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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
28629271 Expression of Interleukin-1 and temporomandibular disorder: Contemporary review of the lit 2018 Jul OBJECTIVE: Temporomandibular disorders (TMD) are a group of conditions affecting the temporomandibular joint (TMJ), leading to jaw dysfunction, joint and muscle pain, and a decrease in quality of life. A communication network of pro- and anti-inflammatory mediators called cytokines maintains the homeostasis of the TMJ. This review will focus on the Interleukin (IL) family of cytokines, which have been quantified in TMJ synovial fluids in a variety of studies. IL-1α and IL-1β have pro-inflammatory effects, while the endogenous receptor antagonist (IL-1RA) inhibits the pro-inflammatory effects of IL-1. METHODS: A literature search (2006-2016) to identify eligible studies was completed using the PubMed database. Studies identified used saline irrigation to quantify cytokine profiles in synovial fluid of healthy and/or dysfunctional joints. RESULTS: The initial search yielded 111 articles, 5 of which met the inclusion criteria after inter-reviewer discussion. CONCLUSIONS: Articles that compared IL-1 concentrations in TMD vs. control groups found significant differences.
29195021 Association Between Marginal Jawbone Loss and Onset of Rheumatoid Arthritis and Relationsh 2018 Apr OBJECTIVE: To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti-citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls. METHODS: Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme-linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity. RESULTS: Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01-1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL-positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA. CONCLUSION: Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL-positive presymptomatic subjects compared with RANKL-negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.
30509997 Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurolo 2018 Dec 18 Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA. In experimental RA, we demonstrated that arthritis induced enrichment of IBA1(+) microglia in the hippocampus. This coincided with inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) and up-regulation of IGF1R in the pyramidal cell layer of the cornus ammoni and in the dentate gyrus, reproducing the molecular features of the IGF1/insulin resistance. The aberrant IGF1R signaling was associated with reduced hippocampal neurogenesis, smaller hippocampus, and increased immobility of RA mice. Inhibition of IGF1R in experimental RA led to a reduction of IRS1 inhibition and partial improvement of neurogenesis. Evaluation of physical functioning and brain imaging in RA patients revealed that enhanced functional disability is linked with smaller hippocampus volume and aberrant IGF1R/IRS1 signaling. These results point to abnormal IGF1R signaling in the brain as a mediator of neurological sequelae in RA and provide support for the potentially reversible nature of hippocampal changes.
30668414 Cinnamaldehyde and eugenol attenuates collagen induced arthritis via reduction of free rad 2019 Feb BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease which leads to bone and cartilage erosion. Oxidative stress and pro-inflammatory cytokines plays crucial role in the pathophysiology of RA. Cinnamaldehyde and eugenol have a long history of medical use in various inflammatory disorders. PURPOSE: The drugs available for the treatment of RA are associated with various side effects. The present study was conducted to evaluate the anti-arthritic effects of cinnamaldehyde and eugenol in rat model of arthritis. METHODS: Type II collagen was intradermally injected to rats for the induction of arthritis. Cinnamaldehyde (10 and 20 mg/kg/day) and eugenol (10 and 20 mg/kg/day) were given orally for 15 days, starting from day 21 to 35. Dexamethasone treated rats served as positive control. Histological, radiological and scanning electron microscopic analysis were done to monitor the effect of compounds on collagen induced arthritis (CIA). Reactive oxygen species (ROS) formation, nitric oxide and antioxidant status were also determined. The markers of biomolecular oxidation (protein, lipid and DNA) and activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, catalase and glutathione reductase) were also evaluated in the joint homogenate and plasma of rats. For detecting inflammation, levels of TNF-α, IL-6 and IL-10 were monitored by ELISA. RESULTS: Our results showed anti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol in arthritic rats. Scanning electron microscopy, histopathological and radiological findings also confirmed the anti-arthritic effects of cinnamaldehyde and eugenol. Both the compounds were effective in bringing significant decrease in the levels of ROS, nitric oxide, markers of biomolecular oxidation and increase in enzymatic and non-enzymatic antioxidants. The levels of TNF-α, IL-6 and IL-10 were also ameliorated by cinnamaldehyde and eugenol treatment. Between the two phytochemicals used, eugenol was found to be more effective than cinnamaldehyde in reducing the severity of arthritis. CONCLUSION: Cinnamaldehyde and eugenol were effective in ameliorating oxidative stress and inflammation in arthritic rats. These findings indicate that cinnamaldehdye and eugenol have a great potential to be used as an adjunct in the management of RA.
30802713 Tibetan medicine Kuan-Jin-Teng exerts anti-arthritic effects on collagen-induced arthritis 2019 Apr BACKGROUND: The stems of Tinospora sinensis (Lour.) Merr commonly named "Kuan-Jin-Teng" in Chinese, have been used to treat rheumatoid arthritis as a Tibetan medicine. PURPOSE: The effects of the EtOAc fraction of ethanolic extract from the stems of T. sinensis (KJT) on the pro-inflammatory cytokines and MAPK pathway were studied in collagen-induced arthritis (CIA) model. STUDY DESIGN: Anti-arthritic activity of KJT was investigated in CIA model. METHODS: The chemical constituents of KJT were analyzed by LC-MS and HPLC. The CIA model was established with injecting the bovine CII emulsified in Freund's adjuvant in Wistar rats. Several doses of KJT (50.0, 100.0 and 200.0 mg/kg) were administrated via oral gavage to CIA rats daily for 4 weeks. The anti-arthritic activity of KJT was investigated by clinical arthritis scoring, paw swelling inspection and hyperalgesia measurement, as well as radiological and histological analysis in CIA rats. The impacts of KJT on the activation of MAPK pathway, production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-17) in ankle joints, serum, and spleen in CIA rats were examined by western blot, immunohistochemical staining, ELISA, and quantitative real-time PCR respectively. Lastly, the effects of KJT on production of the nitric oxide (NO) and pro-inflammatory cytokines as well as the regulation of the phosphorylation of p38 and Erk were detected in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells. RESULTS: KJT significantly alleviated the paw swelling, hyperalgesia and arthritic severity, and reduced the synovial tissue proliferation and inflammatory cell infiltration in the CIA rats. Moreover, KJT suppressed the production of TNF-α, IL-1β, and IL-17 in ankle joints, serum, and spleen and reversed the up-regulation of the phosphorylation of p38 and Erk in CIA rats. KJT was also demonstrated to inhibit the production of NO and pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), and phosphorylation of p38 and Erk in LPS-stimulated RAW264.7 cells. CONCLUSION: These results suggest the mechanisms of KJT performing its anti-arthritis effect may be attributed to inhibiting the production of pro-inflammatory cytokines and down-regulating the MAPK signaling pathway.
29233793 Licochalcone A activates Keap1-Nrf2 signaling to suppress arthritis via phosphorylation of 2018 Feb 1 Licochalcone A (LCA) is derived from glycyrrhizae radix with antimicrobial, antitumor and anti-inflammatory activities. However, the anti-arthritic function of LCA and underlying mechanism has not been yet explored. The current study investigated the anti-arthritic effect of LCA and elucidated the underlying mechanism. The results showed that LCA significantly suppressed arthritis via the activation of SQSTM1 (p62)/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling in the collagen-induced arthritis (CIA) model of DBA mice. In coincided with the results, this anti-arthritic effect of LCA was remarkably diminished in the collagen antibody-induced arthritis (CAIA) model of Nrf2-/- mice. These findings indicate that p62/Nrf2 signaling is a crucial pathway for the induction and treatment of arthritis. To further validate the effect of LCA on the arthritis, rheumatoid arthritis synovial fibroblasts (RASFs) isolated from the synovium of RA patients were employed in the study. In coincided with in vivo results, LCA inhibited the cell proliferation and arrested the cell cycle, induced apoptosis, suppressed pro-inflammatory cytokine secretion and increased expression of antioxidant enzymes via the activation of Keap1-Nrf2 signaling by enhancing p62 phosphorylation and expression, Nrf2 accumulation and Nrf2 nucleus translocation. Findings in the current study provide evidence that p62-Keap1-Nrf2 axis is a pivotal signaling pathway in development of arthritis and therapeutic efficacy of drugs, and LCA activates of Keap1-Nrf2 signaling to suppress arthritis by phosphorylation of p62 at Ser349. Collectively, LCA is valuable to be further investigated as a lead compound for application in anti-arthritis, and interference with the interaction between Nrf2 and Keap1 by phosphorylation of p62 may be a promising strategy for the discovery of anti-arthritic agents.
30486869 The presence of anti-nuclear antibodies alone is associated with changes in B cell activat 2018 Nov 29 BACKGROUND: Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA(+) individuals to determine whether they share any of the cellular immunologic features seen in SARD. METHODS: Healthy ANA(-) controls and ANA(+) (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. RESULTS: A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA(+) subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA(+) subjects and subjects with UCTD clustered  with patients with early SARD, rather than ANA(-) healthy controls. CONCLUSIONS: ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD.
30282855 Effect of Janus kinase inhibition by tofacitinib on body composition and glucose metabolis 2018 Tofacitinib is the first Janus Kinase (JAK) inhibitor to treat moderately to severely active RA. In this study, we investigated whether the effect of tofacitinib have any effects on body composition in mice and female patients with RA. Female C57BL/6 mice fed with a high-fat diet were treated with 30 mg/kg/day tofacitinib or vehicle for 70 days. Following treatment, trunk muscle, subcutaneous fat, and visceral fats were measured using X-ray computed tomography CT scan. Glucose tolerance and insulin sensitivity were assessed. In female RA patients treated with biological disease modified anti-rheumatic-drugs (biological DMARDs) or tofacitinib (n=4 per group), we also evaluated the body composition after 3 months from the start of treatment initiation using bioelectrical impedance analysis. Treatment with tofacitinib did not affect the body weight, and body composition in C57BL/6 mice. It also did not affect glucose, and insulin tolerance in mice. In patients with RA, treatment with biological DMARDs did not affect the body composition whereas the muscle mass was unchanged after receiving tofacitinib and the fat mass was significantly increased. J. Med. Invest. 65:166-170, August, 2018.
29709523 Knee Arthroplasty Patients Predicted Versus Actual Recovery: What Are Their Expectations A 2018 Nov OBJECTIVES: (1) To determine evidence-based guidance for the length of time to return to specific valued functional and leisure activities after knee arthroplasty (KA). (2) To determine what patients feel are the most important functional or leisure activities to recover after KA. (3) To collect information about patients' expectations and compare them to the actual time it takes to return. DESIGN: Prospective longitudinal cohort observational survey. SETTING: Specialist orthopedic hospital. PARTICIPANTS: Patients (N=99) with osteoarthritis or rheumatoid arthritis (mean=69.9y [range 44-88]) listed for total knee arthroplasty (TKA) or unicompartmental knee arthroplasty. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Valued activities list (VAL) used to select activities patients expect to return to and report the actual time taken to return. RESULTS: Participants in unicompartmental knee arthroplasty group returned to the 6 most popular valued activities (walking >1km, stair climbing, housework, driving, gardening, and kneeling) 8%-33% more quickly than TKA group, and they were satisfied with performing these activities sooner on average (4%-18%) than the TKA group. The percentage of participants satisfied at 12 months postsurgery ranged from 96% returning to housework to 36% returning to kneeling. The Wilcoxon signed-rank test was used to compare the expected time and the actual time to return: Housework (Z=-5.631, P<.05, effect size=0.64) and swimming (Z=-3.209, P<.05, effect size=0.59) were quicker than expected, and walking >1 km (Z=-2.324, P<.05, effect size=0.27) was slower than expected. CONCLUSIONS: A more tailored and personalized approach with consideration of prior level of activity and comorbidities must be taken into account and adequately discussed to help bridge the gap between the expected and actual recovery time.
29022101 Microflow imaging: New Doppler technology to detect low-grade inflammation in patients wit 2018 Mar AIM: To assess the efficacy of microvascular imaging in detecting low-grade inflammation in arthritis compared with Power Doppler ultrasound (PDUS). METHOD AND MATERIALS: Patients presenting for ultrasound with arthralgia were assessed with grey-scale, PDUS and Superb Microvascular Imaging (SMI). Videoclips were stored for analysis at a later date. Three musculoskeletal radiologists scored grey-scale changes, signal on PDUS and/or SMI within these joints. If a signal was detected on both PDUS and SMI, the readers graded the conspicuity of vascular signal from the two Doppler techniques using a visual analogue scale. RESULTS: Eighty-three patients were recruited with 134 small joints assessed. Eighty-nine of these demonstrated vascular flow with both PD and SMI, whilst in five no flow was detected. In 40 joints, vascularity was detected with SMI but not with PDUS (p = 0.007). Out of the 89 joints with vascularity on both SMI and PDUS, 23 were rated as being equal; while SMI scored moderately or markedly better in 45 cases (p <0.001). CONCLUSION: SMI is a new Doppler technique that increases conspicuity of Doppler vascularity in symptomatic joints when compared to PDUS. This allows detection of low grade inflammation not visualised with Power Doppler in patients with arthritis. KEY POINTS: • SMI detects vascularity with improved resolution and sensitivity compared to Power Doppler. • SMI can detect low-grade inflammation not seen with Power Doppler. • Earlier detection of active inflammation could have significant impact on treatment paradigms.
30043583 Effects of Astragalus glycoprotein on Th17/Treg cells in mice with collagen-induced arthri 2018 Jul In this study of Th17/Treg cells, the therapeutic effect of Astragalus glycoprotein on collagen-induced arthritis in mice (CIA) was explored, and a basis for the clinical treatment of rheumatoid arthritis is provided. Sixty mice were selected for the establishment of a CIA mouse model, and were then randomly divided into a CIA model group, a hydrocortisone control group, a low, medium, and high dose group of Astragalus glycoprotein, respectively. The same number of control groups with same number of mice was established and after basic immunization, intraperitoneal injections were given once daily for two weeks in the treatment. At the end of the treatment, the mice in each group were selected and the proportion of Th17/Treg cells was detected by flow cytometry. The expression and positive expression of RORt, Foxp3, P-STAT3 and P-STAT5 protein were detected by Western blot and immunohistochemistry. Astragalus glycoprotein was shown to potentially improve the diet and mental state, reduce the arthritis index score and improve the pathological state of synovial membranes in the mice. Moreover, flow cytometry results showed that, compared with the CIA model group, the proportion of Th17 cells in the four other groups of mice decreased, while the proportion of Treg cells increased. This difference was statistically significant (P less than 0.05). From the experiment, the following conclusions were drawn: Astragalus glycoprotein can reduce Th17 cells and their transcription factors in the peripheral blood of CIA mice, up-regulate Treg cells and their transcription factors, and correct the balance of Th17/Treg cells so as to achieve an effective of treatment for CIA mice.
29545455 Glucocorticoids Are Associated with an Increased Risk for Vertebral Fracture in Patients w 2018 May OBJECTIVE: To identify the effects of glucocorticoids (GC) on various types of fractures in patients with rheumatoid arthritis (RA). METHODS: We used the Korean National Healthcare Claims database from 2010 to establish a retrospective cohort of patients with RA ≥ 19 years old. We then followed those patients through December 2013. The incidence rates of total and major fractures were calculated. We evaluated the effects of GC dose and duration on fractures using multivariable logistic regression analyses. We also examined the influence of GC on fractures in RA patients without a history of osteoporosis. RESULTS: A total of 11,599 fractures was observed in 9964 out of 138,240 patients with RA. During followup, 68.2% of patients used oral GC for > 3 months. Adjusted analysis showed the risk of vertebral fractures was increased by the following characteristics: duration of GC ≥ 6 months (OR 1.76, p < 0.01); mean dose of GC ≥ 2.5 mg (OR range = 1.37-1.71, p < 0.01); and highest daily dose of GC ≥ 10 mg (OR range = 1.23-1.75, p < 0.03). However, neither the duration nor the dose of oral GC increased the risk of hip and nonvertebral/nonhip fractures in patients with RA. Consistent results were observed in RA patients without osteoporosis. CONCLUSION: Longer duration and higher dose of oral GC in patients with RA increased the risk of vertebral fractures. However, the dose and duration of GC did not influence the risk of hip and nonvertebral/nonhip fractures.
30129338 [Effectiveness of one-stage total knee arthroplasty with tibial stem extender for knee art 2018 Sep 15 ABSTRACT: To evaluate the early effectiveness of one-stage total knee arthroplasty (TKA) with tibial stem extender for knee arthritis complicated with tibial stress fractures. METHODS: Between January 2014 and November 2016, 12 patients (12 knees) with knee arthritis and tibial stress fractures underwent one-stage TKA with tibial stem extender. There were 5 males and 7 females with an average age of 71.5 years (range, 60-77 years). There were 8 cases with osteoarthritis and 4 cases with rheumatoid arthritis. The radiographic examination showed the 6 cases of intra-articular fractures and 6 of extra-articular fractures (including transverse fractures in 4 cases and short oblique fractures in 2 cases); 2 cases complicated with middle and upper fibular stress fractures; all patients of varus deformities. Preoperative Knee Society Score (KSS) clinical score was 31.5±8.4 and functional score was 33.3±9.0. The preoperative range of motion (ROM) of the knee was (65.6±9.6)°. RESULTS: All indexes healed primarily and no wound infection or skin necrosis occurred. All patients were followed up 36.5 months on average (range, 6-52 months). X-ray films showed that all fractures healed at 3-7 months (mean, 4 months); the position of the prosthesis was good, and no loosening or signs of infection occurred. At last follow-up, the KSS clinical score was 90.5±8.9 and functional score was 92.1±7.8; the ROM of the knee was (115.0±9.8)°. All indicators were significantly improved than those before operation ( t=40.340, P= 0.000; t=32.120, P=0.000; t=8.728, P=0.000). CONCLUSION: One-stage TKA with tibial stem extender for patients with knee arthritis and tibial stress fractures can restore limb alignment, facilitate fracture healing, and obtain the satisfactory early effectiveness.
30477056 Prevalence and Clinical Use of Anti-Thyroid Antibodies in RA Patients: A Prospective Case- 2018 May AIM: To evaluate the prevalence of anti-thyroid antibodies in a cohort of rheumatoid arthritis (RA) patients from south India and their clinical use. METHODS: A cross-sectional epidemiological study was conducted including 1217 patients aged more than 14 years with fever and thrombocytopenia admitted in the medical wards from October 2013 to September 2014. Detailed clinical examination and routine investigations were done; specific investigations like blood culture, widal test, antigen test for malaria, IgM ELISA leptospira, IgM ELISA dengue, bone marrow aspiration/biopsy etc. were done as and when indicated. The data are presented as percentage and numbers. Rates and ratios are computedThe prospective case-control study, conducted for 3 consecutive months in a tertiary care hospital based in India, evaluated 103 RA patients (active group) and 36 age-matched healthy controls without the disease. Both the control and active groups were compared for thyroid autoantibodies, and the clinical evaluation included assessment of swollen joint counts (SJC), tender joint counts (TJC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), pain scale, disease activity score (DAS), rheumatoid factor (RF), anti-nuclear antibody (ANA) and anti-cyclic citrullinated peptide (anti-CCP). The active group subjects were further subdivided into RA patients with and without hypothyroidism, and were compared for normal and abnormal levels of thyroid autoantibodies and the variations were statistically analysed. RESULTS: The corresponding mean age of the subjects belonging to the active and control groups were 47.09±11.29 and 41.03±11, with a female to male ratio of 1:0.12 and 1:0.29 respectively. Among the various thyroid autoantibodies compared between the active and control groups, a significant correlation (P=0.00936) was observed for anti-TTG antibodies. Also, the study has noted a significantly elevated level of anti-TPO antibodies in RA patients with hypothyroidism compared to the group without hypothyroidism (P=0.0074). CONCLUSION: A significantly increased level of anti-TPO antibodies was noted in RA patients with hypothyroidism.
29402521 Methotrexate Dose in Patients With Early Rheumatoid Arthritis Impacts Methotrexate Polyglu 2018 Feb PURPOSE: Methotrexate (MTX) and adalimumab are well-recognized treatments of rheumatoid arthritis (RA), the efficacy of which may be driven by intracellular polyglutamates (PGs). The aim of this analysis was to characterize MTX PG concentrations and adalimumab pharmacokinetics in the CONCERTO trial. In addition, the relationships between MTX dose/pharmacokinetics, adalimumab pharmacokinetics, and efficacy were evaluated. METHODS: CONCERTO was a double-blind, parallel-arm study in patients with early RA randomized to adalimumab 40 mg SC every other week plus blinded MTX 2.5, 5, 10, or 20 mg PO once weekly, for 26 weeks. Blood samples were obtained through week 26 for the determination of concentrations of MTX PG, adalimumab, and anti-adalimumab antibody (AAA). Clinical outcomes were also assessed. FINDINGS: A total of 395 patients were included in the analysis (MTX, 329; adalimumab, 395). The mean time to steady-state MTX PG concentration was increased with MTX dose, from 8 to >26 weeks, depending on PG chain length. Dose proportionality changed with PG chain length. As MTX dose was increased, the percentage of short-chain PGs increased less than dose proportionally, while the percentage of long-chain PGs increased more than dose proportionally. For very-long-chain PGs, dose proportionality could not be assessed due to the nonmeasurable concentrations in the 2.5- and 5-mg MTX dose groups. As MTX dose increased, mean adalimumab concentrations also increased (P < 0.001). The percentage of patients with AAA decreased with increasing MTX dose, and at week 26, AAA(+) status was significantly correlated with MTX dose level (P = 0.005). In general, rates of response, defined using the 28-joint count disease activity score based on C-reactive protein (DAS28[CRP]; response, <3.2), were greater in the subgroup without AAA. The likelihood of a patient achieving a DAS28(CRP) response was related to the baseline measurement (P < 0.001) and to the concentration of adalimumab (P = 0.001), but not to the MTX regimen (P = 0.689). IMPLICATIONS: The dose-response characteristics of MTX PG pharmacokinetics and the resultant effects of MTX on adalimumab exposures should be considered when determining the benefit-risk profile of MTX and adalimumab combination therapy in patients with early RA. ClinicalTrials.gov identifier: NCT01185301.
30487791 Sulforaphane Inhibits Inflammatory Responses of Primary Human T-Cells by Increasing ROS an 2018 The activity and function of T-cells are influenced by the intra- and extracellular redox milieu. Oxidative stress induces hypo responsiveness of untransformed T-cells. Vice versa increased glutathione (GSH) levels or decreased levels of reactive oxygen species (ROS) prime T-cell metabolism for inflammation, e.g., in rheumatoid arthritis. Therefore, balancing the T-cell redox milieu may represent a promising new option for therapeutic immune modulation. Here we show that sulforaphane (SFN), a compound derived from plants of the Brassicaceae family, e.g., broccoli, induces a pro-oxidative state in untransformed human T-cells of healthy donors or RA patients. This manifested as an increase of intracellular ROS and a marked decrease of GSH. Consistently, increased global cysteine sulfenylation was detected. Importantly, a major target for SFN-mediated protein oxidation was STAT3, a transcription factor involved in the regulation of T(H)17-related genes. Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and downregulated the expression of the transcription factor RORγt, and the T(H)17-related cytokines IL-17A, IL-17F, and IL-22, which play a major role within the pathophysiology of many chronic inflammatory/autoimmune diseases. The inhibitory effects of SFN could be abolished by exogenously supplied GSH and by the GSH replenishing antioxidant N-acetylcysteine (NAC). Together, our study provides mechanistic insights into the mode of action of the natural substance SFN. It specifically exerts T(H)17 prone immunosuppressive effects on untransformed human T-cells by decreasing GSH and accumulation of ROS. Thus, SFN may offer novel clinical options for the treatment of T(H)17 related chronic inflammatory/autoimmune diseases such as rheumatoid arthritis.
29872265 The role of concomitant methotrexate dosage and maintenance over time in the therapy of rh 2018 OBJECTIVE: To evaluate the pattern of prescription and maintenance over time of concomitant methotrexate (MTX), and its impact on a 2-year clinical response in a cohort of rheumatoid arthritis (RA) patients treated with a first-line tumor necrosis factor alpha inhibitor (TNFi). PATIENTS AND METHODS: The study population included all RA patients receiving adalimumab or etanercept a as first-line biologic drug, extracted from a local registry. Enrolled patients were stratified into 3 subgroups according to baseline concomitant MTX: no MTX, low-dose MTX (≤10 mg/wk), and high-dose MTX (≥12.5 mg/wk). The 2-year persistence of the initial MTX regimen was computed by the Kaplan-Meier method, and a Cox proportional hazard model was developed to examine potential predictors of MTX withdrawal/change of dosage. European League Against Rheumatism remission and good-to-moderate response were evaluated according to baseline MTX regimen and MTX maintenance over time. RESULTS: A total of 330 patients (163 treated with adalimumab and 167 with etanercept) were included; 141 were prescribed TNFi without MTX and 112 received low-dose and 77 high-dose concomitant MTX. Male sex, younger age, and shorter mean disease duration were predictors of high-dose MTX use. Among MTX users (76.2% parenteral and 23.8% oral), initial MTX dose persisted over time in 79.9% at 1 year and 70.2% at 2 years. Fifty-one patients (27%) underwent MTX dose de-escalation/discontinuation because of intolerance/adverse events. The 2-year EULAR remission rate was higher in the patients receiving and maintaining high-dose MTX than in those receiving low-dose or no MTX (46.2% vs 29.5% and 23.4%, respectively; p=0.009). The same was true for good-to-moderate response rate (71.2% vs 52.6% and 50.4%, respectively; p=0.031). CONCLUSION: In a real-life setting, about one-third of RA patients treated with TNFis experienced dose reduction/discontinuation of concomitant MTX because of intolerance/adverse events over a 2-year follow-up period. Initial high-dose MTX and its maintenance over time are associated with better 2-year clinical response.
29252093 Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients w 2018 Jul OBJECTIVES: Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzyme elevation in a hospital-based cohort study. METHODS: Study participants were 114 Japanese adult RA outpatients prescribed MTX. Sixteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation period was 1 year after beginning MTX. Associations between MTX-induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model. RESULTS: Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB1 3435C>T and ATIC 347C>G were associated with abnormal hepatic enzyme elevation. CONCLUSIONS: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.
29691581 [Upregulation of miR-498 suppresses Th17 cell differentiation by targeting STAT3 in rheuma 2018 Apr 25 To investigate the effect and mechanism of miR-498 on Th17 cell differentiation of peripheral blood mononuclear cells (PMBCs) in rheumatoid arthritis (RA) patients, peripheral blood samples were collected from RA patients and healthy controls, respectively. The proportion of CD4(+)IL-17(+) T cells (Th17 cells) or CD4(+)FOXP3(+) T cells (Tregs) in T cells and the Th17/Treg ratio were identified by the flow cytometer. The STAT3 and miR-498 expression were measured by Western blot and real-time PCR, respectively. ELISA was used to detect IL-17 concentrations. Luciferase assay was performed to confirm that miR-498 directly targeted the 3' untranslated region (3'UTR) of STAT3 in CD4(+) T cells. The effect of miR-498 on Th17 cell differentiation was explored by transfection of miR-498 mimic and/or pcDNA-STAT3 into CD4(+) T cells. In PMBCs of RA patients, the Th17/CD4(+) T cell ratio was significantly increased, while the Tregs/CD4(+) T cell ratio was obviously decreased, leading to a higher Th17/Treg ratio. The results showed a reduced miR-498 expression and an increased STAT3 protein expression in PMBCs, and an increased IL-17 concentration in serum of RA patients. In cells transfected with wild-type-STAT3-LU, miR-498 mimic significantly reduced the luciferase activity, STAT3 gene and protein expression, and miR-498 inhibitor had an opposite function. While the miR-498 mimic/inhibitor had no effect on the luciferase activity and STAT3 expression in cells transfected with mutant-STAT3-LU. CD4(+) T cells transfected with miR-498 mimic had a lower Th17/CD4(+) T cell ratio and IL-17 concentration, however, transfection of pcDNA-STAT3 reversed the effect of miR-498 mimic on Th17/CD4(+) T cell ratio and IL-17 concentration. These results suggest that overexpression of miR-498 suppresses Th17 cell differentiation by targeting STAT3 in RA patients.
29701536 Concentrations of infliximab and anti-drug antibodies in relation to clinical response in 2018 Sep OBJECTIVE: The efficacy of anti-tumour necrosis factor-α (anti-TNF-α) treatment with infliximab (IFX) may be reduced by the development of anti-drug antibodies (ADAs). This study evaluated drug concentration and the presence of ADAs, relative to response, in rheumatoid arthritis (RA) patients treated with IFX. METHOD: Ninety-four RA patients were consecutively included and assessed for disease activity at baseline, and after 14, and 30 or 52 weeks. Serum IFX concentration and ADAs were analysed using in-house enzyme-linked immunosorbent assays. ADA analysis was based on binding to TNF-α-coated plates, with the lower detection limit set at mean + 2 sd of controls. RESULTS: At 14 and 52 weeks, 74.5% of the patients had moderate to good response. Good responders had significantly higher IFX concentrations than moderate and poor responders at 52 weeks (6.6 ± 1.4 µg/mL vs 3.6 ± 1.3 µg/mL and 2.6 ± 1.6 µg/mL, respectively). An IFX concentration ≥4.66 µg/mL at 14 weeks yielded a moderate to good response at 30/52 weeks, with 91.3% specificity and 39.3% sensitivity. Eleven patients dropped out owing to lack of efficacy and eight owing to side effects; three with IFX concentration ≤ 0.5 µg/mL were ADA positive. At an IFX concentration ≤ 0.5 µg/mL, 43.8% and 30.1% at 14 and 52 weeks, respectively, were ADA positive. None of the good responders had ADAs. CONCLUSION: One-quarter of patients had an IFX concentration ≤ 0.5 µg/mL but only 11.7% had ADAs. High IFX concentration was related to a good response, suggesting that the lack of response could be due to a lack of IFX, rather than to the presence of ADAs.