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ID PMID Title PublicationDate abstract
25848939 Variation at FCGR2A and functionally related genes is associated with the response to anti 2015 OBJECTIVE: Anti-TNF therapies have been highly efficacious in the management of rheumatoid arthritis (RA), but 25-30% of patients do not show a significant clinical response. There is increasing evidence that genetic variation at the Fc receptor FCGR2A is associated with the response to anti-TNF therapy. We aimed to validate this genetic association in a patient cohort from the Spanish population, and also to identify new genes functionally related to FCGR2A that are also associated with anti-TNF response. METHODS: A total of 348 RA patients treated with an anti-TNF therapy were included and genotyped for FCGR2A polymorphism rs1081274. Response to therapy was determined at 12 weeks, and was tested for association globally and independently for each anti-TNF drug (infliximab, etanercept and adalimumab). Using gene expression profiles from macrophages obtained from synovial fluid of RA patients, we searched for genes highly correlated with FCGR2A expression. Tag SNPs were selected from each candidate gene and tested for association with the response to therapy. RESULTS: We found a significant association between FCGR2A and the response to adalimumab (P=0.022). Analyzing the subset of anti-CCP positive RA patients (78%), we also found a significant association between FCGR2A and the response to infliximab (P=0.035). DHX32 and RGS12 were the most consistently correlated genes with FCGR2A expression in RA synovial fluid macrophages (P<0.001). We found a significant association between the genetic variation at DHX32 (rs12356233, corrected P=0.019) and a nominally significant association between RGS12 and the response to adalimumab (rs4690093, uncorrected P=0.040). In the anti-CCP positive group of patients, we also found a nominally significant association between RGS12 and the response to infliximab (rs2857859, uncorrected P=0.042). CONCLUSIONS: In the present study we have validated the FCGR2A association in an independent population, and we have identified new genes associated with the response to anti-TNF therapy in RA.
26125863 Osteoprotegerin polymorphisms in Chinese Han patients with rheumatoid arthritis. 2015 Jun 12 In order to investigate the association between osteoprotegerin (OPG) gene polymorphisms and rheumatoid arthritis (RA), we studied OPG rs3102735 T/C and rs2073618 G/C polymorphisms in a Chinese Han population comprising 574 patients with RA and 804 controls. Genotyping by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was conducted. Our data indicated that OPG rs3102735 T/C and rs2073618 G/C polymorphisms were not associated with the risk of RA. However, among older patients (≥55 years), patients with the OPG rs3102735 TC (TC vs TT: OR = 0.68, 95%CI = 0.49‑0.96, P = 0.029) and TC/CC (TC+CC vs TT: OR = 0.69, 95%CI = 0.49‑0.96, P = 0.026) genotypes showed a significantly lower risk of RA than patients with the TT genotype, while patients with the OPG rs2073618 GC (GC vs GG: OR = 1.53, 95%CI = 1.13‑2.07, P = 0.006) and GC/CC (GC+CC vs GG: OR = 1.43, 95%CI = 1.07‑1.92, P = 0.015) genotypes showed a significantly higher risk of RA than patients with the GG genotype. We also found a significantly increased risk of RA associated with the OPG rs2073618 GC (GC vs GG: OR = 1.44, 95%CI = 1.07‑1.93, P = 0.018) and GC/CC (GC+CC vs GG: OR = 1.39, 95%CI = 1.04‑1.86, P = 0.024) genotypes among functional class III+IV patients. Our results were obtained from only a moderate-sized sample and, thus, a larger study with a more diverse ethnic population is needed to confirm these results.
25970542 An appendectomy increases the risk of rheumatoid arthritis: a five-year follow-up study. 2015 Many studies have reported a possible association of an appendectomy with rheumatoid arthritis (RA). However, findings of the relationship between an appendectomy and RA remain inconsistent. Furthermore, all such studies were conducted in Western societies, and relevant studies on the relationship between an appendectomy and RA in Asian countries are still lacking. In this study, we investigated the relationship between an appendectomy and the subsequent risk of RA using a population-based dataset. We retrieved data for this retrospective cohort study from the Taiwan "Longitudinal Health Insurance Database 2005". We included 4,294 subjects who underwent an appendectomy in the study cohort and 12,882 matched subjects in the comparison cohort. We individually tracked each subject for a 5-year period from their index date to identify those who developed RA. A stratified Cox proportional hazard regression was performed to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI) for the subsequent development of RA during the 5-year follow-up period between subjects who underwent an appendectomy and comparison subjects. Of the sampled subjects, 93 (0.54%) received a diagnosis of RA during the 5-year follow-up period: 33 from the study cohort (0.77% of subjects who underwent an appendectomy) and 60 from the comparison cohort (0.47% of comparison subjects) (p<0.001). After censoring individuals who died during the follow-up period and adjusting for subjects' monthly income and geographic region, the HR of RA during the 5-year follow-up period was 1.61 (95% CI = 1.05~2.48) for subjects who underwent an appendectomy compared to comparison subjects. We found that among females, the adjusted HR of RA was 1.76 (95% CI = 1.04~2.96) for subjects who underwent an appendectomy compared to comparison subjects. However, there was no increased hazard of RA for males who underwent an appendectomy compared to comparison subjects. We concluded that female subjects who undergo an appendectomy have a higher risk of RA than comparison female subjects.
26226612 Are All Biologics the Same? Optimal Treatment Strategies for Patients With Early Rheumatoi 2015 Dec BACKGROUND: The use of biologic agents has revolutionized the treatment of rheumatoid arthritis (RA). However, there is much uncertainty about whether any agent may be preferable. PURPOSE: The aim of the study was to evaluate the comparative efficacy of biologic agents with a disease-modifying antirheumatic drug (DMARD) in RA patients without prior exposure to a DMARD, that is, DMARD naive. METHODS: MEDLINE, Cochrane, and Clinicaltrials.gov were searched from 1990 to August 2013 for randomized controlled trials comparing biologic agents in conjunction with a DMARD and DMARDs alone in DMARD (methotrexate [MTX])-naive RA patients. Information on patient characteristics, disease duration, and the American College of Rheumatology (ACR) 20/50/70/90 response rates after 52 weeks was extracted. RESULTS: Six randomized controlled trials totaling 9 study arms fulfilled the inclusion criteria. Data were analyzed by direct and indirect pairwise comparisons of 2 drugs against a common comparator. In the direct comparison, all 6 biologic therapies were associated with significantly higher likelihood of achieving an ACR20 compared with MTX alone (mean ORs, 1.43-2.99). For ACR50 and ACR70, all biologic agents except golimumab showed statistically significant mean ORs of 1.31 to 2.52 (ACR20) and 1.79 to 2.59 (ACR50). At ACR90, abatacept 10 mg/kg, adalimumab 40 mg, and rituximab 500 and 1000 mg were significantly better compared with MTX (mean ORs 1.92-2.89). The indirect comparison for ACR20 showed etanercept 50 mg significantly favored against adalimumab 40 mg (OR, 1.05-3.34), golimumab 50 mg (OR, 1.16-4.07), infliximab 3 mg/kg (OR, 1.21-3.61), and infliximab 6 mg/kg (OR, 1.02-3.06). At ACR50, etanercept 50 mg and rituximab 1000 mg showed significantly higher ORs compared with golimumab 100 mg at ORs 1.06 to 3.42 and ORs 1.07 to 3.42, respectively. No significant differences were observed in the biologic agents for indirect pairwise comparisons at ACR70 and ACR90.Lack of head-to-head clinical trial data directly comparing biologic agents makes indirect meta-analysis the only substitute. Safety and cost of these agents were not evaluated. Only a small number of trials could be evaluated because of the strict inclusion criteria required for an indirect meta-analysis. Unmeasured confounders could contribute to trial heterogeneity. The data on golimumab were difficult to reconcile with the other trials because of methodological differences. CONCLUSIONS: Overall, biological agents in conjunction with a DMARD performed similarly in the settings evaluated. However, there were some statistically significant differences. Etanercept 50 mg appears superior to adalimumab 40 mg, golimumab 50 mg, and infliximab 3 and 6 mg/kg at ACR20. Rituximab 1000 mg and etanercept 50 mg appeared superior to golimumab 100 mg at ACR50 in DMARD-naive patients. No agent was superior to all others at each ACR level.
26084325 Effectiveness and survival-on-drug of certolizumab pegol in rheumatoid arthritis in clinic 2015 OBJECTIVES: Evidence regarding the efficacy and effectiveness of certolizumab pegol (CZP) in rheumatoid arthritis (RA) patients who have failed to respond to treatment with a tumour necrosis factor inhibitor (TNFi) is limited. The aim of this study was to describe the effectiveness and survival-on-drug of CZP in a real-life setting, both in TNFi-naïve patients and in patients who had previously failed TNFis, and in relation to disease activity at baseline. METHOD: The national Swedish Rheumatology Quality Register (SRQ) was used to identify patients with RA starting treatment with CZP between 2009 and 2013. The effectiveness of treatment was assessed using the 28-joint Disease Activity Score (DAS28), the Health Assessment Questionnaire (HAQ), measures of remission, the European League Against Rheumatism (EULAR) response during 0-6 months from start of treatment, and survival-on-drug during the first 30 months. RESULTS: A total of 945 RA patients started treatment with CZP. Of these, 540 (57.1%) received CZP as the first biological treatment, 215 (23%) had failed one previous TNFi, and 190 (20%) had failed at least two TNFis. Overall, 71% achieved at least a EULAR moderate response and 38% had a EULAR good response at 6 months from baseline. TNFi-naïve patients achieved significantly better results and had better survival-on-drug compared to patients who had failed previous TNFis. Around 20% of patients who had not responded to two or more prior TNFis achieved EULAR good response to therapy and a similar percentage achieved remission. Patients who had high baseline disease activity had a higher risk of discontinuing treatment compared to those without high disease activity. CONCLUSIONS: In this real-life RA cohort, CZP was associated with significant clinical improvement. The effectiveness and survival-on-drug vary markedly depending on the line of treatment.
26307354 Rheumatoid factor, not antibodies against citrullinated proteins, is associated with basel 2015 Aug 26 INTRODUCTION: Although the prognostic value of rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPAs) in patients with rheumatoid arthritis (RA) is well established, their association with RA disease activity remains unclear. Here, we investigate this association in a large study using data from clinical trials. METHODS: We used baseline data from four recent randomized controlled clinical trials of RA. We investigated individual and composite measures of disease activity. The relationship of RF and ACPAs with these measures was investigated by using stratified analysis (comparing four groups of patients according to the presence or absence of RF and ACPAs) and matched analysis (disease activity levels compared between patients negative and patients highly positive for one autoantibody who were matched for levels of the other autoantibody as well as for age, gender, and duration of RA). RESULTS: A total of 2118 patients were analysed in the different cohorts. In the stratified analysis, RF(+) patients, regardless of ACPA status, had the highest levels of disease activity, whereas ACPA(+) patients had disease activity that was similar to or lower than that of ACPA(-) patients, both in the presence and in the absence of RF. When matched for ACPA levels, patients with highly positive RF had significantly higher disease activity for all composite indices compared with patients who were RF(-) (P = 0.0067), whereas ACPA-highly-positive and ACPA-negative patients matched for RF levels had similar disease activity, again even with the tendency toward lower disease activity for ACPA(+) patients (P = 0.054). CONCLUSION: The data presented suggest that the presence of RF has a clear association with higher levels of disease activity but that the presence of ACPAs has not and even appears to be associated with lower disease activity.
25644535 Genotyping in rheumatoid arthritis: a game changer in clinical management? 2015 Mar Rheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation characterized by painful inflammation of synovial joints. Despite advances in its management afforded by biologic drug development, efforts to improve outcomes for patients are confounded by the condition's heterogeneous pathobiology, and consequent variability in therapeutic responses. Great strides have been made in understanding the genetic epidemiology of rheumatoid arthritis since its association with the HLA locus was established in the 1980s, with over 100 additional disease-associated variants now confirmed through cumulative genome-wide association studies. Yet translation of this new knowledge for patient benefit - whether as a route to predicting disease risk, drug development or personalized medicine - has been slow. To address this, collaborating teams of interdisciplinary scientists will need to pool resources, including ever larger, well-characterized patient cohorts and sophisticated biostatistical approaches. Recent advances suggest that the fruits of these endeavors are beginning to come within reach.
25437122 Approach to the diagnosis of unusual carpal ankylosis from ancient Egypt. 2015 Jan OBJECTIVES: Carpal fusion is not an uncommon finding in archaeological bones. The majority of cases are due to inflammatory or infectious diseases and those are usually associated with other major alterations in the skeleton. METHODS: Two distinct individual cases, both adult females recovered from the Necropolis of Sharuna in the Middle Egypt from the Ptolemaic Period (IV to I BC) are presented in this study. Specimen 4323/1 shows a fusion of the scaphoid, lunate and triquetral bones in the right wrist. Specimen 4323/2 is a very rare fusion of a dysplastic lunate bone with the radius in the left wrist. In the proximal end of that left wrist, two possible remains of the flattened scaphoid and triquetral bones are also present. RESULTS: A differential diagnosis of both abnormalities as well as broad research into similar paleopathological cases were carried out: the most probable diagnosis for the specimen 4323/1 is an uncommon carpal coalition of three bones from the same row; the diagnosis of the specimen 4323/2 is more dubious with both rheumatoid arthritis and septic arthritis being strong candidates. CONCLUSIONS: In archaeological remains, carpal fusion should be thoroughly studied in order to ensure an accurate differential diagnosis.
27272985 Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I lo 2016 Jun 8 Considerable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran's homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (PHeterogeneity = 9.6 × 10(-9) at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and PMeta = 4.2 × 10(-13) in Asians; ORMeta = 1.00 and PMeta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
25370437 Usefulness of monitoring of B cell depletion in rituximab-treated rheumatoid arthritis pat 2015 Apr Our objective was to evaluate the contribution of monitoring B cell subset depletion after rituximab in patients with rheumatoid arthritis (RA) in order to guide reintroduction to forestall relapse. This prospective, monocentre study included all RA patients receiving two 1-g rituximab infusions at a 15-day interval. The patients were followed clinically and biologically every 2 months until rituximab reintroduction. The physician was blinded to lymphocyte-typing results to diagnose relapse and, hence, retreatment. Among the 39 patients included between March 2010 and December 2011 and followed until April 2013, seven received two rituximab cycles, yielding a total of 46 cycles for analysis. After the two rituximab cycles, the total number of CD19(+) B cells decreased significantly (0·155 versus 0·0002 G/l, P < 0·0001), with complete depletions in all patients of CD19(+) CD38(++) CD24(++) (transitional) (P < 0·0001) and CD19(+) CD27(+) (memory) B lymphocytes. A significant majority of patients relapsed within the 4 months following repopulation of total B (P = 0·036), B transitional (P = 0·007) and B memory (P = 0·01) lymphocytes. CD19(+) B lymphocyte repopulation preceded clinical RA relapse and enabled its prediction 4 months in advance. Hence, monitoring of CD19(+) B lymphocytes could serve as a tool to predict those relapses.
26862118 Experiences of Patients With Rheumatoid Arthritis: A Qualitative Study. 2017 Jun Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that greatly impacts one's physical and psychosocial well-being. The purpose of this study was to explore the experiences and support needs of adult patients living with RA. A descriptive qualitative study was conducted, and 16 adults with RA were interviewed from October 2013 to January 2014. The transcribed data were analyzed using thematic analysis. Five themes were identified: altered physical capacity and well-being, psychological and emotional challenges, changes in social life, coping strategies, and support received and further support needs. This study provided insights into the experiences and support needs of patients with RA in Singapore. Physical and psychosocial challenges experienced by patients affected their daily and social activities. Patients' needs for variety of support should be addressed.
26336889 Management of hyperlipidemia among patients with rheumatoid arthritis in the primary care 2015 Sep 3 BACKGROUND: Rheumatoid arthritis (RA) has been associated with an increased risk of cardiovascular morbidity and mortality but this has not translated to optimal management of traditional cardiovascular risk factors such as hyperlipidemia. The objectives of this study were to 1) determine the prevalence of screening for hyperlipidemia in patients with RA followed by primary care practitioners (PCP); 2) examine initiation of lipid-lowering therapy in patients with an indication, and 3) assess whether proposed modifications to cardiovascular risk calculations change the percentage of RA patients with an indication for therapy. METHODS: We performed a retrospective cohort study using an academic medical center-based medical record database in the United States. Patients with RA defined by the presence of at least one ICD-9 code between 2005-2010 and followed by a PCP within the health care system were included. The positive predictive value of ICD-9 codes for accurately identifying patients with RA was 96.7%. Descriptive statistics were used to report the prevalence of screening and use of lipid-lowering therapy among those with an indication. Factors associated with not receiving lipid screening were examined using logistic regression models. Indication for and receipt of therapy were then assessed before and after the application of the European Union League Against Rheumatism (EULAR) recommended multiplier to the Framingham risk score. RESULTS: Among 1,056 patients with RA followed by PCPs and eligible for lipid screening, lipid screening was ordered for 539 (51%) within the 3-year follow-up period. Patients with diabetes, hypertension, chronic kidney disease, obesity or age >50 were more likely to be screened. Of those with lipid results (N = 290), 25 (9%) patients had an indication for lipid-lowering therapy based on Adult Treatment Panel III guidelines. Ten (40%) patients with an indication for lipid-lowering therapy received therapy did not receive therapy. Applying the EULAR multiplier only changed the indication for lipid-lowering therapy in two patients. CONCLUSIONS: Screening and management of traditional cardiovascular risk factors, including hyperlipidemia, need to be optimized.
27101816 Treatment Patterns, Direct Cost of Biologics, and Direct Medical Costs for Rheumatoid Arth 2016 Jun PURPOSE: The aims of this article were to characterize the patterns of treating rheumatoid arthritis with biologics and to evaluate costs using claims data from the Japan Medical Data Center Co, Ltd. METHODS: Patients aged 16 to <75 years who were diagnosed with rheumatoid arthritis and prescribed adalimumab (ADA), etanercept (ETN), infliximab (IFX), tocilizumab (TCZ), abatacept, certolizumab, or golimumab between January 2005 and August 2014 were included. For the cross-sectional analysis, the annual costs of ETN, IFX, ADA, and TCZ from 2009 to 2013 were assessed. For the longitudinal analysis, patients prescribed these biologics as the first line of biologics, from January 2005 to August 2014, were included. The cost of biologic treatment over 1, 2, and 3 years (including prescription of subsequent biologics) and direct medical costs (including treatment of comorbidities) were compared between groups. Discontinuation and switching rates in each group were estimated, and multivariate analyses were conducted to estimate an adjusted hazard ratio of discontinuation and switching rates among each group. The dose of each first-line biologic treatment until discontinuation was analyzed to calculate relative dose intensity. FINDINGS: The cross-sectional annual biologic costs of ETN, IFX, ADA, and TCZ were ~$8000 (2009 and 2013), $13,000 (2009) and $15,000 (2013), $10,000 (2009) and $11,000 (2013), and $9000 (2009) and $8000 (2013), respectively. In longitudinal analyses (n = 764), 276 (36%) initiated ETN; 242 (32%), IFX; 147 (19%), ADA; and 99 (13%), TCZ. The 1-year cumulative annual biologic costs per patient from the initial prescription of ETN, IFX, ADA, and TCZ as the first-line biologic treatment were ~$11,000, $19,000, $16,000, and $12,000. The corresponding direct medical costs over 1 year from the initial prescription were ~$17,000, $26,000, $22,000, and $22,000. Costs remained greatest in the IFX-initiation group at year 3. The discontinuation rates at 36 months with ETN, IFX, ADA, and TCZ were 37.7%, 52.3%, 55.8%, and 39.5%; the switching rates were 12.5%, 27.1%, 31.0%, and 16.7%. The mean (95% CI) relative dose intensities until discontinuation of ETN 25 mg, ETN 50 mg, IFX, ADA, and TCZ were 1.02 (0.95-1.10), 0.82 (0.79-0.85), 1.16 (1.12-1.20), 0.95 (0.90-0.99), and 0.96 (0.93-1.00). IMPLICATIONS: Considered costs and discontinuation and switching event rates were lowest with ETN versus IFX, ADA, or TCZ used as the first-line biologic. Despite limitations, these findings imply clinical cost-reductive benefits of ETN as the first-line biologic treatment option for rheumatoid arthritis in Japan.
26922083 MMP-3 as a predictor for structural remission in RA patients treated with MTX monotherapy. 2016 Feb 27 BACKGROUND: The study was undertaken to assess the efficacy of methotrexate (MTX) monotherapy on the radiographic progression of individual rheumatoid arthritis (RA) patients, each of whom had received MTX monotherapy for 3 years with an option to change to biological disease-modifying anti-rheumatic drugs (bDMARDs). We also looked for predictors of radiographic non-progression in these patients. METHODS: Rheumatoid patients (n = 161) were prospectively followed for 3 years while receiving low-dose MTX monotherapy unless disease was otherwise active and/or adverse events appeared. Their disease activity and radiographic progression were evaluated with reference to disease activity score 28 (DAS28), modified health assessment of questionnaire (mHAQ) and other indices. The change in van der Heijde-modified total Sharp score per year (∆TSS) was assessed using probability plots, in which the patients were classified into the subgroups showing structural remission (REM; ∆TSS ≤0.5), radiographic progression (∆TSS >3) or rapid radiographic progression (RRP; ∆TSS >5). RESULTS: MTX monotherapy, continued until disease became active and/or adverse event appeared, was associated with a significant improvement (p <0.0001) in the DAS28-ESR (3) scores, % DAS28 remission, and mHAQ scores each year, from baseline to 3 years. The mHAQ remission rate (∆mHAQ <0.5) and Boolean remission were also improved from 16 to 60 % and 0.8 to 24.0 %, respectively. We found that the ratio of patients classified as REM increased yearly from 62/161 (38.5 %) to 69/137 (50.4 %), while those classified as ∆TSS >3 decreased from 55/161 (34.2 %) to 28/137 (20.4 %) and those in RRP decreased from 35/161 (21.7 %) to 15/137 (10.9 %). Receiver operating characteristic (ROC) curve analyses showed that serum matrix metalloproteinase-3 (MMP-3) <103.7 ng/ml at outset predicts a patient subgroup that exhibits no radiographic progression. CONCLUSIONS: Half of rheumatoid patients treated with MTX monotherapy for 3 years exhibited structural remission, and this outcome can be predicted at the outset by lower serum MMP-3.
26538147 PTGER4 gene variant rs76523431 is a candidate risk factor for radiological joint damage in 2015 Nov 5 INTRODUCTION: Prostaglandin E receptor 4 (PTGER4) is implicated in immune regulation and bone metabolism. The aim of this study was to analyze its role in radiological joint damage in rheumatoid arthritis (RA). METHODS: Six independent cohorts of patients with RA of European or North American descent were included, comprising 1789 patients with 5083 sets of X-rays. The Hospital Clínico San Carlos Rheumatoid Arthritis, Princesa Early Arthritis Register Longitudinal study, and Hospital Universitario de La Paz early arthritis (Spain) cohorts were used as discovery cohorts, and the Leiden Early Arthritis Clinic (The Netherlands), Wichita (United States), and National Databank for Rheumatic Diseases (United States and Canada) cohorts as replication cohorts. First, the PTGER4 rs6896969 single-nucleotide polymorphism (SNP) was genotyped using TaqMan assays and available Illumina Immunochip data and studied in the discovery and replication cohorts. Second, the PTGER4 gene and adjacent regions were analyzed using Immunochip genotyping data in the discovery cohorts. On the basis of pooled p values, linkage disequilibrium structure of the region, and location in regions with transcriptional properties, SNPs were selected for replication. The results from discovery, replication, and overall cohorts were pooled using inverse-variance-weighted meta-analysis. Influence of the polymorphisms on the overall radiological damage (constant effect) and on damage progression over time (time-varying effect) was analyzed. RESULTS: The rs6896969 polymorphism showed a significant association with radiological damage in the constant effect pooled analysis of the discovery cohorts, although no significant association was observed in the replication cohorts or the overall pooled analysis. Regarding the analysis of the PTGER4 region, 976 variants were analyzed in the discovery cohorts. From the constant and time-varying effect analyses, 12 and 20 SNPs, respectively, were selected for replication. Only the rs76523431 variant showed a significant association with radiographic progression in the time-varying effect pooled analysis of the discovery, replication, and overall cohorts. The overall pooled effect size was 1.10 (95 % confidence interval 1.05-1.14, p = 2.10 × 10(-5)), meaning that radiographic yearly progression was 10 % greater for each copy of the minor allele. CONCLUSIONS: The PTGER4 gene is a candidate risk factor for radiological progression in RA.
25073613 Presence of comorbidity affects both treatment strategies and outcomes in disease activity 2015 Mar To clarify the impact of comorbidities on treatment strategies and outcomes in patients with rheumatoid arthritis (RA) using a large observational RA cohort, the presence of comorbidities was assessed using the Charlson Comorbidity Index (CCI). Changes in medication, disease activity by Disease Activity Score-28 joint count (DAS28) over 6 months, disability assessed by the Japanese version of the Health Assessment Questionnaire (J-HAQ), and quality of life by EuroQOL-5-Dimensions (EQ-5D) over 1 year in patients with high disease activity (DAS28 > 5.1) at baseline were assessed according to age-adjusted CCI (CCI(A)) and categorized into four groups (CCI(A) 0, 1-2, 3-4, and ≥5). Among 5,317 patients, 975 patients (18.3%) had at least one comorbidity listed by CCI. DAS28, J-HAQ, and EQ-5D increased in severity with increased CCI(A) levels. Among patients with high disease activity (n = 267), treatment with methotrexate and/or biologics and improved DAS28 scores, shown by attenuated intensity, were associated with increased CCI(A) levels. J-HAQ improved from 1.29 ± 0.31 to 0.87 ± 0.37 in 1 year in the CCI(A) 0 group. The adjusted difference (standard error) in J-HAQ at 1 year in CCI(A) 1-2, 3-4, and ≥5 groups was worse than J-HAQ in the CCI(A) 0 group by 0.32 (0.09, p < 0.001), 0.45 (0.10, p < 0.001), and 0.45 (0.15, p < 0.01), respectively. The magnitude of improvement of EQ-5D was significantly attenuated with increasing CCI(A) levels. Thus, patients with comorbidities may not experience the same degree of benefit from recent RA treatments compared with patients without comorbidities in daily practice.
25355728 MRI assessment of suppression of structural damage in patients with rheumatoid arthritis r 2016 Jan OBJECTIVE: To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy. METHODS: Patients were randomised to receive two infusions of placebo (n=63), rituximab 500 mg (n=62), or rituximab 1000 mg (n=60) intravenously on days 1 and 15. MRI scans and radiographs of the most inflamed hand and wrist were acquired at baseline, weeks 12 (MRI only), 24 and 52. The primary end point was the change in MRI erosion score from baseline at week 24. RESULTS: Patients treated with rituximab demonstrated significantly less progression in the mean MRI erosion score compared with those treated with placebo at weeks 24 (0.47, 0.18 and 1.60, respectively, p=0.003 and p=0.001 for the two rituximab doses vs placebo) and 52 (-0.30, 0.11 and 3.02, respectively; p<0.001 and p<0.001). Cartilage loss at 52 weeks was significantly reduced in the rituximab group compared with the placebo group. Other secondary end points of synovitis and osteitis improved significantly with rituximab compared with placebo as early as 12 weeks and improved further at weeks 24 and 52. CONCLUSIONS: This study demonstrated that rituximab significantly reduced erosion and cartilage loss at week 24 and week 52 in MTX-inadequate responder patients with active RA, suggesting that MRI is a valuable tool for assessing inflammatory and structural damage in patients with established RA receiving rituximab. TRIAL REGISTRATION NUMBER: NCT00578305.
27147781 The Impact of Low-Dose Disease-modifying Anti-rheumatics Drugs (DMARDs) on Bone Mineral De 2016 Apr INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarthritis and multisystemic involvement. OBJECTIVE: The aim of this study was to assess the impact of low dose of methotrexate on bone mineral density (BMD) in patients with early rheumatoid arthritis (RA). MATERIALS AND METHODS: This paper follows a retrospective study, which involves 60 female patients with early onset RA diagnosed according to the American Rheumatism Association Criteria (ACR/EULAR 2010). The patients were divided into two groups group I was composed of thirty patients treated with dose of 7.5 mg/weekly methotrexate (MTX), while group II included thirty patients treated with dose of 2 g/daily sulfasalazine (SSZ). The Disease Activity was measured by a combination of Erythrocyte Sedimentation Rate (ESR) and Disease Activity Score (DAS-28). Bone mineral density of the lumbar spine (L2-4), and femoral neck, was measured by dual energy X-ray absorptiometry (DEXA) (Stratos 800). Laboratory findings included: In this study, we found no negative effect on BMD in RA patients treated with low dose MTX in comparison to patients treated with SSZ. There was not observed significant difference in BMD of the lumbar spine, femur neck or trochanter, of MTX and SSZ patients in the pretreatment phase, nor after 12 months of treatment. No significant change in the biochemical parameters of the both groups. CONCLUSION: Based on the results of our study, low dose of methotrexate has no negative effect on BMD in premenopausal RA patients. We believe that these results might provide new insights and that further longitudinal studies with larger groups of premenopausal RA patients are required.
26803640 Investigating the Role of Toll-Like Receptors in Models of Arthritis. 2016 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation leading to tissue destruction and progressive loss of joint function. Here we describe two methods that can be used to assess the contribution of toll-like receptors (TLRs), and their potential ligands, to RA pathogenesis. We focus on the antigen-induced model of murine arthritis and human synovial tissue explant models. Both enable detection of TLR, and TLR ligand, expression, as well as investigation of the effect of inhibition of these molecules. Each offers a unique insight into disease; with murine models allowing kinetic analysis in live animals and explant models allowing examination of inflamed human tissue, which together can help us to dissect the role of TLRs in the onset and progression of RA.
26315300 Amelioration of experimental arthritis by intra-articular injection of an epidermal growth 2015 Nov OBJECTIVES: Selectively targeting signalling pathways represents a promising pharmacological approach in rheumatoid arthritis (RA). Abundant levels of epidermal growth factor receptor (EGFR) are expressed in the synovial lining layers, and the anti-arthritis effect of erlotinib and lapatinib, small-molecule EGFR tyrosine kinase inhibitors (TKIs), has been demonstrated through the systemic administration on experimental arthritis models. Nevertheless, their therapeutic responses by the intra-articular (i.a.) route remain to be explored in rheumatoid joint. METHODS: The administration of an EGFR TKI (a gefitinib analogue) was explored in two in vivo models of collagen-induced arthritis (CIA) and in vitro experiments by using synovial fibroblasts (SF) from RA patients and CIA rats. RESULTS: There was a significant reduction of arthritis scores in CIA mice receiving the daily intraperitoneal injection. After the onset of arthritis in CIA rats, ankle joints receiving a single i.a. injection had significant lower articular indexes with reduced synovial inflammation, pannus formation and erosion on cartilage and bone as well as total histological scores by histopathological analyses. In CIASF or RASF, upon in vitro human EGF stimulation, there was a dose-dependent increase in cell proliferation and Akt activation with suppressed responses under the EGFR TKI treatment. CONCLUSIONS: These findings demonstrate the effect of i.a. injection of an EGFR TKI on amelioration of rheumatoid joint through the suppression of synovial inflammation, pannus formation and erosion on cartilage and bone in experimental arthritis, implicating targeting the i.a. EGFR signalling transduction as a pharmacological strategy.