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ID PMID Title PublicationDate abstract
28728565 Identification of differential co-expressed gene networks in early rheumatoid arthritis ac 2017 Jul 20 BACKGROUND: Methotrexate is endorsed to be used as first-line treatment in rheumatoid arthritis (RA). However, a large proportion of patients need additional treatment with a biological disease-modifying anti-rheumatic drug (DMARD) to adequately suppress their disease activity. A better understanding of genotypes could help to distinguish between patients with different pathogenic mechanisms. The aim of this study was therefore to identify networks of genes within DMARD-naive early RA patients associated with achieving sustained drug-free remission (sDFR) after initiating tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy. METHODS: Samples were used from 60 patients from the U-Act-Early study who received tocilizumab plus methotrexate, tocilizumab, or methotrexate therapy, and who achieved sDFR (≥3 months in drug-free remission until the end of the study, n = 37) after therapy was tapered and subsequently stopped, or who were not able to discontinue the therapy as controls (n = 23). Whole blood samples were collected and ribonucleic acid (RNA) was isolated from positive cluster of differentiation 4 (CD4(+)) and CD14(+) cells and analysed using high-throughput sequencing. Weighted gene co-expression network analyses were performed to identify clusters (i.e. modules) of differently expressed genes associated with achieving sDFR and which were subsequently used for pathway analyses. RESULTS: Network analyses within CD4(+) cells identified two significant modules in the tocilizumab plus methotrexate arm and four modules in the tocilizumab and methotrexate arms, respectively (p ≤ 0.039). Important pathways in the module best correlating with achieving sDFR were in the tocilizumab plus methotrexate arm related to processes involved with transcription and translation; in the tocilizumab arm, pathways were related to migration of white blood cells and G-protein coupled receptors, and in the methotrexate arm pathways were involved with the response to a bacterial or biotic (i.e. biological material)-related stimulus. No relevant networks could be identified in the sequenced CD14(+) cells. CONCLUSIONS: Within networks of co-expressed genes, several pathways were found related to achieving sDFR after initiating therapy with tocilizumab, methotrexate, or the combination. Between the three strategy arms, we identified different networks of predisposing genes which indicates that specific gene expression profiles, depending on the treatment strategy chosen, are associated with a higher chance of achieving sDFR. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01034137 . Registered on 16 December 2009.
28223071 Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune a 2017 Jun Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2. Treatment with IDO2-specific mAb alleviated arthritis in two independent preclinical arthritis models, reducing autoreactive T and B cell activation and recapitulating the strong anti-arthritic effect of genetic IDO2 deficiency. Mechanistic investigations identified FcγRIIb as necessary for mAb internalization, allowing targeting of an intracellular antigen traditionally considered inaccessible to mAb therapy. Taken together, our results offer preclinical proof of concept for antibody-mediated targeting of IDO2 as a new therapeutic strategy to treat RA and other autoantibody-mediated diseases.
28963634 Intra-articular methotrexate versus corticosteroid injections in medium-sized joints of rh 2018 Feb The effects of intra-articular methotrexate (I/A MTX) in knee synovitis in rheumatoid arthritis have been previously evaluated. I/A MTX has not been studied in other joints. Ultrasonography (US) has been little studied in monitoring the effect of I/A MTX. The aim of the study is to test the efficacy of I/A MTX in suppression of persistent synovitis in medium-sized joints (ankle, wrist, and elbow) in rheumatoid arthritis patients. Patients were divided into two groups: group 1 (methotrexate group): 56 patients in which 84 joints (32 ankles, 28 wrists, and 24 elbows) were injected intra-articularly by 10 mg of methotrexate in the targeted joint on a weekly basis for 8 weeks and group 2 (steroid group): 44 patients in which 70 joints (26 ankles, 24 wrists, and 20 elbows) were injected once by Triamcinolone acetonide 40 mg. Clinical, ultrasonographic, and power Doppler US (PDUS) evaluation was done before the first injection (W0), after 2 months (W8), and after 5 months (W20). Synovial thickness and the intra-articular power Doppler signal were graded on a semiquantitative scale from 0 to 3 during the US examination. Clinical parameters improved significantly in both groups between baselines and 2 months. In both groups, gray-scale US and power Doppler US showed that synovial thickness and intra-articular power signals were reduced significantly between W0 and W8. The improvement of clinical parameters continued in the methotrexate group up to W20, but in the corticosteroid group, clinical parameters at W20 were similar to clinical parameters at W0. In the methotrexate group, there was an insignificant increase in synovial thickness between W8 and W20 while there was a significant increase in power Doppler signals between W8 and W20, p < 0.05. In the corticosteroid group, there was a significant increase in both synovial thickening and power Doppler signals between W8 and W20, p < 0.001. In the MTX group, all patients at week 0 showed that the Doppler signal in grades 2 and 3 is 100%; at 8 weeks, most of the patients showed that the power Doppler in grade 0 is 76%; and at week 20, most of the patients showed that the power Doppler signal in grade 0 is 28% and in grade 1 is 47%, while in grades 2 and 3 is 23.6%, so there is an improvement compared to the baseline of treatment. Repeated I/A MTX resulted in a decrease in the degree of synovitis of medium-sized joints in RA patients both clinically and by power Doppler US.
28332497 Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific f 2017 Mar 23 A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.
28444364 Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung d 2017 Aug 1 OBJECTIVE: To evaluate the effect of rituximab (RTX) in patients with RA-related interstitial lung disease (RA-ILD) and identify factors associated with outcome after treatment. METHODS: An observational study of patients with RA-ILD was conducted from a cohort of RTX-treated RA patients in a single centre for >10 years. Progression was defined by any of the following: a decrease of pre-RTX forced vital capacity (FVC) >10% or diffusion capacity of carbon monoxide (DLCO) >15% predicted, worsening of the ILD score or death from progressive ILD. RESULTS: Of 700 RA patients treated with RTX, 56 had RA-ILD (prevalence = 8%). After RTX, new ILD was diagnosed in 3/700 patients (incidence = 0.4%). Data for lung assessment were available for 44/56 patients. The median relative change pre- and post-RTX for FVC were -2.4% and +1.2% ( P = 0.025) and for DLCO were -4.4% and -1.3% ( P = 0.045). Post-RTX, 23/44 (52%) were stable and 7/44 (16%) had improved. Of the 14 (32%) with ILD that progressed, 9/56 (16%) were deaths due to progressive ILD. Factors associated with ILD progression were radiologic pattern of usual interstitial pneumonia, a previous history of lung progression and pre-RTX DLCO <46% predicted. Of those whose ILD progressed, 11/14 (79%) had severe ILD before RTX [median DLCO 42% predicted (interquartile range 41-49)]. CONCLUSION: In this cohort of patients where RTX was given for arthritis, most patients with ILD pre-RTX remained stable/improved after treatment over a prolonged follow-up period. Patients who deteriorated/died had the most severe ILD pre-RTX, suggesting the drug was not contributory. RTX appears to be an acceptable therapeutic choice for patients with RA-ILD and further studies are warranted.
28502419 The performance of the GAP model in patients with rheumatoid arthritis associated intersti 2017 Jun BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Similarities have been observed between patients with idiopathic pulmonary fibrosis (IPF) and the UIP (usual interstitial pneumonia) form of RA-ILD. The GAP (gender, age, physiology) model has been shown to predict mortality in patients with IPF, but its ability to predict mortality in RA-ILD is not known. METHODS: We identified 309 patients with RA-ILD at 4 academic centers with ongoing longitudinal cohorts of patients with ILD. The primary endpoint was mortality. To handle missing data (n = 219 subjects with complete dataset), multiple imputation by iterative chained equations was used. Using the GAP model as a baseline, we assessed improvements in mortality risk prediction achieved by incorporating additional variables. Model discrimination was assessed using the c-index, and calibration was checked by comparing observed and expected incidence of death. RESULTS: Patients had a mean age of 65 years and were predominantly female (54%). The mean forced vital capacity (FVC) % predicted was 73 and the mean diffusing capacity for carbon monoxide (DL(CO)) % predicted was 55. Twenty-four percent of the 236 patients with a high-resolution computed tomography scan available for review had a definite UIP pattern. The original GAP model, including gender, age, FVC%, and DL(CO)%, had a c-index of 0.746 in our cohort. Calibration of this model was satisfactory at 1, 2 and 3 years. Model discrimination was not meaningfully improved by adding other clinical variables. CONCLUSION: The GAP model that was derived for IPF performs similarly as a mortality risk prediction tool in RA-ILD.
27941390 Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repa 2017 Mar PURPOSE OF REVIEW: Mesenchymal stromal/stem cells (MSCs) have potent anti-inflammatory and immunomodulatory properties, in addition to their ability to form cartilage and bone. The purpose of this review is to highlight recent developments and current knowledge gaps in our understanding of the protective effects of MSCs against inflammatory arthritis, and to discuss their clinical exploitation for the treatment of rheumatoid arthritis (RA). RECENT FINDINGS: The weight of evidence for protective mechanisms of exogenously administered MSCs is on immunomodulatory effects, including inhibition of dendritic cell maturation, polarization of macrophages to an anti-inflammatory phenotype, and activation of regulatory T cells, thereby dampening inflammation and preventing joint damage. Evidence for direct effects on tissue repair is scant. Recent studies have identified MSC subsets in vivo and an important question is whether MSCs in their native tissues have similar immunoregulatory functions. Recent proof-of-concept clinical studies have shown a satisfactory safety profile of allogeneic MSC therapy in RA patients with promising trends for clinical efficacy. SUMMARY: Allogeneic MSCs could be effective in RA. Larger, multicentre clinical studies are needed to provide robust evidence, and MSC treatment at early stages of RA should be explored to 'reset' the immune system.
28342364 Therapeutic effect of quercetin in collagen-induced arthritis. 2017 Jun Quercetin, a bioactive flavonoid with anti-inflammatory, immunosuppressive, and protective properties, is a potential agent for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis (CIA) is the most commonly used animal model for studying the pathogenesis of RA. This study analysed the therapeutic role of quercetin in collagen-induced arthritis in C57BL/6 mice. The animals were allocated into five groups that were subjected to the following treatments: negative (untreated) control, positive control (arthritis-induced), arthritis+methotrexate, arthritis+quercetin, and arthritis+methotrexate+quercetin. Assessments of weight, oedema, joint damage, and cytokine production were used to determine the therapeutic effect of quercetin. This study demonstrated for the first time the anti-inflammatory and protective effects of quercetin in vivo in CIA. The results also showed that the concurrent administration of quercetin and methotrexate did not offer greater protection than the administration of a single agent. The use of quercetin as a monotherapeutic agent resulted in the lowest degree of joint inflammation and the highest protection. The reduced severity of the disease in animals treated with quercetin was associated with decreased levels of TNF-α, IL-1β, IL-17, and MCP-1. In conclusion, this study determined that quercetin, which was non-toxic, produced better results than methotrexate for the protection of joints from arthritic inflammation in mice. Quercetin may be an alternative treatment for RA because it modulates the main pathogenic pathways of RA.
29059655 [analysis of adherence and compliance to methotrexate therapy in rheumatoid arthritis pati 2017 Rheumatoid arthritis is chronic inflammatory disease leading to disability and increasing the risk of premature death. Early treatment is crucial for remission and maintaining it for a maximal time. Adherence of the patient to the therapeutic recommendations is necessary. Although this issue is important, its role in achieving of therapeutic success is not fully noted by patients as well as medical stuff. Patients with RA are often non-adherent to rheumatologist's recommendations and non-compliance to the therapy regimen. The causes of this phenomenon are numerous and lie in the patient's attitude to therapy or are patient-independent. To effectively increase the level of adherence and compliance, the detailed medical care, including education of the patient, as well as adaptation of the drug form, by concentrating the active compound, is essential.
28919343 Characterizing pathology in erythrocytes using morphological and biophysical membrane prop 2017 Dec The inflammatory burden of the complex rheumatoid arthritis (RA) disease affects several organ-systems, including rheological properties of blood and its formed elements. Red blood cells (RBCs) are constantly exposed to circulating dysregulated inflammatory molecules that are co-transported within the vasculature; and their membranes may be particularly vulnerable to the accompanying oxidative stress. In the current study, we investigate biophysical and ultrastructural characteristics of RBCs obtained from a cohort of patients using atomic force microscopy (AFM), scanning electron microscopy (SEM) and confocal microscopy (CM). Statistical analyses of AFM data showed that RA RBCs possessed significantly reduced membrane elasticity relative to that of RBCs from healthy individuals (P-value <0.0001). SEM imaging of RA RBCs revealed increased anisocytes and poikilocytes. Poikilocytes included knizocytes, stomatocytes, dacryocytes, irregularly contracted cells, and knot cells. CM imaging of several RA RBCs, spectrin, and band 3 protein networks portrayed the similar morphological profiles. Analyses of CM images confirmed changes to distribution of band-3 skeletal protein, a protein critical for gaseous exchange functions of the RBC and preventing membrane surface loss. Decreased membrane deformability impairs the RBC's capacity to adequately adapt its shape to navigate blood vessels, especially microvasculature, and this decrease is also reflected in the cell's morphology. Changes to morphology and deformability may also indicate loss of functional domains and/or pathological protein and lipid associations. These findings suggest that RA disease and/or its concomitant factors impact on the RBC and its membrane integrity with potential for exacerbating pathological cellular function, hemorheology, and cardiovascular function.
28187436 Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid 2017 Feb 21 Dishevelled (Dvl) not only links the canonical Wnt and non-canonical Wnt pathways but can also crosstalk with other pathways. As there is no systematic study to date on Dvl in rheumatoid arthritis (RA), we explored the impact of Dvl2 on proliferation and inflammatory cytokine secretion in RA fibroblast-like synoviocytes (FLSs). Expression of Dvl2 in RA synovial tissue and RA-FLSs was measured. Dvl2 was overexpressed in collagen-induced arthritis rats and human RA-FLSs,. the apoptosis and secretion of inflammatory cytokines were observed. Genetic changes and corresponding mechanisms caused by overexpressing Dvl2 in RA-FLSs were assessed. Dvl2 was found to be overexpressed in RA synovial tissue and RA-FLSs. Overexpression of Dvl2 increased apoptosis and inhibited inflammatory cytokine secretion by RA-FLSs in vivo and in vitro, and Dvl2 inhibited expression of anti-apoptotic and inflammatory genes. One possible mechanism is that Dvl2 decreases the nuclear translocation of P65 and inhibits its ability to bind to the promoters of NF-κB target genes. Our findings reveal an underappreciated role of Dvl2 in regulating inflammation and RA-FLS apoptosis and provide insight into crosstalk between the Wnt and nuclear factor-κB (NF-κB) pathways.
28560778 Daily oral administration of low-dose methotrexate has greater antirheumatic effects in co 2017 Sep OBJECTIVES: Methotrexate (MTX) is administered once or thrice weekly to patients with rheumatoid arthritis (RA). Even though RA continually progresses, MTX is not administered daily. Therefore, we investigated whether the daily administration of a low dose of MTX inhibits the progression of arthritis in collagen-induced arthritis (CIA) rats. METHODS: Methotrexate was orally administered once weekly, thrice weekly and once daily to CIA rats, and arthritis scores were measured. KEY FINDINGS: When the same dose of MTX was administered, the exacerbation of arthritis was inhibited significantly more in the once-daily group than in the other groups. When the dose in the once-daily group was reduced to one-fourth that of the current standard dosing method, arthritis scores were markedly lower in the once-daily group than in the once and thrice-weekly groups. CONCLUSIONS: The daily administration of a low dose of MTX not only maintained normal levels that estimated adverse effects but also suppressed the progression of arthritis significantly more than the current standard dosing method. The results indicate that the reconsideration of dosing schedules based on the characteristics of MTX will lead to more effective RA therapy than that currently used in clinical practice.
28749607 "Assessment of relationship between xerostomia and oral health-related quality of life in 2017 Nov OBJECTIVE: To determine the relationship between xerostomia and oral health-related quality of life in patients with rheumatoid arthritis. MATERIALS AND METHOD: Two hundred patients with rheumatoid arthritis were assessed using Fox and OHIP-14 questionnaires concerning xerostomia and oral health-related quality of life, respectively. The sum of decayed, missing, and filled teeth (DMFT) was determined via an intra-oral examination. In addition, intergroup comparisons were evaluated using t test, chi-square, regression, and Tukey analysis. RESULT: Among rheumatoid arthritis patients, 51% had been afflicted with xerostomia. We found a statistically significant relationship between xerostomia and oral health-related quality of life (p-value=.004), as xerostomia cases have significantly worse oral health-related quality of life. Also, there was a statistically significant association between oral health-related quality of life and gender as well as DMFT. CONCLUSION: Because there seem to be a high prevalence of xerostomia in patients with rheumatoid arthritis, screening in such population is highly recommended. Therefore, educational programs and/or workshops should be encouraged among healthcare providers to prevent worsening of oral health-related quality of life.
28766140 Assessment of the effects of switching oral bisphosphonates to denosumab or daily teripara 2018 Jul The aim of this observational, non-randomized study was to clarify the unknown effects of switching oral bisphosphonates (BPs) to denosumab (DMAb) or daily teriparatide (TPTD) in patients with rheumatoid arthritis (RA). The characteristics of the 194 female patients included in the study were 183 postmenopausal, age 65.9 years, lumbar spine (LS) T score -1.8, femoral neck (FN) T score -2.3, dose and rate of taking oral prednisolone (3.6 mg/day) 75.8%, and prior BP treatment duration 40.0 months. The patients were allocated to (1) the BP-continue group (n = 80), (2) the switch-to-DMAb group (n = 74), or (3) the switch-to-TPTD group (n = 40). After 18 months, the increase in bone mineral density (BMD) was significantly greater in the switch-to-DMAb group than in the BP-continue group (LS 5.2 vs 2.3%, P < 0.01; FN 3.8 vs 0.0%, P < 0.01) and in the switch-to-TPTD group than in the BP-continue group (LS 9.0 vs 2.3%, P < 0.001; FN 4.9 vs 0.0%, P < 0.01). Moreover, the switch-to-TPTD group showed a higher LS BMD (P < 0.05) and trabecular bone score (TBS) (2.1 vs -0.7%; P < 0.05) increase than the switch-to-DMAb group. Clinical fracture incidence during this period was 8.8% in the BP-continue group, 4.1% in the switch-to-DMAb group, and 2.5% in the switch-to-TPTD group. Both the switch-to-DMAb group and the switch-to-TPTD group showed significant increases in LS and FN BMD, and the switch-to-TPTD group showed a higher increase in TBS compared to the BP-continue group at 18 months. Switching BPs to DMAb or TPTD in female RA may provide some useful osteoporosis treatment options.
28489009 [Vanishing lungs - a case report]. 2017 Mai A 55 year old female with rheumatoid arthritis who was repeatedly admitted to internal medicine for fever, shortness of breath and pleuritic chest pain. Laboratory work up showed normal WBC but elevated CRP and sedimentatation rate. Cultures were negative. Imaging studies revealed elevated diaphragms, bilateral atelectasis and pleural fluid but normal lung parenchyma. Lung function testing showed restriction. Anti-dsDNA and anti-Ro/SSA were elevated. A clinical diagnosis of anti-TNF-induced lupus secondary to infliximab and shrinking lung syndrome was made. The patient showed improvement on steroids but subsequent worsening when tapered. Rituximab was then initiated with good results. Key words: rheumatoid arthritis, infliximab, restrictive lung disease, shrinking lung syndrome, anti-TNF induced lupus. Correspondence: Thorunn Halldora Thordardottir, thorhtho@landspitali.is.
28329404 Tofacitinib in the Treatment of Rheumatoid Arthritis and Chronic Plaque Psoriasis. 2017 Mar Tofacitinib is an oral immunosuppressant approved for the treatment of rheumatoid arthritis (RA) and is currently undergoing investigation (Phase III trials) for treating chronic plaque psoriasis. Tofacitinib inhibits Janus kinases (JAKs), which are essential for the signaling of multiple inflammatory pathways and have been implicated in the pathogenesis of RA and psoriasis. The efficacy and safety of tofacitinib in the treatment of RA and psoriasis have been demonstrated in Phase III trials. Across all studies, the efficacy of tofacitinib in alleviating symptoms of RA and psoriasis were superior to placebo. Moreover, treatment was generally well-tolerated, with the most frequently reported adverse events, for both RA and psoriasis, being nasopharyngitis and upper respiratory tract infection. As such, tofacitinib proves to be an effective therapeutic option for RA and a promising new therapy for psoriasis.
28835673 The case for periodontitis in the pathogenesis of rheumatoid arthritis. 2017 Oct Rheumatoid arthritis (RA), an autoimmune disease that affects ∼1% of the human population, is driven by autoantibodies that target modified self-epitopes, whereas ∼11% of the global adult population are affected by severe chronic periodontitis, a disease in which the commensal microflora on the tooth surface is replaced by a dysbiotic consortium of bacteria that promote the chronic inflammatory destruction of periodontal tissue. Despite differences in aetiology, RA and periodontitis are similar in terms of pathogenesis; both diseases involve chronic inflammation fuelled by pro-inflammatory cytokines, connective tissue breakdown and bone erosion. The two diseases also share risk factors such as smoking and ageing, and have strong epidemiological, serological and clinical associations. In light of the ground-breaking discovery that Porphyromonas gingivalis, a pivotal periodontal pathogen, is the only human pathogen known to express peptidylarginine deiminase, an enzyme that generates citrullinated epitopes that are recognized by anti-citrullinated protein antibodies, a new paradigm is emerging. In this Review, the clinical and experimental evidence supporting this paradigm is discussed and the potential mechanisms involved in linking periodontitis to RA are presented.
28707530 Cartilage quantification using contrast-enhanced MRI in the wrist of rheumatoid arthritis: 2017 Aug OBJECTIVE: To quantify wrist cartilage using contrast MRI and compare with the extent of adjacent synovitis and bone marrow edema (BME) in patients with rheumatoid arthritis (RA). METHODS: 18 patients with RA underwent post-contrast fat-suppressed T(1)weighted coronal imaging. Cartilage area at the centre of the scaphoid-capitate and radius-scaphoid joints was measured by in-house developed software. We defined cartilage as the pixels with signal intensity between two thresholds (lower: 0.4, 0.5 and 0.6 times the muscle signal, upper: 0.9, 1.0, 1.1, 1.2 and 1.3 times the muscle signal). We investigated the association of cartilage loss with synovitis and BME score derived from RA MRI scoring system. RESULTS: Cartilage area was correlated with BME score when thresholds were adequately set with lower threshold at 0.6 times the muscle signal and upper threshold at 1.2 times the muscle signal for both SC (r(s)=-0.469, p < 0.05) and RS (r(s)=-0.486, p < 0.05) joints, while it showed no significant correlation with synovitis score at any thresholds. CONCLUSION: Our software can accurately quantify cartilage in the wrist and BME associated with cartilage loss in patients with RA. Advances in knowledge: Our software can quantify cartilage using conventional MR images of the wrist. BME is associated with cartilage loss in RA patients.
29026298 Therapeutic effects of lornoxicam-loaded nanomicellar formula in experimental models of rh 2017 BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease treated by nonsteroidal anti-inflammatory drugs (NSAIDs) including lornoxicam (LX). Nanocarriers have been used to increase the efficacy and reduce the side effects of various drugs. The objective of the present study was to compare the therapeutic efficacy of systemic administration of lornoxicam-loaded nanomicellar formula (LX-NM) with that of free LX. MATERIALS AND METHODS: The LX-loaded mixed polymeric nanomicellar formula was prepared by direct equilibrium technique. Two rat models were used in the study: carrageenan-induced acute edema and Freund's complete adjuvant (FCA)-induced chronic arthritis. RESULTS: The inhibitory effect of LX-NM on carrageenan-induced edema was higher than free LX for the same dose (1.3 mg/kg, i.p.). LX-NM (0.325 mg/kg, i.p.) produced effects comparable to that of diclofenac, which served as a standard. In the FCA model, daily treatment with LX-NM (0.325 mg/kg, i.p.) starting on day 14 significantly reduced the percentage of edema and increased weight growth. However, the same dose of LX failed to confer any significant change. Additionally, LX-NM significantly attenuated the rise of tumor necrosis factor-α (TNF-α), interleukin-1β, prostaglandin E2, nuclear factor-κβ, malondialdehyde and nitric oxide serum levels. In contrast, LX failed to show any significant reduction in elevated serum biomarkers except for TNF-α. CONCLUSION: LX-NM is an alternative delivery system that is simply prepared at low costs. It showed a superior therapeutic efficacy against RA compared to free LX. Thus, LX-NM can be considered as a promising candidate for treatment of RA and similar inflammatory disorders.
28413214 Circulating Biomarkers for Predicting Infliximab Response in Rheumatoid Arthritis: A Syste 2017 Apr 17 BACKGROUND Infliximab shows good efficacy in treating refractory rheumatoid arthritis (RA). However, many patients responded poorly and related studies were inconsistent in predictive biomarkers. This study aimed to identify circulating biomarkers for predicting infliximab response in RA. MATERIAL AND METHODS Public databases of Gene Expression Omnibus (GEO) and ArrayExpress were searched for related microarray datasets, focused on the response to infliximab in RA. All peripheral blood samples were collected before infliximab treatment and gene expression profiles were measured using microarray. Differential genes associated with infliximab efficacy were analyzed. The genes recognized by half of the datasets were regarded as candidate biomarkers and validated by prospective datasets. RESULTS Eight microarray datasets were identified with 374 blood samples of RA patients, among which 191 (51.1%) were diagnosed as non-responders in the subsequent infliximab treatment. Five genes (FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1) were associated with the efficacy and recognized by half of the datasets. The 5-gene model showed a good predictive power in random- and prospective-designed studies, with AUC (area under receiver operating characteristic [ROC] curve)=0.963 and 1.000, and it was also applicable at the early phase of treatment (at week 2) for predicting the response at week 14 (AUC=1.000). In the placebo group, the model failed to predict the response (AUC=0.697), indicating the model's specificity in infliximab treatment. CONCLUSIONS The model of FKBP1A, FGF12, ANO1, LRRC31, and AKR1D1 in peripheral blood is useful for efficiently predicting the response to infliximab treatment in rheumatoid arthritis.