Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 32170389 | Methotrexate-related toxicity in patients with rheumatoid arthritis and renal dysfunction. | 2020 May | There are limited studies regarding the safety of methotrexate (MTX) in patients with reduced renal function. This study aimed to investigate methotrexate (MTX)-related toxicity in patients with rheumatoid arthritis (RA) and renal dysfunction. This retrospective cohort study included patients with RA and renal dysfunction. Renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m(2). We classified the patients into two groups according to the onset of renal dysfunction: newly and previously developed group. MTX-associated toxicity included renal toxicity, hepatotoxicity, serious infection, pancytopenia, leukopenia, thrombocytopenia and mucositis. Cox analysis was performed to determine the factors associated with toxicity. The study included 120 patients with RA and renal dysfunction receiving MTX (66: newly developed; 54: previously developed). The median eGFR was 52.1 mL/min/1.73 m(2) [IQR 47.1-57.3]. Thirty-five patients (29.2%) experienced toxicity, and the median time to toxicity events was 23 months (IQR 10-57). Toxicity was distributed as follows: leukopenia (10%, 12/120), renal toxicity (5.8%, 7/120), hepatotoxicity (7.5%, 9/120), serious infection (8.3%, 10/120), pancytopenia (5.0%, 6/120), thrombocytopenia (5.8%, 7/120), and mucositis (5.8%, 7/120). The toxicity rate did not differ significantly between newly and previously developed group [23/66 (34.8%) vs. 12/54 (22.2%), P = 0.130]. Multivariate analysis revealed that hydroxychloroquine use (HR 0.425, 95% CI 0.212-0.853, P = 0.016), baseline eGFR (HR 0.938, 95% CI 0.890-0.988, P = 0.015) and being female (HR 10.538, 95% CI 1.375-80.793, P = 0.023) were associated with MTX-related toxicity. Toxicity occurred in approximately 30% of patients with RA and renal dysfunction receiving MTX treatment. Hydroxychloroquine use exhibited a protective effect against MTX-associated toxicity development. | |
| 32435045 | [Probable rheumatoid meningitis complicated by cryptococcal meningitis: A case report]. | 2020 Jun 6 | We report a case of rheumatoid meningitis complicated with cryptococcal meningitis in a 59-year-old female with rheumatoid arthritis. Migraine symptoms were followed by abnormal behavior, and the patient was admitted with fever and headache. On admission, her cerebrospinal fluid (CSF) contained 115 cells/μl, a protein content of 95 mg/dl, and a sugar level of 47 mg/dl; Her serum anti-cyclic citrullinated peptide (CCP) antibody value was high (174 U/ml), and a brain MRI showed enhanced gadolinium lesions in the cerebral/cerebellar pia mater and subarachnoid space, etc. Probable rheumatoid meningitis was clinically diagnosed, and a prednisolone (PSL) pulse was started. Several days later, a CSF culture test was positive for Cryptococcus neoformans, and the antigen titer was 128-fold. Liposomal-amphotericin B (L-AMB) was started for cryptococcal meningitis, combined with three PSL pulses for rheumatoid meningitis. After about 4 weeks, the number of CSF cells and anti-CCP antibodies decreased rapidly. At 2 months after the onset, the meningitis recurred. The MRI contrast lesions reappeared, and the CSF cells increased to 24/μl. Serum and CSF anti-CCP antibodies increased at the time of recurrence, but the cryptococcal antigen titer decreased. Thus, we concluded that the rheumatoid meningitis mainly involved the pathogenesis of both types of meningitis. The number of PSL pulses was limited to four. Post-perioral therapy was avoided. Methotrexate was continued for the rheumatoid meningitis, fluconazole was continued for the cryptococcal meningitis, and neither type of meningitis has recurred. | |
| 32039570 | Association of a Type 2-Polarized T Cell Phenotype With Methotrexate Nonresponse in Patien | 2020 Jul | OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease mediated through complex immunologic pathways. Among RA patients receiving low-dose methotrexate (MTX) monotherapy, approximately one-half exhibit a meaningful clinical response within the first 6 months of starting treatment. Whether baseline immune phenotypes differ between subsequent MTX responders and nonresponders is unknown. This study utilized comprehensive T cell immunophenotyping to identify specific immunologic pathways associated with MTX-nonresponsive joint inflammation in patients with RA. METHODS: In total, 32 patients with recent-onset RA were treated with MTX therapy. After 6 months, 15 patients were categorized as responders and 17 as nonresponders. Comprehensive blood T cell immunophenotyping, using multiparameter immunofluorescence flow cytometry analyses, was performed at baseline and following 6 months of treatment. RESULTS: Baseline measures of disease activity (Disease Activity Score in 28 joints [DAS28], C-reactive protein level, and erythrocyte sedimentation rate) did not differ between MTX responders and nonresponders following MTX treatment. Frequencies of CD4+ and CD8+ T cells were skewed to favor higher CD4:CD8 T cell ratios in MTX responders compared to nonresponders (P < 0.05). The proportion of inducible costimulator-expressing Treg cells was significantly greater among MTX nonresponders. Interleukin-13 (IL-13)-producing, but not interferon-γ- or IL-17-producing, CD4+ effector memory T (Tem) cells were significantly more frequent in MTX nonresponders (P < 0.05). The ratio of IL-13+:IL-17+ Tem cells among CD4+ Tem cells was 1.9-fold higher in MTX nonresponders compared to responders (P < 0.05). Both the CD4:CD8 T cell ratio and the frequency of IL-13+CD4+ Tem cells correlated with changes in the DAS28 score following MTX treatment, whereas T cell expression of immune checkpoint inhibitor markers (CTLA-4, programmed death 1, and T cell immunoglobulin and mucin domain-containing protein 3) did not differ between MTX responders and nonresponders. CONCLUSION: We observed a bias toward type 2-polarized T cell inflammatory responses in the peripheral blood of MTX-nonresponsive RA patients. Targeting the IL-13+CD4+ T cell pathway could be a new therapeutic strategy in RA patients whose disease remains resistant to MTX. | |
| 32461524 | Methotrexate-associated Hodgkin Lymphoma in a Patient with Rheumatoid Arthritis Successful | 2020 Sep 1 | A 53-year-old woman had been diagnosed with rheumatoid arthritis (RA) in X-6. She was started on methotrexate (MTX) in X-1. She developed a cough, and chest computed tomography showed abnormalities. In X, MTX was discontinued, but the cough persisted. A lung biopsy revealed a diagnosis of nodular sclerosis classic Hodgkin lymphoma (CHL-NS). She was considered to have "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD), MTX-associated Hodgkin lymphoma (MTX-HL). She received six courses of brentuximab vedotin (BV) in addition to AVD (BV+AVD). A complete metabolic response was obtained, and the RA went into remission. This is the fourth reported case of BV+AVD for MTX-HL. | |
| 31267801 | Effectiveness, safety, and methotrexate dose-tapering pattern over two years of treatment | 2020 May | Objectives: To investigate the long-term effectiveness, safety, and methotrexate (MTX) dose-tapering patterns in patients with rheumatoid arthritis (RA) receiving adalimumab plus high-dose MTX.Methods: In this prospective, postmarketing study (2012-2017), conducted at 128 sites in Japan, biologic-naïve patients with RA (duration ≤2 years) previously treated with MTX for ≥3 months, initiated treatment with adalimumab and MTX (≥12 mg/week). Effectiveness by Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP), safety, and MTX dose-tapering were assessed from baseline to 104 weeks.Results: In the effectiveness analysis set (n = 292), DAS28-CRP remission (<2.6) was achieved in 92.3% (n = 120/130) of patients at week 104. The proportions of patients receiving MTX dose <10 mg/week increased to 32.3% (n = 50/155) and ≥12 mg/week reduced to 52.9% (n = 82/155) by week 104. Per univariate regression analysis, MTX dose tapering was associated with longer adalimumab drug survival. Of 70 patients with joint X-rays available, 59 (84.3%) achieved Δ modified total Sharp score ≤1.0 at 104 weeks. In the safety analysis set (n = 300), 143 adverse drug reactions were reported in 92 patients (30.7%, non-serious; 24.7%, serious 8.7%).Conclusion: The long-term effectiveness and safety of adalimumab with high-dose MTX was confirmed in biologic-naïve patients with early RA in a real-world setting in Japan.Clinical Trial Registration: This study is registered at ClinicalTrials.gov (identifier: NCT01736189; retrospectively registered 29 November 2012, due to administrative reasons). | |
| 33268527 | Active conventional treatment and three different biological treatments in early rheumatoi | 2020 Dec 2 | OBJECTIVE: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES: The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. RESULTS: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. TRIAL REGISTRATION: EudraCT2011-004720-35, NCT01491815. | |
| 32591978 | Investigation of Potential Drug-Drug Interactions between Peficitinib (ASP015K) and Methot | 2020 Sep | BACKGROUND: Methotrexate is frequently used to treat rheumatoid arthritis. Peficitinib (ASP015K; Smyraf(®)), an oral Janus kinase inhibitor indicated for the treatment of rheumatoid arthritis, may be coadministered with methotrexate. OBJECTIVE: The objective of this study was to investigate potential drug-drug interactions of peficitinib with methotrexate and the short-term safety of coadministration. PATIENTS AND METHODS: This phase I, open-label, single-sequence study included patients with rheumatoid arthritis taking a stable dose of methotrexate. Patients received their prescribed methotrexate dose (Day 1) and then peficitinib (100 mg) twice daily from Day 3 until the morning of Day 9; a second methotrexate dose was coadministered with peficitinib on Day 8. Serial blood samples were collected for methotrexate concentration after dosing on Days 1 (methotrexate alone) and 8 (methotrexate plus peficitinib) and for peficitinib concentration after dosing on Days 7 (peficitinib alone) and 8 (methotrexate plus peficitinib). Pre-dose concentrations of peficitinib were measured (Days 3-8). RESULTS: Peficitinib concentrations reached steady state on Day 5. Administration of peficitinib did not result in changes to methotrexate area under the concentration-time curve from time zero to infinity or maximum observed concentration following a methotrexate dose (15-25 mg), and there was no significant effect of methotrexate (15-25 mg) on peficitinib area under the concentration-time curve within a 12-hour dosing interval. There were no new tolerability or safety signals after coadministration of peficitinib and methotrexate. One patient experienced two serious adverse events and withdrew from the study without receiving peficitinib. CONCLUSIONS: Pharmacokinetic results showed no significant interactions between peficitinib and methotrexate. CLINICALTRIALS. GOV IDENTIFIER: NCT01754805. | |
| 31106666 | Predictive value of serum amyloid a levels for requirement of concomitant methotrexate in | 2020 May | Objectives: To identify predictive factors for remission by tocilizumab monotherapy in rheumatoid arthritis (RA) patients.Methods: This is a post hoc analysis of the SURPRISE study, a 2-year randomized, controlled study comparing the efficacy of tocilizumab with (ADD-ON) and without methotrexate (SWITCH). The primary endpoint was DAS28-ESR remission (<2.6) at week 24. The change in modified total Sharp score from baseline to week 52 (ΔmTSS/year) was also assessed as an endpoint. The effect of clinical parameters at baseline on remission was estimated by logistic regression analysis.Results: In SWITCH (n = 96), CRP, SAA, RF, and DAS28 at baseline showed predictive value for DAS28 remission in unadjusted analysis. Adjusted analysis confirmed SAA and DAS28 as predictive factors, with SAA having the highest value (ROC-AUC = 0.731). Furthermore, structural remission (ΔmTSS/year ≤ 0.5) rate was significantly higher in patients with SAA of < 50.0 μg/mL than other patients. In contrast, in ADD-ON (n = 98), only DAS28 showed predictive value for DAS28 remission. In patients with SAA < 50.0 μg/mL, both DAS28 remission and structural remission rate were comparable between SWITCH and ADD-ON.Conclusion: RA patients with low SAA levels at baseline may benefit similarly from tocilizumab with and without methotrexate.Trial registration number: NCT01120366. | |
| 33236554 | A Study of the Efficacy and Safety of Subcutaneous Injections of Tocilizumab in Adults wit | 2020 Sep | BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration. | |
| 31965234 | [Neurological symptoms in a patient on anti-TNF therapy, methotrexate and prednisolone fo | 2020 Mar | A 78-year-old woman with rheumatoid arthritis on TNF-α inhibitor, methotrexate and prednisolone presented with severe but unspecific symptoms such as leg weakness, shivering, bifrontal headache, nausea and staggering. The broad range of differential diagnoses lead to intricate and time-consuming diagnostic procedures. Serology, magnetic resonance imaging and microbiological investigations represent important steps to make the final diagnosis of cerebral toxoplasmosis. Both diagnostic approach and therapy require close cooperation of different disciplines. Therapies of rheumatoid arthritis as well as of toxoplasmosis are based on a long-term treatment and could be associated with numerous harmful side effects. Continuous monitoring and permanent adjustment of therapy regimes are therefore mandatory. | |
| 32347340 | Tocilizumab treatment in Felty's syndrome. | 2020 Jul | Felty's syndrome (FS) is a deforming disease, characterized by the triad of rheumatoid arthritis (RA), neutropenia, and splenomegaly. Currently, FS patients are treated mainly with immunosuppressants, such as methotrexate and glucocorticoids, which however are not suitable to some patients and may cause severe side effects. Here we report a clinical FS case that was treated with Tocilizumab (TCZ) successfully. The patient had symmetrical swelling and pain of multiple joints, deformity of elbow joints with obvious morning stiffness. Joint color Doppler ultrasound showed synovial hyperplasia and bone erosion of wrist and proximal interphalangeal joints and CT scan suggested splenomegaly. Further examination showed neutropenia and anemia, a high titer of anti-cyclic citrullinated peptide antibody, rheumatoid factor and anti-nuclear antibodies, positive p-ANCA, and elevated IgA and IgG. After treating with TCZ, the patient has been relieved of clinical symptoms. His spleen has recovered to normal size. The absolute neutrophil count (ANC) tended to be stable, and joint erosion did not deteriorate. We have reviewed the literatures on FS treatment with biological agents and found only a few reports using TNF-α antagonist and rituximab treating FS, but none with TCZ. So, it is the first time to report a successful FS case treated with TCZ. This case suggests that the TCZ may be a new choice for FS treatment, under the condition of closely monitoring the ANC. | |
| 32098857 | Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis. | 2020 Feb | BACKGROUND: Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS: Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS: In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29 IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100 IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION: HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown. | |
| 32011430 | Cost-effectiveness analysis of etanercept plus methotrexate vs triple therapy in treating | 2020 Jan | OBJECTIVE: This study aimed to explore the cost-effectiveness of etanercept plus methotrexate (ETN+MTX) compared to triple disease-modifying anti-rheumatic drugs (DMARDs) in treating Chinese rheumatoid arthritis (RA) patients. METHODS: The 134 Chinese RA patients who were about to initiate ETN+MTX or triple DMARDs therapy based on treat-to-target strategy were consecutively recruited and categorized into ETN+MTX group (N = 49) or triple DMARDs group (N = 85). Treatment efficacy was assessed at month 3 (M3)/M6/M9/M12 after initiation of treatment. Also, 1-year treatment cost was evaluated, and cost-effectiveness analysis and sensitivity analysis were conducted. RESULTS: RA patients in ETN+MTX group exhibited similar disease activity and quality of life at each time point while elevated 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) change (M0-M12) and low disease activity rate compared with triple DMARDs group. For 1-year treatment cost, ETN+MTX required increased drug cost, decreased other medical cost, and finally elevated total cost compared with triple DMARDs. Meanwhile, compared to triple DMARDs, ETN+MTX produced an additional quality-adjusted life year (QALY) of 0.015, resulting in an incremental cost-effectiveness ratio (ICER) of ¥2,939,506.7 per QALY that was 53.1 folds of gross domestic product (GDP) per capita in China. More interestingly, sensitivity analysis revealed that the ETN price had to be reduced at least by 71.3% before ETN+MTX became cost-effectiveness compared to triple DMARDs. CONCLUSION: ETN+MTX is less cost-effective in treating Chinese RA patients compared with triple DMARDs. | |
| 32243486 | A novel indomethacin/methotrexate/MMP-9 siRNA in situ hydrogel with dual effects of anti-i | 2020 Apr 21 | Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammatory cell infiltration, and cartilage and bone disruption, which ultimately leads to loss of joint function. Current treatments for RA only focus on anti-inflammatory activity but neglect to prevent further damage to articular cartilage and bone. Here we attempted to co-deliver indomethacin (IND), methotrexate (MTX) and a small-interfering RNA targeting MMP-9 using an in situ hydrogel loaded with PEI-SS-IND-MTX-MMP-9 siRNA nanoparticles (D/siRNA-NGel) to treat RA synergistically and comprehensively. IND, MTX and MMP-9 siRNA were able to escape from the endosome and down-regulate the expression of MMP-9 and inflammatory cytokines of Raw-264.7 cells. After intra-articular injection in arthritic mice, the D/siRNA-NGel effectively relieved joint swelling and significantly reduced the expression of TNF-α, IL-6 and MMP-9 in the ankle fluid, knee joint fluid and plasma of RA mice without causing any side effects. Most importantly, the co-delivery system restored the morphological parameters of the ankle joints close to normal. The D/siRNA-NGel could achieve good anti-inflammatory activity and reverse cartilage disruption through a synergistic effect between chemical drugs and MMP-9 siRNA. This co-delivery system should have promising applications in the treatment of rheumatoid arthritis and other metabolic bone diseases which cause serious bone erosion. | |
| 32629668 | Efficacy and safety of low-dose glucocorticoids combined with methotrexate and hydroxychlo | 2020 Jul 2 | INTRODUCTION: Glucocorticoids (GCs), especially low-dose GCs, are commonly prescribed for rheumatoid arthritis (RA), although the risk/benefit ratio is controversial. A randomized, double-blind clinical trial was performed to evaluate the efficacy and safety of low-dose oral GCs combined with methotrexate (MTX) and hydroxychloroquine (HCQ) in early RA (ERA). METHODS: Eighty untreated ERA patients were randomized into the trial (GCs + MTX + HCQ) and control (placebo + MTX + HCQ) groups, for 1-year treatment. Therapeutic evaluation indices were American College of Rheumatology (ACR) 20 of ACR, disease activity score (DAS) 28- erythrocyte sedimentation rate (ESR), visual analog scale scores, joint function, health assessment questionnaire-disability index score, morning stiffness duration, C-reaction protein and ESR. The clinical indicators were evaluated pre-treatment and at 1st, 3th, 6th and 12th month of treatment. The MRI data of single joint (ie, the most swollen joint) for each patient were acquired with a revised OMERACT RAMRIS Scoring System before and after treatment. The correlation analysis was adopted to confirm whether the efficacy of GC treatment is related to the time of RA onset. The side effects (eg, gastrointestinal reactions, liver dysfunction, upper respiratory tract infection, leukocyte reduction) were also monitored. RESULTS: At 1st month, 55% and 20% cases in the experimental and control groups achieved ACR20 response, respectively, indicating a significant difference (χ = 16.157, P < .001). This trend continued until 6th month. At 12th month, the number of patients achieved ACR20 response was similar in both groups. At 1st to 6th month, DAS28- ESR scores in the experimental group were significantly lower than control values (all p < .05). The experimental group showed improved inflammation, quality of life and radiological symptoms. Bone erosion remained unchanged in the experimental group, while worsening in control group. Correlation coefficients between RA duration and DAS28-ESR score were 0.496, 0.464, 0.509, and 0.550 at 1st, 3th, 6th, and 12th month, respectively. No differences were found in adverse events between the 2 groups. CONCLUSIONS: Low-dose GCs combined with MTX and HCQ significantly achieves disease remission indexed by ACR20 and DAS28-ESR, and improves clinical and radiological outcomes in ERA patients at the early stage, with superiority over placebo + MTX + HCQ, without enhancing adverse reactions. | |
| 32791152 | Polymyxin B prevents the development of adjuvant arthritis via modulation of TLR/Cox-2 sig | 2020 Oct 15 | AIMS: Several microbial toll-like receptor (TLR) ligands, bacterial DNA and bacterial cell wall fragments have been identified in the synovium of rheumatoid arthritis (RA) patients, proving bacterial involvement in the pathogenesis of RA. The current study aimed to verify that low dose polymyxin B could prevent the development of chronic inflammatory arthritis. METHODS: Twelve days post adjuvant injection, Sprague-Dawley rats were treated twice weekly with methotrexate (0.5 mg/kg) or daily with polymyxin B (1 mg/kg) or with combination of both for 1 or 2 weeks. Arthritis progression was assessed by hind paw swelling, serum levels of tumor growth factor-1β (TGF-1β), tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (HS-CRP) and nuclear factor kappa B (NF-κB) were measured using ELISA. Cyclooxygenase-1 (Cox-1) and Cox-2 activities, as well as mRNA expression of TLR-2 and TLR-4 were determined. Histopathological examination of the ankle joint was performed as well as immunohistochemistry for anti-TLR-4. Histopathological assessment of toxic effects on the kidney was performed. KEY FINDINGS: Adjuvant arthritis led to a significant swelling of the hind paw and alteration in all serum parameters, TLR-2 and TLR-4 expression, as well as Cox-2 activity. These alterations were associated with histopathological changes of the joints. Polymyxin B reduced significantly all biomarkers of inflammation, showing better effect of the combination in most of the studied parameters, with minimal signs of nephrotoxicity. SIGNIFICANCE: In conclusion, results showed that polymyxin B possesses significant anti-arthritic activity which may be attributed to inhibition of the TLR-4, NF-κB and Cox-2 signaling pathway. | |
| 33021133 | Updates on management strategies of hepatitis B virus reactivation in patients with resolv | 2021 Jul | With the introduction of methotrexate, biological disease-modifying antirheumatic drugs (bDMARDs), and targeted synthetic DMARDs (tsDMARDs), the disease activity of patients with rheumatoid arthritis has been dramatically ameliorated. However, these drugs have strong immunosuppressive effects and can cause reactivation of hepatitis B virus (HBV) in patients with resolved HBV infection. Corticosteroids or immunosuppressants used for other connective tissue diseases or vasculitis also carry a risk of inducing reactivation of HBV. Therefore, every rheumatologist should know how to detect the resolved infection of HBV in patients with rheumatic diseases receiving immunosuppressive therapy and how to monitor it when resolved infection is revealed. Of note, the cut-off index was changed from 2.1 log copies/ml to 20 IU/ml (1.3 Log IU/ml) in 2017. Rheumatologists should start nucleic acid analog administration at reactivation of HBV while performing ongoing immunosuppressive therapy in order to prevent severe or fulminant hepatitis. A low titer of HBs antibody (Ab) or lack of HBs Ab is a risk factor of reactivation of HBV. However, the reactivation of HBV cannot be prevented by HBs Ab titers at baseline or changes overtime. Rheumatologists should recognize that every immunosuppressive therapy, regardless of the mode of action, has a potential risk of reactivation. To facilitate proper management of patients with HBV infection, collaboration between rheumatologists and hepatologists is strongly encouraged. Patients' education, systems for checking electronic medical charts, and multidisciplinary efforts are considered important for detecting HBV reactivation. | |
| 31969328 | EULAR recommendations for the management of rheumatoid arthritis with synthetic and biolog | 2020 Jun | OBJECTIVES: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost. | |
| 32508063 | Tocilizumab Increases Body Weight and Serum Adipokine Levels in Patients with Rheumatoid A | 2020 Jun 8 | BACKGROUND: Causes of weight change after tocilizumab treatment are unclear. We aimed to investigate the effects of tocilizumab treatment on body weight and serum adipokine levels in patients with rheumatoid arthritis (RA). METHODS: In this retrospective cohort study, we evaluated weight changes in patients with RA who received methotrexate (Cohort I) or tocilizumab with methotrexate (Cohorts II and III) for 24 weeks. Adipokine concentrations at baseline and 24 weeks were analyzed in Cohorts I and III. Cohorts I and II received tocilizumab therapy for an additional 48 weeks, during which weight changes were monitored (24-72 weeks). RESULTS: No significant weight change occurred after 24 weeks of methotrexate treatment (mean difference, -0.2 kg; P = 0.630), but was observed after 24 weeks of tocilizumab treatment (mean difference, +0.9 kg; P = 0.010). Weight changed regardless of the treatment response in both treatment groups. The leptin-adiponectin ratio (P = 0.015) and levels of adiponectin (P < 0.001), leptin (P < 0.001), and resistin (P = 0.003) increased significantly after 24 weeks of tocilizumab, but not methotrexate treatment. After 24, 48 and 72 weeks of tocilizumab treatment in Cohort II, mean (95% confidence interval [CI]) weight changes from baseline were +0.7 (0.0-1.4), +1.2 (0.4-2.0) and +1.1 (0.2-2.0) kg, respectively, and mean (95% CI) percent weight changes from baseline were +1.3% (0.1%-2.6%), +2.2% (0.7%-3.6%), and +2.0% (0.4%-3.7%) at 24, 48, and 72 weeks, respectively. CONCLUSION: Weight and the leptin-adiponectin ratio increased after tocilizumab treatment. Given that cardiovascular (CV) risk factors may deteriorate in patients with RA who receive tocilizumab, further studies are required to determine the effects of weight gain on CV outcomes in these patients. | |
| 32726514 | Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizuma | 2021 Jan | We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin-6 (IL-6), soluble IL-6 receptor, and C-reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single-dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8Â mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target-mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7-15 days for CRP and 3-5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies. |