure, while the standard methods based on normal assumption cannot detect this association.
24963082 Total wrist arthroplasty: a systematic review of the evidence from the last 5 years. 2015 Jun We reviewed evidence on total wrist replacement from the last 5 years. Eight articles met a minimum set standard. The results of 405 prostheses were available, including seven different manufacturers. The mean follow up was 2.3-7.3 years with an average age of 52-63. Rheumatoid arthritis was the indication in 42% of patients. Motec demonstrated the best post-operative DASH scores. Only Maestro achieved a defined functional range of motion post-operatively. Universal 2 displayed the highest survival rates (100% at 3-5 years), while Elos had the lowest (57% at 5 years). Biaxial had the highest complication rates (68.7%), while Remotion had the lowest (11%). Wrist arthroplasty preserves some range of motion. Functional scores improved and were maintained over the mid- to long-term. Complication rates were higher than wrist fusion, with reports of radiological loosening and osteolysis. The evidence does not support the widespread use of arthroplasty over arthrodesis, and careful patient selection is essential.
25072264 Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. 2014 Nov Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.
24612941 Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Cur 2014 Mar 1 BACKGROUND: Methotrexate (MTX) is currently considered the drug of choice, among the disease-modifying antirheumatic drugs, for the treatment of rheumatoid arthritis (RA) because of its favorable risk/benefit ratio, good safety profile, and low costs. Despite MTX's widespread use and large experience accumulated over the many years since its introduction into clinical practice, specific guidelines have not been published. OBJECTIVE: We report here the available research regarding the optimal dosage and route of MTX administration. METHODS: MEDLINE and the Cochrane Library were systematically searched for articles published between 1990 and 2013, using terms related to RA and MTX. The search was conducted by using both MeSH terms and free text. The references of the retrieved studies were also screened manually for additional articles. RESULTS: For the treatment of rheumatic diseases, the antimetabolite drug MTX can be administered weekly by different routes: oral, subcutaneous, or intramuscular. One of the goals of treatment is to minimize acute and chronic toxicity. A starting dose of 15 mg/week orally, escalating to 25 to 30 mg/week or the highest tolerable dose (with a subsequent switch to parenteral administration in cases of insufficient response), seems to be the optimal evidence-based strategy for MTX treatment of RA. Oral MTX is widely preferred because of its low costs and patient preferences; the bioavailability of parenteral MTX is higher, however. This is supported by data from observational studies, in which patients switching from parenteral to oral MTX at an equal dose had disease exacerbations. In several trials, the subcutaneous formulation of MTX was considered, by both physicians and patients, to be more advantageous in terms of discomfort and compliance. In addition, a significant proportion of patients reported that this formulation led to greater independence, with a resulting improvement in quality of life. CONCLUSIONS: Although MTX treatment can be initiated by using the oral administration route, parenteral administration of MTX is indicated in those patients with poor compliance toward the oral form. The subcutaneous route seems to be more effective than the oral route for MTX administration based on the results of several studies, and this route may be preferred because of better usability and absence of pain at the infusion site.
23394392 Methotrexate pharmacogenetics in rheumatoid arthritis: a status report. 2013 Feb Methotrexate (MTX), an antifolate drug, is the first-line disease-modifying agent for the treatment of rheumatoid arthritis (RA) worldwide. MTX has excellent long-term efficacy, tolerability and safety. Early initiation of MTX in patients with RA controls joint destruction and slows progression of disease. However, the clinical response to MTX and frequency of adverse effects from the drug exhibit marked interpatient variability. Over the past decade, there has been a quest to identify genetic markers that reliably predict MTX efficacy and toxicity and help optimize MTX therapy in RA; that is, the field of MTX pharmacogenetics. This review will summarize key pharmacogenetic studies examining SNPs in the genes encoding enzymes in the MTX cellular pathway and their association with MTX response in RA. As evident from this review, MTX pharmacogenetics in RA remains a muddled field, mostly due to inconsistent results from several small underpowered studies.
23876175 Molecular targeting of hepatocyte growth factor by an antagonist, NK4, in the treatment of 2013 Jul 22 INTRODUCTION: Hepatocyte growth factor (HGF) is a potent proangiogenic molecule that induces neovascularization. The HGF antagonist, NK4, competitively antagonizes HGF binding to its receptor. In the present study, we determined the inhibitory effect of NK4 in a rheumatoid arthritis (RA) model using SKG mice. METHODS: Arthritis was induced in SKG mice by a single intraperitoneal injection of β-glucan. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was also injected intravenously at the time of or 1 month after β-glucan injection. Ankle bone destruction was examined radiographically. The histopathologic features of joints were examined using hematoxylin and eosin and immunohistochemical staining. Enzyme-linked immunosorbent assays were used to determine the serum levels of HGF, interferon γ (IFN-γ, interleukin 4 (IL-4) and IL-17 production by CD4⁺ T cells stimulated with allogeneic spleen cells. RESULTS: The intravenous injection of AdCMV.NK4 into SKG mice suppressed the progression of β-glucan-induced arthritis. Bone destruction was also inhibited by NK4 treatment. The histopathologic findings of the ankles revealed that angiogenesis, inflammatory cytokines and RANKL expression in synovial tissues were significantly inhibited by NK4 treatment. Recombinant NK4 (rNK4) proteins inhibited IFN-γ, IL-4 and IL-17 production by CD4⁺ T cells stimulated with allogeneic spleen cells. CONCLUSIONS: These results indicate that NK4 inhibits arthritis by inhibition of angiogenesis and inflammatory cytokine production by CD4⁺ T cells. Therefore, molecular targeting of angiogenic inducers by NK4 can potentially be used as a novel therapeutic approach for the treatment of RA.