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ID PMID Title PublicationDate abstract
25747027 Role of innate immune sensors, TLRs, and NALP3 in rheumatoid arthritis and osteoarthritis. 2014 Innate immune sensors, Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain-like receptors (NLRs) participate in the induction of innate inflammatory and adaptive immune responses in rheumatoid arthritis (RA) and osteoarthritis (OA). Danger signals, e.g., heat-shock proteins (HSPs) and high mobility group box-1 protein (HMGB-1), internal ligands of TLRs, have been reported in the patients with RA and OA. In RA, TLR1-9 have been implicated in the pathogenesis. Although the precise role of each receptor is still unknown, immunohistochemical analyses of RA tissues after treatment of biologic disease modifying antirheumatic drugs showed phenotypic changes of immune cell types and residual expression of some TLRs. This suggests the potential for modulation of moderate/severe local joint inflammation, composed in particular of and possibly driven by the "auto-inflammatory" TLR+ cells, still responding to internal ligands derived from destroyed tissues. In OA, systematic profiling of TLR using a histological grading system recently showed that TLR+ cells are greater in number in the surface zone of grades 3 and 4 OA, but interestingly not grade 5. NACHT, LRR, and PYD domains-containing protein (NALP) 3 and related molecules have been also demonstrated both in RA and OA. In addition, a cross talk mechanism of TLR and NALP responsible for increasing joint inflammation has been suggested. Taken together, although OA is not basically an inflammatory disease, and is different from that of RA, pattern recognition receptors-signaling pathways, TLRs and NALP3 may play a role in the pathogenesis of both these conditions, probably as driving forces of progression. Precise and intensive analyses of both receptors, signal pathways, and cross talk mechanisms may provide a new therapeutic approach as molecular targets.
23061423 Crohn's disease diagnosis during adalimumab treatment. 2013 Feb IBD flares or new diagnosis in patients receiving anti-TNF because of other diseases than IBD are rare events but the possibility of a paradoxical reaction must be considered as with psoriasis or uveitis. We present a patient suffering from RA who had a new CD onset after a two-year adalimumab treatment.
25137158 [Cost-minimization analysis of subcutaneous abatacept in the treatment of rheumatoid arthr 2014 Jul 1 OBJECTIVE: To compare the cost of treating rheumatoid arthritis patients that have failed an initial treatment with methotrexate, with subcutaneous abatacept versus other first-line biologic disease-modifying antirheumatic drugs. METHOD: Subcutaneous abatacept was considered comparable to intravenous abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab and tocilizumab, based on indirect comparison using mixed treatment analysis. A cost-minimization analysis was therefore considered appropriate. The Spanish Health System perspective and a 3 year time horizon were selected. Pharmaceutical and administration costs (Euros 2013) of all available first-line biological disease-modifying antirheumatic drugs were considered. Administration costs were obtained from a local costs database. Patients were considered to have a weight of 70 kg. A 3% annual discount rate was applied. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Subcutaneous abatacept proved in the base case to be less costly than all other biologic antirrheumatic drugs (ranging from Euros -831.42 to Euros -9,741.69 versus infliximab and tocilizumab, respectively). Subcutaneous abatacept was associated with a cost of Euros 10,760.41 per patient during the first year of treatment and Euros 10,261.29 in subsequent years. The total 3-year cost of subcutaneous abatacept was Euros 29,953.89 per patient. Sensitivity analyses proved the model to be robust. Subcutaneous abatacept remained cost-saving in 100% of probabilistic sensitivity analysis simulations versus adalimumab, certolizumab, etanercept and golimumab, in more than 99.6% versus intravenous abatacept and tocilizumab and in 62.3% versus infliximab. CONCLUSIONS: Treatment with subcutaneous abatacept is cost-saving versus intravenous abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab and tocilizumab in the management of rheumatoid arthritis patients initiating treatment with biological antirheumatic drugs.
25222440 Fear-avoidance beliefs about physical activity in adults with rheumatoid arthritis. 2015 OBJECTIVES: The aim of this study was to describe fear-avoidance beliefs about physical activity and explore how these beliefs correlate with sociodemographic, disease-specific, and psychosocial factors in adults with rheumatoid arthritis (RA). METHOD: This cross-sectional study is part of the Physical Activity in Rheumatoid Arthritis (PARA) 2010 study. The study participants (n = 2351) were identified through the Swedish Rheumatology Quality (SRQ) registries from six rheumatology clinics in Sweden. Univariate and backwards stepwise logistic regressions were performed. RESULTS: Stepwise logistic regressions showed that male gender [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.26-1.91] and having a below average income (OR 1.35, 95% CI 1.12-1.63) were associated with an increased risk of high scores on the modified Fear Avoidance-Belief Questionnaire (mFABQ). The two disease-specific factors most indicative of high mFABQ scores were high level of pain (OR 1.99, 95% CI 1.40-2.84) and poor health (OR 1.59, 95% CI 1.10-2.29). With regard to psychosocial factors, low health-related quality of life (HRQoL; OR 0.44, 95% CI 0.35-0.55) and a low score on the Exercise Self-Efficacy Scale (ESES; OR 0.66, 95% CI 0.52-0.82) were significantly associated with a high mFABQ score. The model fit was 0.27 (Nagelkerke's R(2)). CONCLUSIONS: High fear-avoidance beliefs about physical activity in patients with RA were found to be associated with being male and having a below average income, a high level of pain, poor health, a low HRQoL, and low ESES score. Additional research is warranted for adults with RA to capture the multiple potential correlates to fear-avoidance beliefs about physical activity.
24504139 Different pattern of T-cell subpopulations in peripheral blood of patients with rheumatoid 2014 INTRODUCTION:  The comparison of changes in peripheral T-cell subpopulations at different stages of rheumatoid arthritis (RA) development may be important to understand the pathomechanism and to elucidate the course of RA. So far, there have been no comprehensive studies regarding the proportions of T cells in early and long‑lasting RA. OBJECTIVES:  The aim of this study was to assess the proportion of the main peripheral T-cell subpopulations in patients at various stages of RA development. PATIENTS AND METHODS:  We enrolled 75 patients who were divided into 4 subgroups depending on the diagnosis: undifferentiated arthritis (UA), which later developed into RA (UA‑RA) and other diseases (UA‑non‑RA); clinically confirmed untreated RA; long-term treated RA; and the control group. Flow cytometry was used to assess T-cell subpopulations. RESULTS:  Patients with clinically confirmed untreated RA differed (P <0.05) in the proportion of CD4+ T-cell subpopulations expressing activation markers compared with controls (CD69, CD25, HLA‑DR, CD95) and UA patients (CD95). Untreated RA patients had the highest proportion of regulatory CD4+ T cells compared with control and other groups. The percentage of CD28- T cells was higher only in the group with clinically confirmed RA but not in those with early RA (at the UA stage). CONCLUSIONS:  The peripheral T lymphocyte phenotype in very early RA is not similar to that observed in clinically‑confirmed RA. Patients with a confirmed diagnosis of RA can be easily differentiated based on the absolute numbers of the main T-cell subpopulations; however, the percentage of the main T-cell subpopulations do not discriminate those patients in the UA cohort who will develop RA.
25475141 Demonstration of extracellular peptidylarginine deiminase (PAD) activity in synovial fluid 2014 Dec 5 INTRODUCTION: Members of the peptidylarginine deiminase (PAD) family catalyse the posttranslational conversion of peptidylarginine to peptidylcitrulline. Citrullination of proteins is well described in rheumatoid arthritis (RA), and hypercitrullination of proteins may be related to inflammation in general. PAD activity has been demonstrated in various cell lysates, but so far not in synovial fluid. We aimed to develop an assay for detection of PAD activity, if any, in synovial fluid from RA patients. METHODS: An enzyme-linked immunosorbent assay using human fibrinogen as the immobilized substrate for citrullination and anti-citrullinated fibrinogen antibody as the detecting agent were used for measurement of PAD activity in synovial fluid samples from five RA patients. The concentrations of PAD2 and calcium were also determined. RESULTS: Approximately 150 times lower levels of recombinant human PAD2 (rhPAD2) than of rhPAD4 were required for citrullination of fibrinogen. PAD activity was detected in four of five synovial fluid samples from RA patients and correlated with PAD2 concentrations in the samples (r = 0.98, P = 0.003). The calcium requirement for half-maximal activities of PAD2 and PAD4 were found in a range from 0.35 to 1.85 mM, and synovial fluid was found to contain sufficient calcium levels for the citrullination process to occur. CONCLUSIONS: We present an assay with high specificity for PAD2 activity and show that citrullination of fibrinogen can occur in cell-free synovial fluid from RA patients.
25216562 Tocilizumab treatment safety in rheumatoid arthritis in a patient with multiple sclerosis: 2014 Sep 12 BACKGROUND: Multiple sclerosis is a relatively rare disease, and complications of multiple sclerosis and rheumatoid arthritis are much rarer. Since anti-tumor necrosis factor therapy increases exacerbations of multiple sclerosis, complications of demyelinating diseases contraindicate anti-tumor necrosis factor therapy. There have been few reports of anti-interleukin-6 receptor therapy for patients with rheumatoid arthritis complicated with multiple sclerosis. CASE PRESENTATION: A 53-year-old Japanese woman with multiple sclerosis and rheumatoid arthritis was admitted to our hospital because her rheumatoid arthritis was uncontrolled with oral methotrexate, tacrolimus, and prednisolone. She had developed multiple sclerosis when she was 25 years old and was treated with glucocorticoid therapy. Her multiple sclerosis was in remission for more than 9 years. Because anti-tumour necrosis factor therapy can exacerbate demyelinating disease, the anti-interleukin-6 receptor antibody tocilizumab was started at 8 mg/kg every 4 weeks. At the second administration of tocilizumab, complete remission was achieved. She has remained in remission with tocilizumab without recurrence of multiple sclerosis for more than 5 years. CONCLUSION: Anti-interleukin-6 therapy was safely used in this patient with rheumatoid arthritis without exacerbations of multiple sclerosis.
24887281 Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid art 2014 Currently, reliable biomarkers that can be used to distinguish rheumatoid arthritis (RA) from other inflammatory diseases are unavailable. To find possible distinctive metabolic patterns and biomarker candidates for RA, we performed global metabolite profiling of synovial fluid samples. Synovial fluid samples from 38 patients with RA, ankylosing spondylitis, Behçet's disease, and gout were analyzed by gas chromatography/time-of-flight mass spectrometry (GC/TOF MS). Orthogonal partial least-squares discriminant and hierarchical clustering analyses were performed for the discrimination of RA and non-RA groups. Variable importance for projection values were determined, and the Wilcoxon-Mann-Whitney test and the breakdown and one-way analysis of variance were conducted to identify potential biomarkers for RA. A total of 105 metabolites were identified from synovial fluid samples. The score plot of orthogonal partial least squares discriminant analysis showed significant discrimination between the RA and non-RA groups. The 20 metabolites, including citrulline, succinate, glutamine, octadecanol, isopalmitic acid, and glycerol, were identified as potential biomarkers for RA. These metabolites were found to be associated with the urea and TCA cycles as well as fatty acid and amino acid metabolism. The metabolomic analysis results demonstrated that global metabolite profiling by GC/TOF MS might be a useful tool for the effective diagnosis and further understanding of RA.
25098142 [Successful fiberoptic tracheal intubation guided by Airwayscope with a thin Intlock blade 2014 Jul We present a case of anticipated difficult airway with severe rheumatoid arthritis in which intubation with fiberoptic bronchoscope (FOB) assisted by Pentax-AWS Airwayscope with the thin Intlock (AWS T) was effective. A 69-year-old woman was scheduled to undergo laparoscopic cholecystectomy for acute cholecystitis in a previous hospital. Tracheal intubation with Glidescope or nasal intubation was unsuccessful and abandoned due to mucosal injury and bleeding. Ventilation via several supraglottic airway devices was unsatisfactory, while mask ventilation was easy after induction of anesthesia. She was referred to our hospital for application of veno-arterial extracorporeal life support in case of 'cannot ventilate and cannot intubate'. We planned to perform tracheal intubation preserving spontaneous breathing under intravenous administration of dexmedetomidine and fentanyl. We could visualize the epiglottis, but could not set the target mark to the invisible glottis with AWS-T. Finally, we could accomplish uneventful tracheal intubation with FOB along with the Intlock's guides of AWS-T.
22985804 Treat to target strategy in rheumatoid arthritis: real benefits. 2013 Mar Treating rheumatoid arthritis (RA) with a goal or «Treat to target» strategy is a therapeutic proposal taken from cardiovascular and endocrine literature. It proposes that the therapeutic target in RA should be a state of remission, or an alternative goal could be a low disease activity. Rheumatologists should measure and register disease activity in every clinical visit and if the goal has not been reached, therapeutic adjustments should be made. Current evidence from clinical trials and a meta-analysis supports the notion that this strategy has important clinical benefits in patients with early RA when compared with routine care. It is also described that using protocolized treatment offers greater benefits. Recent data from Dutch cohorts is presented showing its successful implementation. A discussion is offered on the need of more studies in established RA.
24371010 Induction of bone loss in DBA/1J mice immunized with citrullinated autologous mouse type I 2014 Jan Joint damage in rheumatoid arthritis (RA) is characterized by cartilage and bone loss resulting in pain, deformity, and loss of joint function. Anti-citrullinated protein antibody (ACPA) has been implicated in RA pathogenesis and predicts radiographical joint damage and clinical severity. Therefore, the purpose of this study was to assess bone loss by micro-CT, histological joint damage, and ACPA levels using a mouse model of RA. Arthritis was induced by immunizing DBA/1 mice with autologous citrullinated type II mouse collagen (CIT-CII) weekly for 4 weeks. Mice immunized with autologous CII served as controls. At week 5, mice were killed, ACPA levels determined, and micro-CT performed to quantitatively analyze bone damage. Micro-CT analysis revealed significant loss of bone density, volume, and surface (p < 0.05) in bone peripheral to the inflamed joints of CIT-CII animals compared to CII controls. Histological staining demonstrated cartilage, proteoglycan, joint collagen, and bone collagen loss in the CIT-CII group compared to CII. Serum ACPA levels were increased (p = 0.03) in the CIT-CII group compared to CII, and these levels were inversely correlated with bone quantity and quality. In this study, we demonstrate that immunization with autologous CIT-CII initiates significant systemic bone and articular cartilage loss in the absence of adjuvant. Significant inverse correlations of circulating ACPA and bone quality/quantity were present. ACPA levels predict the adverse bone morphological changes in this model of early RA.
23645094 Leprosy in a rheumatology setting: a challenging mimic to expose. 2013 Oct Leprosy can manifest arthritis both as a complication and a comorbid disorder and can be a challenging differential diagnosis in rheumatology practice due to several common features. Uncommonly, it may present as acute severe polyarthritis with skin lesions and neurological deficit or a digital vasculitis and gangrene. We demonstrate this profile in a retrospective case series analysis of 33 patients (13 females, median age 55 years) in a community-based clinic setting over the period 1998-2012; an electronic search of case records of 41,000 patients was carried out. Rheumatoid arthritis (RA) coexisted in seven patients (three lepromatous, two tuberculoid, and two polyneuritic). Serological rheumatoid factor and antinuclear antibody were often false positive. Several patients of RA were on long-term supervised methotrexate. Rheumatologists should be aware of this clinical mimic to avoid errors in diagnosis and management.
23101488 Second-hand exposure to tobacco smoke and its effect on disease activity in Swedish rheuma 2013 Jan OBJECTIVES: We studied the prevalence and effect on disease activity of ever having had second-hand exposure to tobacco smoke in Swedish rheumatoid arthritis (RA) patients who had never smoked. METHODS: Between 1992 and 2005, 2,800 patients were included in the BARFOT early-RA study in Sweden. Disease Activity Score 28 joints (DAS28), C-reactive protein (CRP), Health Assessment Questionnaire (HAQ), rheumatoid factor (RF), general health and pain visual analogue scales (VAS), and drug treatment were registered at inclusion and at follow-up at 3, 6, and 12 months and 2 and 5 years. EULAR response criteria were applied at the same follow-up points. In 2010, a self-completion postal questionnaire was sent to 2,102 patients in the BARFOT study enquiring about lifestyle habits such as whether they had ever been exposed to tobacco smoke as a result of someone else smoking. RESULTS: A total of 963/1,421 patients (68%) had had second-hand exposure to tobacco smoke. At 3, 6, and 12 months, at 2 years, and at 5 years of follow-up, there were no differences in EULAR response between patients who had never smoked and who had been exposed or had not been exposed second-hand to tobacco smoke (p=0.91, p=0.88, p=0.84, p=0.61 and p=0.85, respectively). CONCLUSIONS: We did not find any association between second-hand exposure to tobacco smoke and disease activity in RA.
24338344 Including adverse drug events in economic evaluations of anti-tumour necrosis factor-α dr 2014 Feb BACKGROUND: Anti-tumour necrosis factor-α drugs (anti-TNFs) have revolutionised the treatment of rheumatoid arthritis (RA). More effective than standard non-biological disease-modifying anti-rheumatic drugs (nbDMARDs), anti-TNFs are also substantially more expensive. Consequently, a number of model-based economic evaluations have been conducted to establish the relative cost-effectiveness of anti-TNFs. However, anti-TNFs are associated with an increased risk of adverse drug events (ADEs) such as serious infections relative to nbDMARDs. Such ADEs will likely impact on both the costs and consequences of anti-TNFs, for example, through hospitalisations and forced withdrawal from treatment. OBJECTIVE: The aim of this review was to identify and critically appraise if, and how, ADEs have been incorporated into model-based cost-effectiveness analyses of anti-TNFs for adult patients with RA. METHODS: A systematic literature review was performed. Electronic databases (Ovid MEDLINE; Ovid EMBASE; Web of Science; NHS Economic Evaluations Database) were searched for literature published between January 1990 and October 2013 using electronic search strategies. The reference lists of retrieved studies were also hand searched. In addition, the National Institute for Health and Care Excellence technology appraisals were searched to identify economic models used to inform UK healthcare decision making. Only full economic evaluations that had used an economic model to evaluate biological DMARDs (bDMARDs) (including anti-TNFs) for adult patients with RA and had incorporated the direct costs and/or consequences of ADEs were critically appraised. To be included, studies also had to be available as a full text in English. Data extracted included general study characteristics and information concerning the methods used to incorporate ADEs and any associated assumptions made. The extracted data were synthesised using a tabular and narrative format. RESULTS: A total of 43 model-based economic evaluations of bDMARDs for adult RA were identified from 2,483 initially identified studies (2,473 published; ten technology appraisals). Of these, nine studies had incorporated the incidence and costs of ADEs and were critically reviewed. One study also explicitly estimated the potential consequences for patient utility. There was a general lack of detail specifically reporting on how ADEs were included in the economic models. Furthermore, there was substantial heterogeneity amongst the nine studies concerning the (i) application of risk-related terminology; (ii) method of incorporating the incidence, costs and consequences of ADEs; and (iii) ADE-related assumptions. CONCLUSIONS: Model-based economic evaluations have played an integral role in healthcare reimbursement and funding decisions relating to anti-TNFs for adult patients with RA. However, current economic models have not routinely or systematically considered the direct costs or consequences of ADEs, which may bias the estimates of the relative cost-effectiveness of anti-TNFs. Omitting information on relevant costs and consequences of interventions for RA will affect the validity of the associated recommendations for informed decision making. To improve current practice it is recommended that (i) greater efforts be made to provide appropriate long-term safety data on the use of anti-TNFs in adult RA; (ii) empirical research be undertaken to identify and quantify the impact of, and possible methods for, including ADEs in economic models to inform future good practice guidelines; and (iii) economic modelling guidelines and reference cases be updated to explicitly identify ADEs as an important treatment outcome and address how they might be incorporated into economic models. Improved consideration of the possible implications of ADEs in economic models will ensure that healthcare decision makers are provided with reliable and accurate information with which to make efficient reimbursement and financing decisions.
22238028 Gene expression patterns in peripheral blood cells associated with radiographic severity i 2013 Jan Gene expression profiling may be used to stratify patients by disease severity to test the hypothesis that variable disease outcome has a genetic component. In order to define unique expression signatures in African American rheumatoid arthritis (RA) patients with severe erosive disease, we undertook a gene expression study using samples of RNA from peripheral blood mononuclear cells (PBMCs). RNA from baseline PBMC samples of 96 African American RA patients with early RA (<2 years disease duration) was hybridized to cDNA probes of the Illumina Human HT-V3 expression array. Expression analyses were performed using the ca. 25,000 cDNA probes, and then expression levels were compared to the total number of erosions in radiographs of the hands and feet at baseline and 36 months. Using a false discovery rate cutoff of Q = 0.30, 1,138 genes at baseline and 680 genes at 36 months significantly correlated with total erosions. No evidence of a signal differentiating disease progression, or change in erosion scores between baseline and 36 months, was found. Further analyses demonstrated that the differential gene expression signature was localized to the patients with the most erosive disease (>10 erosions). Ingenuity Pathway Analysis demonstrated that genes with fold change greater than 1.5 implicated immune pathways such as CTLA signaling in cytotoxic T lymphocytes. These results demonstrate that CLEAR patients with early RA having the most severe erosive disease, as compared to more mild cases (<10 erosions), may be characterized by a set of differentially expressed genes that represent biological pathways with relevance to autoimmune disease.
24714929 Effect of hypertension on echocardiographic parameters in rheumatoid arthritis. 2014 Dec OBJECTIVE: Hypertension (HTN) is common in rheumatoid arthritis (RA) patients. Both HTN and RA have a negative impact on echocardiographically determined parameters including wall thickness, chamber diameter, diastolic function, epicardial adipose tissue (EAT) and carotid intima media thickness (CIMT). We aimed to demonstrate the effect of HTN on these parameters in RA patients. METHODS: Patients were divided into two groups: one group comprised 39 RA patients with HTN (7 male, mean age 56.3 ± 8.4 years) and the second comprised 38 age- and gender-matched RA patients without HTN (10 male, mean age 55.3 ± 7.4 years). We retrospectively analyzed the RA patients without overt structural heart disease by determining the study parameters from echocardiograph recordings. The two groups were compared in terms of echocardiographic parameters and disease characteristics. RESULTS: RA characteristics, chamber sizes and wall thicknesses did not differ between the groups. CIMT was significantly increased in the RA with HTN group (median 0.9 mm, range 0.6-1.2 mm vs. median 0.8 mm, range 0.6-1.0 mm; p = 0.031). EAT was also significantly increased in the RA with HTN group (8.2 ± 1.8 mm vs. 7.4 ± 1.4 mm; p = 0.022). Septal early diastolic E' wave velocities were significantly decreased in the RA with HTN group (8.8 ± 2.4 cm/s vs. 10.2 ± 1.8 cm/s; p = 0.016). CONCLUSION: HTN has a further negative impact on diastolic functions, CIMT and EAT in RA patients.
23073692 No increased mortality in patients with rheumatoid arthritis treated with biologics: resul 2013 Sep OBJECTIVE: To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients. METHODS: RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes ("biologics cohort") were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the "comparator cohort" (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model. RESULTS: Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77-1.47] in the biologics cohort and 1.28 (95 % CI 1.17-1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81-8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24-6.22)], advanced age (HR 1.07, 95 % CI 1.03-1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01-1.17). CONCLUSION: Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics.
25280085 Pharmacokinetic-pharmacodynamic modeling of fostamatinib efficacy on ACR20 to support dose 2015 Mar R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.
23625674 Pneumothorax necessitans in a patient with trapped lung and rheumatoid arthritis. 2013 Apr 25 The authors report the case of a patient with a background of trapped lung following thoracocentesis who developed an anterolateral intercostal pneumothoracocele resulting in a pneumothorax necessitans (PN). Our purpose is to highlight the pathophysiology and interesting radiological features associated with PN in trapped lung. Our case is particularly unique due to the subacute nature of its presentation in a patient with rheumatoid arthritis and unusual pre-existing lung pathology.
24293583 Clinical, functional, and radiographic implications of time to treatment response in patie 2014 Feb OBJECTIVE: Rheumatoid arthritis (RA) treatment recommendations suggest target attainment within the first 3 months of therapy, yet delayed clinical responses can occur. This analysis assessed the longterm clinical, functional, and radiographic outcomes associated with delayed responses to methotrexate (MTX) monotherapy or to the combination of adalimumab (ADA) + MTX. METHODS: In this posthoc analysis, patients with early RA who received MTX monotherapy or ADA + MTX in the PREMIER study were categorized based on clinical responses at 3 and 6 months [American College of Rheumatology response, 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP) improvement and targets]. "Month 3" responders met the clinical measure at both months 3 and 6, and "Month 6" responders met the clinical measure only at Month 6. The odds of achieving longterm outcomes [remission (DAS28-CRP < 2.6), normal function (Health Assessment Questionnaire-Disability Index < 0.5), or rapid radiographic progression (Δ modified total Sharp score > 3 U/yr)] were modeled using logistic regression, including treatment, response, and interaction. RESULTS: A delayed or low-level response was associated with poorer longterm outcomes. Generally, MTX Month 6 responders demonstrated worse clinical, functional, and radiographic outcomes than Month 3 MTX and Month 3 or 6 ADA + MTX responders. Although similar longterm benefit was observed for ADA + MTX responders, delayed (Month 6) responders exhibited downward trends in clinical, functional, and radiographic outcomes that were comparable with those experienced by Month 3 MTX responders. CONCLUSION: Response speed and magnitude predict longterm outcomes in patients with early RA treated with MTX or ADA + MTX. MTX-treated patients failing to demonstrate a Month 3 clinical response have less-favorable outcomes than other groups, while outcomes in ADA + MTX Month 3 and Month 6 responders tended to be comparable.