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ID PMID Title PublicationDate abstract
30407878 GDF11 antagonizes TNF-α-induced inflammation and protects against the development of infl 2019 Mar Growth differentiation factor 11 (GDF11), a key member of the TGF-β superfamily, plays critical roles in various medical conditions. Recently, GDF11 was found to suppress the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and protect against inflammation. This study aimed to investigate the role of GDF11 in the development of rheumatoid arthritis (RA). We demonstrated that GDF11 treatment antagonized TNF-α-induced inflammation in macrophages. Moreover, GDF11 inhibited the development of arthritis in the collagen-induced arthritis and collagen antibody-induced arthritis models. Local gene transfer of GDF11 via adeno-associated virus exerted therapeutic effects, while local knockdown of GDF11 exaggerated inflammation in our collagen-induced arthritis model, as detected by expression levels of inflammatory biomarkers and the destruction of joint structures. Additionally, the results from both in vitro experiments and luciferase reporter gene mouse experiments implied that the NF-κB pathway might play a critical role in the therapeutic effect of GDF11 in RA. This study presents GDF11 as a potential target for the treatment of inflammatory arthritis, including RA.-Li, W., Wang, W., Liu, L., Qu, R., Chen, X., Qiu, C., Li, J., Hayball, J., Liu, L., Chen, J., Wang, X., Pan, X., Zhao, Y. GDF11 antagonizes TNF-α-induced inflammation and protects against the development of inflammatory arthritis in mice.
30289723 Sequential Prodrug Strategy To Target and Eliminate ACPA-Selective Autoreactive B Cells. 2018 Dec 3 Autoreactive B cells are thought to play a pivotal role in many autoimmune diseases. Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the Western population and is hallmarked by the presence of anticitrullinated proteins antibodies (ACPA) produced by autoreactive B cells. We intend to develop a method to target and selectively eliminate these autoreactive B cells using a sequential antigen prodrug targeting strategy. As ACPA-expressing B cells are thought to play essential roles in RA-disease pathogenesis, we used this B cell response as a prototype to analyze the feasibility to generate a construct consisting of a biologically silenced, that is, blocked, antigen connected to a cytotoxic prodrug. Blocking of the antigen is considered relevant as it is anticipated that circulating autoantibodies will otherwise clear the antigen-prodrug before it can reach the target cell. The antigen-prodrug can only bind to the autoantigen-specific B cell receptor (BCR) upon enzymatic removal of the blocking group in close proximity of the B cell surface. BCR binding ultimately induces antigen-specific cytotoxicity after internalization of the antigen. We have synthesized a cyclic citrullinated peptide (CCP) antigen suitable for BCR binding and demonstrated that binding by ACPA was impaired upon introduction of a carboxy- p-nitrobenzyl (CNBz) blocking group at the side chain of the citrulline residue. Enzymatic removal of the CNBz moiety by nitroreductase fully restored citrulline-specific recognition by both ACPA and ACPA-expressing B cells and showed targeted cell death of CCP-recognizing B cells only. These results mark an important step toward antigen-specific B cell targeting in general and more specifically in RA, as successful blocking and activation of citrullinated antigens forms the basis for subsequent use of such construct as a prodrug in the context of autoimmune diseases.
30032418 Study of cannabinoid receptor 2 Q63R gene polymorphism in Lebanese patients with rheumatoi 2018 Nov The cannabinoid (CB) receptor 2, primarily expressed in immune cells, was shown to play important immune-regulatory functions. In particular, the CB2-R63 functional variant has been shown to alter the ability of the CB2 receptor to exert its inhibitory function on T lymphocytes. The aim of this study was to investigate the association between a common dinucleotide polymorphism, Q63R, in the cannabinoid receptor 2 gene (CNR2) and rheumatoid arthritis (RA) in the Lebanese population. One hundred five unrelated Lebanese RA patients and one hundred five controls from different Lebanese governorates were recruited in this study. Genomic DNA was extracted, polymerase chain reaction was performed, and CNR2 was genotyped in a blinded fashion. The χ(2) test was used to determine the differences in genotypes and allele frequencies. CNR2 genotyping showed significantly higher frequencies of the CB2-R63 variant (allele frequencies, P < 0.00001; genotype distribution, P < 0.00001) in RA patients when compared with healthy controls. Moreover, RR carriers had more than 10-fold risk for developing RA (OR = 10.8444, 95% CI = 5.0950-23.0818; P < 0.0001), and QR carriers had more than 3-fold risk (OR = 3.8667, 95% CI = 1.7886-8.3591; P = 0.0006) as compared with QQ carriers. Our preliminary results suggest a role of CB2-Q63R gene polymorphism in the etiology of RA, thus supporting its potential use as a pharmacological target for selective agonists in clinical practice.
30107964 First metatarsophalangeal joint arthrodesis with two orthogonal two hole plates. 2018 Sep OBJECTIVE: First MTP joint fusion is a reliable procedure for advanced arthritis for the first MTP joint. There are many techniques described. The purpose of our study is to report clinical, radiological, functional outcomes and complications of first metatarsophalangeal joint fusion with hand preparation of the joint and fixation with two orthogonal locking plates without a compression screw. METHODS: 32 feet in 26 consecutive patients under went first metatarsophalangeal joint fusion with above technique. There were 23 women and 3 men. Mean age was 64 years and mean follow-up was 49 months. 21 patients had osteoarthritis, 10 had rheumatoid arthritis and one had psoriatic arthritis. Clinical, radiological, American Orthopaedic Foot and Ankle Score and Foot and Ankle Disability Index clinical rating scales were used for evaluation. RESULTS: Fusion was achieved in 27 feet. The incidence of radiological non-union was 15.7%. Mean AOFAS score improved from 37.1 to 80.7 (p < 0.0001) and mean FADI score improved from 40.3 to 86.9 postoperatively (p < 0.0001). Two patients with osteoarthritis and three with Rheumatoid arthritis did not unite. Four of these patients were managing hence revision surgery was not carried out but had low AOFAS and FADI scores. One patient with symptomatic non-union declined further surgery. One patient needed plate removal for a low grade infection and reoperation rate was 3.1%. CONCLUSIONS: In our experience, first metatarsophalangeal joint arthrodesis using two orthogonal two hole plates without a compression screw is associated with a higher non-union rate in our cohort hence we do not recommend this technique. LEVEL OF EVIDENCE: Level IV, therapeutic study.
30562768 [Value of serum matrix metalloproteinase 3 in the assessment of early rheumatoid arthritis 2018 Dec 18 OBJECTIVE: To investigate the expression level of serum matrix metalloproteinase 3 (MMP3) in early rheumatoid arthritis (ERA) patients with normal C-reaction protein (CRP) or erythrocyte sedimentation rate (ESR), and the significance in disease assessment. METHODS: In the study, 133 cases of early RA patients, 25 osteoarthritis (OA) patients and 60 healthy controls in Peking University People's Hospital from 2011 to 2015 were included. The RA patients were further divided into 4 groups according to levels of CRP and ESR: 88 patients with increased CRP and increased ESR, 15 patients with normal CRP and normal ESR, 17 patients with normal CRP but increased ESR, and 13 patients with increased CRP but normal ESR. All the clinical information of the patients was collected, and the serum MMP3 levels of both patients and healthy controls were detected by enzyme-linked immune sorbent assay (ELISA). RESULTS: The serum MMP3 level of RA patients with normal CRP and/or normal ESR [(72.89±6.34) μg/L] was obviously higher than that of OA patients [(42.87±4.14) μg/L] (P=0.002) and healthy controls [(31.62±2.88) μg/L] (P<0.001). The serum MMP3 levels of the patients with normal CRP and normal ESR [(47.04±9.64) μg/L] were higher than those of the healthy controls, and there was statistical significance between the two groups (P<0.05). The serum MMP3 levels of the patients with increased CRP but normal ESR [(94.18±9.11) μg/L] and the patients with normal CRP but increased ESR [(79.42±10.60) μg/L] were both higher than those of the OA patients and healthy controls, and there was obvious statistical difference (P<0.05). In the early RA patients with normal CRP and/or normal ESR, the serum MMP3 level was positively correlated with the CRP level (r=0.336, P=0.024). The positive rate of MMP3 in the patients with normal CRP and/or normal ESR was 44.44%, higher than the positive rate of CRP (28.89%) and the positive rate of ESR (37.78%). In these early RA patients, the positive rate was 52.94% in the patients with normal CRP but increased ESR and 53.85% in the patients with increased CRP but normal ESR. CONCLUSION: The detection of the serum MMP3 level was significant in the assessment of early RA patients within 2-year duration who had normal CRP or ESR value.
28371257 Dietary Intake of Polyunsaturated Fatty Acids and Pain in Spite of Inflammatory Control Am 2018 Feb OBJECTIVE: To investigate potential associations between dietary intake of polyunsaturated fatty acids (FAs) and pain patterns in early rheumatoid arthritis (RA) patients after 3 months of methotrexate (MTX) treatment. METHODS: We included 591 early RA patients with MTX monotherapy from a population-based prospective case-control study, the Epidemiological Investigation of Rheumatoid Arthritis. Dietary data on polyunsaturated FAs (food frequency questionnaires) were linked with data on unacceptable pain (visual analog scale [VAS] >40 mm), noninflammatory/refractory pain (VAS >40 mm and C-reactive protein [CRP] level <10 mg/liter), and inflammatory pain (VAS >40 mm and CRP level >10 mg/liter) after 3 months. Statistical analysis included logistic regression. RESULTS: After 3 months of MTX treatment, 125 patients (21.2%) had unacceptable pain, of which 92 patients had refractory pain, and 33 patients had inflammatory pain. Omega-3 FA intake was inversely associated with unacceptable pain and refractory pain (odds ratio [OR] 0.57 [95% confidence interval (95% CI) 0.35-0.95] and OR 0.47 [95% CI 0.26-0.84], respectively). The omega-6:omega-3 FA ratio, but not omega-6 FA alone, was directly associated with unacceptable pain and refractory pain (OR 1.70 [95% CI 1.03-2.82] and OR 2.33 [95% CI 1.28-4.24], respectively). Furthermore, polyunsaturated FAs were not associated with either inflammatory pain or CRP level and erythrocyte sedimentation rate at followup. Omega-3 FA supplementation was not associated with any pain patterns. CONCLUSION: Omega-3 FA was inversely associated with, and the omega-6:omega-3 FA ratio was directly associated with, unacceptable and refractory pain, but not with inflammatory pain or systemic inflammation. The inverse association between omega-3 FA and refractory pain may have a role in pain suppression in RA.
30092847 Epigenetic modification of mesenchymal stromal cells enhances their suppressive effects on 2018 Aug 9 BACKGROUND: The aim of this study was to investigate if epigenetically modified human mesenchymal stromal cells (hMSCs) can regulate the Th17-related immune responses. METHODS: We tested epigenetic drug combinations at various doses and selected the four combinations that resulted in maximal interleukin (IL)-10 and indoleamine 2,3-dioxygenase gene expression in hMSCs. We examined the effects of epigenetically modified hMSCs (epi-hMSCs) on CD4(+) T-cell proliferation and inflammatory cytokine secretion under Th0- and Th17-polarizing conditions using mixed lymphocyte reactions and enzyme-linked immunosorbent assays (ELISAs). We determined Th17 cytokine levels and the percentage of Th17 cells among synovial fluid mononuclear cells (SFMCs) from rheumatoid arthritis (RA) patients by ELISA and flow cytometry. RESULTS: Epi-hMSCs inhibited the development of IL-17-producing cells in culture. The percentages of IL-17(+) and interferon (IFN)-γ(+) cells among peripheral blood mononuclear cells from healthy donors were lower under both the Th0 and Th17 conditions in the presence of epi-hMSCs than in the presence of no or untreated hMSCs. Epi-hMSC-treated RA patient SFMCs secreted lower levels of IL-17 and IFN-γ than RA patient SFMCs cultured without hMSCs or with untreated hMSCs. CONCLUSIONS: An optimal combination of hypomethylating agents and histone deacetylase inhibitors can enhance the immunomodulatory potential of hMSCs, which may be useful for RA treatment.
30009382 Porphyromonas gingivalis in the tongue biofilm is associated with clinical outcome in rheu 2018 Nov Several studies have suggested a link between human microbiome and rheumatoid arthritis (RA) development. Porphyromonas gingivalis seems involved in RA initiation and progression, as supported by the high occurrence of periodontitis. In this case-control study, we analysed tongue P. gingivalis presence and quantification in a large healthy and RA cohort. We enrolled 143 RA patients [male/female (M/F) 32/111, mean ± standard deviation (s.d.), age 57·5 ± 19·8 years, mean ± s.d. disease duration 155·9 ± 114·7 months); 36 periodontitis patients (M/F 11/25, mean ± s.d., age 56 ± 9·9 years, mean ± s.d. disease duration 25·5 ± 20·9 months); and 57 patients (M/F 12/45, mean ± s.d., age 61·4 ± 10·9 years, mean ± s.d. disease duration 62·3 ± 66·9 months) with knee osteoarthritis or fibromyalgia. All subjects underwent a standard cytological swab to identify the rate of P. gingivalis/total bacteria by using quantitative real-time polymerase chain reaction. The prevalence of P. gingivalis resulted similarly in RA and periodontitis patients (48·9 versus 52·7%, P = not significant). Moreover, the prevalence of this pathogen was significantly higher in RA and periodontitis patients in comparison with control subjects (P = 0·01 and P = 0·003, respectively). We found a significant correlation between P. gingivalis rate in total bacteria genomes and disease activity score in 28 joints (DAS28) (erythrocyte sedimentation rate) (r = 0·4, P = 0·01). RA patients in remission showed a significantly lower prevalence of P. gingivalis in comparison with non-remission (P = 0·02). We demonstrated a significant association between the percentage of P. gingivalis on the total tongue biofilm and RA disease activity (DAS28), suggesting that the oral cavity microbiological status could play a role in the pathogenic mechanisms of inflammation, leading to more active disease.
29251019 The RORγt-CCR6-CCL20 axis augments Th17 cells invasion into the synovia of rheumatoid art 2018 Sep OBJECTIVES: To clarify the pathogenic role of transcription factor expression of CD4 + T helper (Th) cell subsets in the development of rheumatoid arthritis (RA). METHODS: We collected CD4 + T cells from peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) by magnetic cell sorting. The proportion of Th cell subsets were classified from cell surface markers (CD45RA, CXCR5, CXCR3, CCR6) and the expression of their transcription factors (T-bet, GATA3, RORγt) were analyzed by flow cytometry before and at 24 weeks after anti-rheumatic treatment. Chemotaxis assays quantified migratory ability. RESULTS: The expression of CCR6 and RORγt in Th17 cells from PBMC of RA patients was significantly higher than in healthy control volunteers and osteoarthritis patients. The proportion of Th17 cells in SFMCs of RA patients was significantly higher than that in PBMCs. Chemotaxis assays revealed that the migration index of Th17 cells towards CCL20 was remarkably enhanced in RA patients. The expression of CCR6 and RORγt in Th17 cells at 24 weeks post-therapeutic intervention was significantly decreased compared to before treatment. CONCLUSION: The high expression of RORγt might facilitate the migration of Th17 cells to inflamed joints via the enhanced expression of CCR6 and contribute to the pathology of RA.
29415557 Outcomes of Resection and Joint-Preserving Arthroplasty for Forefoot Deformities for Rheum 2018 Mar BACKGROUND: We investigated the clinical outcomes of resection and joint-preserving arthroplasty for forefoot deformities in patients with rheumatoid arthritis. METHODS: Sixteen feet of 14 women (average age, 67.1 years; range, 53-82) underwent resection arthroplasty of the metatarsal head (resection group), and 18 feet of 15 women (average age, 61.3 years; range, 40-73) underwent a metatarsophalangeal joint-preserving procedure with shortening oblique metatarsal osteotomies of the lesser toes (joint preservation group). The mean disease duration in the resection and joint preservation groups was 23.6 and 19.1 years, and the average follow-up period was 37.3 and 33.5 months, respectively. The classification of Larsen was used to assess the severity of destruction of the metatarsophalangeal (MTP) joint. Preoperative and postoperative clinical evaluation included Japanese Society for Surgery of the Foot (JSSF) score and postoperative complications. RESULTS: The number of preoperative radiographic destruction of the MTP joints (Larsen grade II, III, IV, and V) was 0, 29, 39, and 12 joints in the resection group and 13, 67, 9, and 1 joints in the joint preservation group. The mean JSSF score improved significantly from 61.3 to 83.9 points in the resection group ( P < .001) and from 62.2 to 90.8 points in the joint preservation group ( P < .001). In the resection group, recurrence of callosities and claw toe deformity was observed in 6 and 3 feet, respectively. In the joint-preserving group, recurrence of callosities and hammer toe deformity was observed in 1 foot each. CONCLUSION: The resection arthroplasty and joint-preserving procedure showed satisfactory clinical outcomes. However, whether both procedures can maintain the good clinical results without the recurrence of forefoot deformity will require longer follow-up. LEVEL OF EVIDENCE: Level III, retrospective comparative series.
29993142 Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of 2018 Sep Transcriptional regulation of inducible nitric oxide synthase (iNOS) is critically involved in the pathogenesis and progression of rheumatoid arthritis (RA); however, the specific transcription factors that control this process remain largely unidentified. In the present study, it was discovered that expression of the key erythroid factor, globin transcription factor 1 (GATA1), is significantly greater in human RA synovial tissues than in osteoarthritis (OA) tissues. IL 6 was found to induce synovial GATA1 expression in a signal transducer and activator of transcription 3-dependent manner. Functionally, knockdown of GATA1 expression using specific small interfering RNA treatment was found to compromise immunoreaction-elicited expression of proinflammatory cytokines and thus impair invasiveness of the human fibroblast-like synovial cell line MH7A, whereas introduction of exogenous GATA1 was found to promote production of proinflammatory cytokines, leading to greater aggressiveness of MH7A cells. Mechanistically, GATA1 acts as the transcriptional coactivator of NOS2 (the gene encoding iNOS) transcription. Collectively, these data suggest that synovial GATA1 is an essential contributor to development and exacerbation of RA, presumably by inducing NOS2 transcription.
30776205 [Irisin as a new marker for the early diagnosis of low-traumatic fractures in rheumatoid a 2018 The aim of this study was to study the relationship between serum irisin level and the presence of low-traumatic bone fractures in rheumatoid arthritis (RA) patients. We examined 170 people including 110 RA patients and 60 healthy individuals as comparison group. The serum irisin level was determined with solid-phase enzyme-linked immunosorbent assay using ELISA Irisin test system (BioVendor, cat. No. RAG018R). The average level of irisin in the group of healthy individuals was 20.49 ± 4.82 μg/ml (μ±σ). The level of normal values, defined as M ± 2σ, was 10.85-30.13 μg/ml. Decreased irisin level was detected in 41 of 110 patients with RA diagnosis (37% of cases). This group of patients had higher RA activity degree (DAS28), extra-articular manifestations, disease duration from 5 to 10 years, greater class of functional joint's failure, lower level of 25 (OH) -vitamin D. There was also a reliable relationship between serum irisin level and presence of low-fracture bone fractures in the anamnesis.
29234875 Chronic disease list conditions in patients with rheumatoid arthritis in the private healt 2018 May INTRODUCTION: Little is known about the burden of rheumatoid arthritis (RA) in South Africa. The aim of this study was to establish the prevalence of RA and coexisting chronic disease list (CDL) conditions in the private health sector of South Africa. METHODS: A retrospective, cross-sectional analysis was performed on medicine claims data from 1 January 2014 to 31 December 2014 to establish the prevalence of RA. The cohort of RA patients was then divided into those with and those without CDL conditions, to determine the number and type of CDL conditions per patient, stratified by age group and gender. RESULTS: A total 4352 (0.5%) patients had RA, of whom 69.3% (3016) presented with CDL conditions. Patients had a median age of 61.31 years (3.38; 98.51), and 74.8% were female. Patients with CDL conditions were older than those patients without (p < 0.001; Cohen's d = 0.674). Gender had no influence on the presence of CDL conditions (p = 0.456). Men had relatively higher odds for hyperlipidemia (OR 1.83; CI 1.33-2.51; p < 0.001) and lower odds for asthma (OR 0.83; CI 0.48-1.42; p = 0.490) than women. In combination with hyperlipidemia, the odds for asthma were reversed and strongly increased (OR 6.74; CI 2.07-21.93; p = 0.002). The odds for men having concomitant hyperlipidemia, hypertension, type 2 diabetes mellitus and hypothyroidism were insignificant and low (OR 0.40; CI 0.16-1.02; p = 0.055); however, in the absence of hypothyroidism, the odds increased to 3.26 (CI 2.25-4.71; p < 0.001). CONCLUSION: Hypothyroidism was an important discriminating factor for comorbidity in men with RA. This study may contribute to the body of evidence about the burden of RA and coexisting chronic conditions in South Africa.
29669470 Web-based rehabilitation interventions for people with rheumatoid arthritis: A systematic 2019 Jun BACKGROUND: Rehabilitation approaches for people with rheumatoid arthritis include joint protection, exercises and self-management strategies. Health interventions delivered via the web have the potential to improve access to health services overcoming time constraints, physical limitations, and socioeconomic and geographic barriers. The objective of this review is to determine the effects of web-based rehabilitation interventions in adults with rheumatoid arthritis. METHODS: Randomised controlled trials that compared web-based rehabilitation interventions with usual care, waiting list, no treatment or another web-based intervention in adults with rheumatoid arthritis were included. The outcomes were pain, function, quality of life, self-efficacy, rheumatoid arthritis knowledge, physical activity and adverse effects. Methodological quality was assessed using the Cochrane Risk of Bias tool and quality of evidence with the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Six source documents from four trials ( n = 567) focusing on self-management, health information or physical activity were identified. The effects of web-based rehabilitation interventions on pain, function, quality of life, self-efficacy, rheumatoid arthritis knowledge and physical activity are uncertain because of the very low quality of evidence mostly from small single trials. Adverse effects were not reported. CONCLUSION: Large, well-designed trials are needed to evaluate the clinical and cost-effectiveness of web-based rehabilitation interventions in rheumatoid arthritis.
30191329 Modeling Sex Differences in Anti-inflammatory Effects of Dexamethasone in Arthritic Rats. 2018 Sep 6 PURPOSE: Collagen-induced arthritic (CIA) rats are used commonly for preclinical pharmacologic research into rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid (CS), remains an important component in combination therapy for RA. Although sex differences in RA and CS pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, there has been no such comprehensive evaluation of sex differences in CIA rats. METHODS: Paw size measurements were obtained for males and females from four groups of animals: healthy controls, non-drug treated arthritic animals, and both 0.225 and 2.25 mg/kg DEX-treated arthritic animals. A turnover model for disease progression, minimal PBPK model for drug concentrations, and inhibitory indirect response model were applied using population PK/PD modeling. RESULTS: The clearances of DEX were 43% greater in males, but other PK parameters were similar. The temporal profiles of paw swelling exhibited earlier progression, peak edema times, and disease remission in females. DEX suppressed paw edema well in both males and females with similar capacity (I(max)) values (=1.0), but DEX potency was less in females with higher IC(50) values (0.101 versus 0.015 ng/mL). CONCLUSIONS: The pharmacology of DEX was well characterized in CIA rats. This study addresses knowledge gaps about sex differences and can be a guide for more mechanistic assessment of sex, drug, and disease differences in RA.
29808722 RNA sequencing to predict response to TNF-α inhibitors reveals possible mechanism for non 2018 Jul BACKGROUND: Several studies have employed microarray-based profiling to predict response to tumor necrosis factor-alpha inhibitors (TNFi) in rheumatoid arthritis (RA); yet efforts to validate these targets have failed to show predictive abilities acceptable for clinical practice. METHODS: The eighty most extreme responders and nonresponders to TNFi therapy were selected from the observational BiOCURA cohort. RNA sequencing was performed on mRNA from peripheral blood mononuclear cells (PBMCs) collected before initiation of treatment. The expression of pathways as well as individual gene transcripts between responders and nonresponders was investigated. Promising targets were technically replicated and validated in n = 40 new patients using qPCR assays. RESULTS: Before therapy initiation, nonresponders had lower expression of pathways related to interferon and cytokine signaling, while also showing higher levels of two genes, GPR15 and SEMA6B (p = 0.02). The two targets could be validated, however, additional analyses revealed that GPR15 and SEMA6B did not independently predict response, but were rather dose-dependent markers of smoking (p < 0.0001). CONCLUSIONS: The study did not identify new transcripts ready to use in clinical practice, yet GPR15 and SEMA6B were recognized as candidate explanatory markers for the reduced treatment success in RA smokers.
28340066 Diagnostic test accuracy of ultrasound for synovitis in rheumatoid arthritis: systematic r 2018 Jan 1 OBJECTIVE: To evaluate diagnostic test accuracy of US compared with MRI for the detection of synovitis in RA patients. METHODS: A systematic literature search was performed in the PubMed, EMBASE, Cochrane Library and Web of Science Core Collection databases. Studies evaluating the diagnostic test accuracy of US for synovitis detected by MRI as the reference standard for wrist, MCP, PIP and knee joints were included. To assess the overall accuracy, we calculated the diagnostic odds ratio using a DerSimonian-Laird random effects model and the area under the curve (AUC) for the hierarchical summary receiver operating characteristics using Holling's proportional hazards models. The summary estimate of the sensitivity and specificity were obtained using the bivariate model. RESULTS: Fourteen of 601 identified articles were included in the review. The diagnostic odds ratio was 11.6 (95% CI 5.6, 24; I2 = 0%), 28 (95% CI 12, 66; I2 = 11%), 23 (95% CI 6.5, 84; I2 = 19%) and 5.3 (95% CI 0.60, 48; I2 = 0%) and the AUC was 0.81, 0.91, 0.91 and 0.61 for wrist, MCP, PIP and knee joints, respectively. The summary estimates of sensitivity and specificity were 0.73 (95% CI 0.51, 0.87)/0.78 (95% CI 0.46, 0.94), 0.64 (95% CI 0.43, 0.81)/0.93 (95% CI 0.88, 0.97), 0.71 (95% CI 0.33, 0.93)/0.94 (95% CI 0.89, 0.97) and 0.91 (95% CI 0.56, 0.99)/0.60 (95% CI 0.20, 0.90) for wrist, MCP, PIP and knee joints, respectively. CONCLUSION: US is a valid and reproducible technique for detecting synovitis in the wrist and finger joints. It may be considered for routine use as part of the standard diagnostic tools in RA.
29076110 Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumato 2018 Aug BACKGROUND AND OBJECTIVES: Upadacitinib is a janus kinase (JAK) 1 inhibitor being developed for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. This work characterized upadacitinib population pharmacokinetics in healthy subjects and RA patients and the effects of covariates on upadacitinib exposure. METHODS: Upadacitinib plasma concentrations (n = 6399) from 107 healthy subjects and 466 RA patients from three phase I and two 12-week RA phase IIb trials (1-48 mg immediate-release doses across studies) were analyzed using non-linear mixed-effects modeling. The models were qualified using bootstrap and stochastic simulations. RESULTS: A two-compartment model with first-order absorption and elimination described upadacitinib pharmacokinetics. Estimates (95% bootstrap confidence interval) for upadacitinib oral clearance, steady-state volume of distribution, absorption lag time, and mean absorption time were 39.7 (37.8-41.5) L/h, 210 (196-231) L, 0.48 (0.47-0.49) h, and 0.08 (0.04-0.12) h, respectively, for a typical healthy male. Matching on other covariates, a 16 and 32% higher upadacitinib area under the concentration-time curve (AUC) was estimated for females relative to males, and for subjects with RA relative to healthy volunteers, respectively. Subjects with RA with mild or moderate renal impairment were estimated to have 16 and 32% higher upadacitinib AUC, respectively, compared with subjects with RA with normal renal function. Upadacitinib clearance was not correlated with body weight. CONCLUSIONS: Upadacitinib pharmacokinetics follow dose-proportional, bi-exponential disposition. A slightly lower upadacitinib clearance is estimated in subjects with RA than in healthy volunteers, consistent with observations for other JAK inhibitors. Other covariates (weight, sex, mild or moderate renal impairment) are not associated with clinically relevant effects on upadacitinib exposure. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifiers: NCT01741493, NCT02066389, and NCT01960855.
29709696 IMSYC immunologic synovitis score: A new score for synovial membrane characterization in i 2019 Jan OBJECTIVES: Krenn synovitis Score has been developed by Krenn et al. in order to assess synovitis severity and is used in synovial research. Cell signature of synovial tissue can be studied using immunohistochemistry and is of interest as a biomarker for both prognosis and prediction of response to treatment. However, no synovitis score including immunohistochemistry exists yet. In order to answer this unmet need, we propose a new Immunologic Synovitis score (IMSYC) adding 5 components to the Krenn score: CD68, CD3, CD20, CD31 and Ki67 immunostaining. In this study, we aimed to validate this new IMSYC by studying its diagnostic performances in a well-defined collection of synovial samples. METHODS: Synovial samples from patients were obtained during surgical procedures. CD68, CD3, CD20, CD31 and KI67 immunohistochemistry were performed. RESULTS: In total, 77 patients were included. In total, 45 were females, mean age was 63.1 years. Forty had inflammatory arthritis, mainly rheumatoid arthritis (31/40). Non inflammatory arthritis group included 35 patients with mainly osteoarthritis. Mean Krenn score and IMSYC were significantly higher in the inflammatory group (P<0.001). ROC analysis of diagnostic performances determined the score of 13.5 out of 24 as the cut-off that gave the best ratio for discrimination between inflammatory and non-inflammatory arthritis with a sensitivity of 71.8% and specificity of 98%. CONCLUSION: We propose a new synovitis score including immunohistochemistry. This score has a better sensitivity and specificity than the Krenn score and represents a more functional synovitis evaluation. IMSYC could be further used in better categorizing synovial tissue phenotype and give a basis for tissue driven therapy.
29302826 The relationship of PADI4_94 polymorphisms with the morbidity of rheumatoid arthritis in C 2018 Feb Rheumatoid arthritis (RA) is a systemic autoimmune disease that is characterized by chronic, destructive, and debilitating arthritis. Peptidyl arginine deiminase type 4 (PADI4) polymorphisms (PADI4_94) have been reported to play a vital role in the disease. Nevertheless, the results were inconclusive. An electronic search of Embase, PubMed, CNKI, and WANFANG Date was performed to the identification of relevant studies published from 2003 to 2017. A total of 20 studies were enrolled as being eligible for analysis. In overall analysis, we had found a significant correlation between the PADI4_94 polymorphisms and RA under T vs. C (OR = 1.05, 95% CI 1.01-1.08, P = 0.01). Nevertheless, there were no significant associations under other four genetic models. In the subgroup analysis, we had observed the similar results in Asian population (T vs. C: OR = 1.11, 95% CI 1.05-1.17, P = 0.001), whereas no significant difference were observed in Caucasian population under any genetic model (P > 0.05). In conclusion, our meta-analysis demonstrated that the PADI4_94 polymorphisms might contribute to RA susceptibility especially in Asian populations but not in Caucasian populations. More well-designed studies with larger sample size are still required to further elucidate the relationship.