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31888728 Evaluating the therapeutic efficacy of the Chinese herbal medicine Yishen Tongbi decoction 2019 Dec 30 BACKGROUND: Rheumatoid arthritis (RA) is a common chronic autoimmune disease that seriously affects the quality of life of patients because of damage to joints. Presently, RA is mainly treated with disease-modifying antirheumatic drugs (DMARDs) or biological agents; however, they offer limited efficacy in some patients. Therefore, additional therapeutic strategies need to be developed. Yishen Tongbi decoction is a traditional Chinese medicine formulation widely used to treat RA in China. However, currently, there is insufficient evidence to recommend its use for the treatment of RA. Therefore, we aim to verify the efficacy of Yishen Tongbi decoction to treat RA by a noninferiority trial, and to provide a basis for its use with a full-scale clinical trial. METHODS/DESIGN: One hundred eligible patients with RA will be randomized into two groups of 50 patients. One group will receive Yishen Tongbi decoction and placebo replacing methotrexate (MTX), while the other group will receive MTX and placebo replacing Yishen Tongbi decoction. Patient's whose visual analogue scale score for pain is greater than 40 mm will be administered nonsteroidal anti-inflammatory drugs (such as enteric-coated diclofenac sodium, 25 mg three times a day); administration of all medications will be recorded. The clinical indicators of patients and their disease activity will be assessed at baseline and at 4, 12 and 24 weeks after treatment initiation. The primary outcome of efficacy will be the proportion of patients who demonstrate a favourable response based on their Clinical Disease Activity Index score at 24 weeks after treatment. All adverse events will be reported. DISCUSSION: Traditional Chinese medicine theory and modern western medicine research have identified the efficacy of Yishen Tongbi decoction to treat RA. Previous clinical observation and efficacy trials of Yishen Tongbi decoction in animal models for the treatment of RA has demonstrated significant effect. Because of the potential benefits of Yishen Tongbi decoction in the treatment of patients with RA, we designed this double-blind, prospective, randomized controlled trial; the results and conclusions of the trail will be published after the completion of the study. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR1900024902. Registered on 3 August 2019.
31450285 The impacts of oral health symptoms, hygiene, and diet on the development and severity of 2019 Jul 15 Numerous studies have suggested a correlation between oral health, the oral microbiome, and various dermatologic conditions, particularly psoriasis. In this study, we utilize a specially designed questionnaire administered to 265 patients at The Ohio State University's dermatology clinics to explore the relationship between psoriasis and a combination of factors that included dietary habits, oral health, and oral hygiene practices. Age, family history of psoriasis, previous diagnosis of strep throat or rheumatoid arthritis, and oral pain or discomfort experienced within the last 12 months were all found to be significant predictors of psoriasis. Additionally, higher body mass index scores, poor gum health, and speech difficulties related to dental problems were all correlated with more severe psoriasis symptoms. Conversely, patients who reported consuming fresh fruit at least once a day experienced milder symptoms. Our goal is to develop a better understanding of how and why psoriasis incidence is correlated with some of the oral health factors under review.
31820713 Expression of Galectin-9 and correlation with disease activity and vascular endothelial gr 2020 Jul OBJECTIVES: Despite the important role of Galectin-9 (Gal-9) in inflammation and angiogenesis, only a few studies on Galectin-9 expression have been performed in rheumatoid arthritis (RA) patients. The present study aimed to identify the concentration of Galectin-9 in plasma, its expression in peripheral blood T cell subsets in RA patients, and the association between Galectin-9 and vascular endothelial growth factor (VEGF) in RA. METHODS: One hundred and five active RA patients and 52 age- and sex-matched healthy controls (HCs) were enrolled in the study. Gal-9, vascular endothelial growth factor (VEGF), and tumour necrosis factor (TNF)-α level in plasma were determined by ELISA. The intracellular positive expression rates and medium fluorescence intensity (MFI) of Gal-9 and VEGF in T cell subsets, were examined by flow cytometry. RESULTS: Plasma Gal-9, TNF-α, and VEGF levels were higher in the RA group than in the HCs group. The plasma Gal-9 level positively correlated with Gal-9 expression in the total lymphocyte and CD3+ T cell, CRP, SDAI, and CDAI of RA patients. The Gal-9 expressions in the cytoplasm of CD4+ T, CD8+ T, Treg, and DNT cells positively correlated with plasma TNF-α levels in RA patients. The Gal-9 expressions in CD4+ T and CD8+ T subsets also positively correlated with plasma VEGF levels. The plasma VEGF levels and VEGF expressions in CD4+ T, CD8+ T, and Treg subsets positively correlated with SDAI and CRP in RA patients. CONCLUSIONS: Gal-9 can be a potential biomarker for RA disease activity. Gal-9 is probably associated with angiogenesis processing in RA.
31882961 Comorbidity status in hospitalized elderly in Japan: Analysis from National Database of He 2019 Dec 27 The detailed comorbidity status of hospitalized elderly patients throughout Japan has remained largely unknown; therefore, our goal was to rigorously explore this situation and its implications as of the 2015 fiscal year (from April 2015 to March 2016). This study was based on a health insurance claims database, covering all insured policy holders in Japan aged ≥60 years (male: n = 2,135,049, female: 1,969,019) as of the 2015 fiscal year. Comorbidity status was identified by applying principal factor analysis to the database. The factors identified in male patients were [1] myocardial infarction, hypertension, dyslipidemia, and diabetes mellitus; [2] congestive heart failure (CHF), cardiac arrhythmia, and renal failure; [3] Parkinson's disease, dementia, cerebrovascular disease, and pneumonia; [4] cancer and digestive disorders; and [5] rheumatoid arthritis and hip fracture. However, in female patients, the results obtained for the quaternary and quinary factors were the opposite of those obtained in male patients. In superelderly patients, dementia, cerebrovascular disease, and pneumonia appeared as the tertiary factor, and hip fracture and osteoporosis appeared as the quaternary factor. The comorbidities in the elderly patients suggest the importance of coronary heart disease and its related metabolic disorders; in superelderly patients, fracture and osteoporosis appeared as factors, in addition to dementia and pneumonia.
31586977 [Paraneoplastic rheumatologic syndromes in the elderly]. 2019 Risk of development of malignant tumors increases in elderly people. There are numerous clinical symptoms mimicking primary rheumatic diseases in the course of cancers, referred to as paraneoplastic rheumatologic syndromes. They are not caused directly by the tumor or its metastases, but result from the action of biologically active substances released by cancer cells and abnormal immunological reactions. Paraneoplastic rheumatologic syndromes may precede the diagnosis of cancer, occur simultaneously or occur after the diagnosis of malignancy. In clinical practice, it is very difficult to distinguish paraneoplastic syndromes from idiopathic rheumatic diseases. However, some clinical features may suggest the paraneoplastic nature of rheumatic diseases, including the onset of symptoms in old age, atypical and rapidly progressive course or poor response to conventional treatment. Early and well-targeted diagnostics allow the diagnosis of often latent neoplasm, and its effective treatment may lead to resolution of paraneoplastic rheumatic symptoms. This paper discusses selected paraneoplastic rheumatologic syndromes that often occur in older people, including carcinomatous polyarthritis, remitting seronegative symmetrical synovitis with pitting edema (RS3PE), palmar fasciitis-polyarthritis syndrome, hypertrophic osteoarthropathy, tumor-induced osteomalacia, cancerassociated myositis, paraneoplastic scleroderma like syndrome, paraneoplastic vasculitis and paraneoplastic Raynaud's syndrome.
31043548 Placebo Response in Rheumatoid Arthritis Clinical Trials. 2020 Jan OBJECTIVE: Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization. METHODS: The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)-naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time. RESULTS: There were 32 trials in total: anti-tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09-0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04-0.31, p = 0.01) that remained significant after controlling for potential confounders. CONCLUSION: There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.
31300830 [Cutaneous alterations in vasculitides : Part 2: Special aspects of diseases of large, me 2019 Aug Cutaneous vasculitides present with typical clinical signs depending on the size and distribution of the affected vessels. Since there are no large vessels in the skin, giant cell arteritis and Takayasu's arteritis only rarely lead to cutaneous symptoms. The classical systemic polyarteritis nodosa (PAN) is very rare. More frequent is cutaneous PAN presenting with a typical localized livedo racemosa and palpable subcutaneous nodules. The ANCA-associated vasculitides, which belong to the small vessel vasculitides, usually show systemic involvement and manifest on the skin with a diverse picture. Immune complex vasculitides are characterized by deposition of immunoglobulins on the walls of small vessels. The most common form is IgA vasculitis with the cardinal symptoms of palpable, round or oval and partially branched (retiform) purpura and a clear predilection for the legs. Serum disease is a príme example of systemic immune complex diseases due to large circulating immune complexes. Cryoglobulinemic vasculitis primarily involves small as well as medium sized vessels. Simultaneous involvement of vessels of different sizes is characteristic for vasculitis in systemic lupus erythematosus (SLE), Sjögren's syndrome, rheumatoid arthritis and sarcoidosis. Recurrent macular vasculitis in hypergammaglobulinemia is an episodic macular vasculitis of the small blood vessels. Bacteremic vasculitis of the small vessels (without direct microbial infection of the vessel wall) can typically also affect capillaries of dermal papillae and is usually accompanied by a disseminated intravascular coagulation (DIC). In some cases more than one distinct cutaneous vasculitis can occur in the same patient.
31779676 Risk stratification and clinical course of hepatitis B virus reactivation in rheumatoid ar 2019 Nov 28 BACKGROUND: The prophylaxis for hepatitis B virus (HBV) reactivation assumes that hepatic injury after reactivation is often rapidly progressive and can evoke fulminant hepatitis. The incidence and prognosis of reactivation in patients with rheumatoid arthritis (RA) may be different from those receiving organ transplantation and cancer chemotherapy. This study aimed to investigate the incidence, risk factors, and clinical course of HBV reactivation and develop a scoring system for risk stratification in RA patients with resolved infection. METHODS: HBV DNA was measured using real-time polymerase chain reaction, and patient data were collected for 4 years in RA patients with resolved HBV infection who were treated with steroids or synthetic or biologic immunosuppressive drugs. RESULTS: Among 1127 patients, HBV DNA was detected in 57 patients (1.65/100 person-years); none of the reactivated patients exhibited worsening of hepatic function. Multivariate logistical analysis revealed that age > 70 years and HB core antibody (HBcAb) positivity alone were independent risk factors for HBV reactivation. HBV DNA ≥ 2.1 log copies/mL was observed in 15 patients (0.43/100 person-years); seven patients were treated with nucleic acid analogs (NAAs), whereas the remaining eight were observed without treatment. Among reactivated cases, 15 cases changed to HBV DNA-negative status spontaneously, whereas 24 cases remained HBV DNA positive < 2.1 log copies/mL during the observation period. We designed the following scoring system: HBV reactivation risk score = 1 × (age > 70 years) + 2 × (HBcAb positivity alone) + 1 × (treatment other than methotrexate monotherapy). This revealed that patients with the highest score had an odds ratio of 13.01 for HBV reactivation, compared to those with the lowest score. CONCLUSIONS: Rapid progression and poor outcomes after HBV reactivation were not frequent in RA patients with resolved infection. Our new risk scoring system might be useful for screening and optimization of prophylactic treatment by distinguishing patients with significantly lower reactivation risk.
31129759 Spa therapy and rehabilitation of musculoskeletal pathologies: a proposal for best practic 2020 Jun Spa therapy is a heterogeneous collection of treatments and methods based on natural resources. It is often considered as an option in the common therapeutic approach to many musculoskeletal disorders, as well as respiratory, vascular, and dermatological disorders. The objective of this paper is to highlight possible interactions between rehabilitation and spa medicine in the field of musculoskeletal disorders, through an analysis of the scientific literature, in order to give the practitioner the ability to integrate good clinical practice in the field of rehabilitation through practical application involving spa therapies. The literature search was conducted using Medline, PEDro, Cochrane Database, and Google Scholar. Only studies published in English and works concerning the implementation of spa thermal treatment in neuro-musculoskeletal diseases were included. Specifically, the publications analyzed dealt with the treatment of diseases such as arthritis, rheumatic arthritis, ankylosing spondylitis, and low back pain through the use of thermal spa therapies. In conjunction with its widespread use in clinical practice, many studies in the literature suggest the effectiveness of crenobalneotherapy for a number of musculoskeletal disorders, generally those which are chronic and debilitating, finding significant clinical improvement both in terms of pain and functional limitations. Some of the guidelines formulated by national and international bodies on the treatment of specific diseases, such as the Italian Rheumatology Society (SIR) and the Osteoarthritis Research Society International (OARSI) guidelines, recognize the value of thermal medicine as a complement, but not a replacement, for conventional therapy (pharmacological or not).
31020684 Pectolinarin inhibits proliferation, induces apoptosis, and suppresses inflammation in rhe 2019 Sep Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), a pathological hallmark of rheumatoid arthritis (RA), exhibit the characteristics of tumor cells. The extracts of Cirsium japonicum var. ussuriense have been shown to possess antitumor and anti-inflammatory activities. Our study aimed to investigate the effects of pectolinarin, a flavonoid compound isolated from C. japonicum var. ussuriense, on RA. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Apoptosis was determined by flow cytometry analysis and Western blot analysis of Bax and Bcl-2 levels. Inflammation was assessed by detecting the expressions and secretion of interleukin (IL)-6 and IL-8 using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The production of nitric oxide (NO) and prostaglandin E2 (PGE2) was also measured. The effects of pectolinarin on the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway were examined by Western blot. We found that pectolinarin significantly inhibited cell viability at 24 and 48 hours in a dose-dependently manner in RA-FLSs. Pectolinarin reduced the apoptotic rate, increased Bax level, and decreased Bcl-2 level in RA-FLSs. Pectolinarin inhibited the messenger RNA expression and secretion of IL-6 and IL-8, as well as the production of PGE2 and NO in RA-FLSs. Furthermore, pectolinarin inactivated the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway in RA-FLSs. Activation of the PI3K/Akt pathway by 740Y-P impaired the effects of pectolinarin on cell viability, apoptosis, and inflammation in RA-FLSs. In conclusion, pectolinarin suppressed cell proliferation and inflammatory response and induced apoptosis in RA-FLSs via inactivation of the PI3K/Akt pathway.
30353269 Factors associated with long-term retention of treatment with golimumab in a real-world se 2019 Mar The retention rate of a biological drug (percentage of patients remaining on treatment over time) provides an index of a drug's overall effectiveness. The golimumab retention rate as first-line biological therapy was high in clinical trial extensions lasting 5 years. Real-world studies also indicate good retention rates but have been of shorter duration. The probability of retention with golimumab treatment was assessed, as any line of anti-tumor necrosis factor-alpha therapy, for up to 5 years in patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA) or psoriatic arthritis (PsA), associated factors were analyzed. A retrospective database analysis of the Spanish registry of patients with rheumatic disorders receiving biological drugs (BIOBADASER) was performed. Among 353 patients, 29.8% had RA, 41.6% SpA and 28.6% PsA. Golimumab was the first biological drug in 40.1% of patients, second in 30.1% and third/later in 29.8%. The overall probability of retention of golimumab at years 1, 2, 3, 4 and 5 was 85.9% (95% confidence interval 81.4-89.5%), 73.7% (67.1-79.1%), 68.5% (60.5-75.1%), 60.6% (50.2-69.5%) and 57.1% (44.9-67.5%), respectively. Retention was similar across indications (p = 0.070) but was greater when golimumab was used as the first biological agent compared with later therapy lines (p < 0.001). Factors associated with higher retention of golimumab treatment (Cox regression) were use as a first-line biological and concomitant methotrexate treatment; corticosteroid need was associated with lower retention. The long-term probability of golimumab retention was high in this real-world study of patients with rheumatic diseases, especially when used as the first biological drug.
30074624 Erythema elevatum diutinum: a case report and review of literature. 2019 Apr Erythema elevatum diutinum (EED) is a rare cutaneous leukocytoclastic vasculitis thought to be related to increased levels of circulating antibodies. It has been shown to be associated with HIV infection, tuberculosis, as well as various autoimmune diseases. A retrospective review of all cases of EED indexed in PubMed between 1990 and 2014 was performed. Inclusion criteria for articles was availability of full text in English and a biopsy-confirmed diagnosis of EED. All other articles were excluded. Cases were stratified by age and anatomic location of the lesions. Treatment response was coded as "complete," "partial," and "none." A total of 133 cases of EED with 381 lesions detailed in case reports and case series were included. Twenty-one cases were associated with HIV. Of 47 patients with reported paraproteinemias, IgA paraproteinemia was found in 57.45%, IgG paraproteinemia in 29.8%, IgM paraproteinemia in 10.6%, and IgD paraproteinemia in 2.1% of cases. Of 40 (30.1%) patients with reported comorbid autoimmune disease, rheumatoid arthritis was associated with 10 cases. Cancer was found to be associated with 9.77% of cases. Seventy-five patients were treated with dapsone, with 36 (48%) achieving complete treatment response, 24 (32%) achieving partial response, and seven (9.3%) achieving no response. Keeping the clinical associations of EED in mind, especially malignancy, is critical in management of the disease. More structured studies need to take place in order to fully define the mechanisms and strength of these associations.
31119302 TNF-α/calreticulin dual signaling induced NLRP3 inflammasome activation associated with H 2019 Jul OBJECTIVE: The present study was undertaken to validate whether TNF-α and calreticulin (CRT) serve as dual signaling to activate nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and HUVECs. The effect of human antigen R (HuR) in NLRP3 inflammasome activation was also explored in RA FLS. METHODS: Immunofluorescence was used to determine the expression of NLRP3 and adaptor protein apoptosis associated speck-like protein containing a CARD (ASC) in RA synovial tissue and HuR location in RA FLS. Western blot and quantitative real-time PCR were employed to measure the priming effect of NLRP3 inflammasome in cells and HuR expression in synovial tissue. The concentrations of IL-1β and IL-18 were detected by enzyme linked immunosorbent assay. Immunohistochemistry was used to visualize the expression of HuR in synovial tissue. HuR knockdown in RA FLS was achieved by siRNA-mediated gene silencing. RESULTS: Higher expression of NLRP3 and ASC in RA synovial tissue than those in osteoarthritis was detected. The staining of NLRP3, ASC and cleaved IL-1β were observed in FLS and vascular endothelial cells in RA synovium. Expression of NLRP3 and pro-IL-1β in RA FLS and HUVECs treated with TNF-α was increased. The pro-IL-18 expression was also enhanced in HUVECs, but not in RA FLS. TNF-α/CRT dual stimulation of cells gave rise to caspase-1 p20 expression and the secretion of IL-1β. The secreted IL-18 was also elevated in HUVECs but not in RA FLS. HuR expression was significantly elevated in RA synovial tissue. TNF-α initiated the nucleocytoplasmic shuttling of HuR in both FLS and HUVECs. The knockdown of HuR in FLS incubated with TNF-α led to reduced caspase-1 p20 protein expression and further resulted in decreased secretion of IL-1β in the presence of CRT. CONCLUSIONS: TNF-α/CRT dual signaling induced NLRP3 inflammasome activation, which could be suppressed by HuR knockdown presumably due to the block of HuR translocating from nucleus to cytoplasma.
31275302 Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update. 2019 Granulocyte-macrophage colony-stimulating factor (GM-CSF) was first described as a growth factor that induces the differentiation and proliferation of myeloid progenitors in the bone marrow. GM-CSF also has an important cytokine effect in chronic inflammatory diseases by stimulating the activation and migration of myeloid cells to inflammation sites, promoting survival of target cells and stimulating the renewal of effector granulocytes and macrophages. Because of these pro-cellular effects, an imbalance in GM-CSF production/signaling may lead to harmful inflammatory conditions. In this context, GM-CSF has a pathogenic role in autoimmune diseases that are dependent on cellular immune responses such as multiple sclerosis (MS) and rheumatoid arthritis (RA). Conversely, a protective role has also been described in other autoimmune diseases where humoral responses are detrimental such as myasthenia gravis (MG), Hashimoto's thyroiditis (HT), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE). In this review, we aimed for a comprehensive analysis of literature data on the multiple roles of GM-CSF in autoimmue diseases and possible therapeutic strategies that target GM-CSF production.
28988490 The measurement of functioning using the International Classification of Functioning, Disa 2019 Mar BACKGROUND: The International Classification of Functioning, Disability and Health is the international standard for describing and monitoring functioning. While the categories, the units of the classification, were not designed with measurement in mind, the hierarchical structure of the classification lends itself to the possibility of summating categories into some higher order domain. Focusing on the chapters of d4 Mobility, d5 Self-Care and d6 Domestic Life, this study seeks to ascertain if qualifiers rating of categories (0-No problem to 4-Complete problem) within those chapters can be summated, and whether such derived measurement is consistent with estimates obtained from well-known instruments which purport to measure the same constructs. METHODS: The current study applies secondary analysis to data previously collected in the context of validating Core Sets for stroke, rheumatoid arthritis, and osteoarthritis. Data included qualifier-based ratings of the categories in the Core Sets, and the physical functioning sub-scale of the Short-Form 36, and the World Health Organization Disability Assessment Schedule 2.0. To examine qualifier-comparator scale item agreement Kappa statistics were used. To identify whether appropriate gradients of the comparator scales were observed across qualifier levels, an Independent Sample Median Test of the ordinal scores was deployed. To investigate the internal validity of the summated ICF categories, the Rasch model was applied. RESULTS: Data from 2,927 subjects from Europe, Australasia, Middle East and South America were available for analysis; 36.3% had experienced a stroke, 35.8% osteoarthritis, and 27.9% had rheumatoid arthritis. The items from the Short-Form 36 could not match directly the qualifier categories as the former had only 3 response options. The Kappa between World Health Organization Disability Assessment Schedule 2.0 items and categories was low. For all qualifiers, a significant (<0.001) overall gradient was observed across the comparator scales. Only in few of the World Health Organization Disability Assessment Schedule 2.0 items could no discrete level be detected. The aggregation of the qualifiers at the Chapter and higher order levels mostly revealed fit to the Rasch model. Almost all ICF qualifiers showed ordered thresholds suggesting that the current structure and response options of the qualifiers worked as intended. CONCLUSIONS: The findings of this study provide supporting evidence for the use of the professionally rated categories and associated qualifiers to measure functioning. Implication for Rehabilitation This study provides evidence that functioning data can be collected directly with the International Classification of Functioning, Disability and Health (ICF) by using the ICF categories as items and the ICF qualifiers as rating scale. The findings of this study show the aggregated ratings of ICF categories from the chapters d4 Mobility, d5 Self-care, and d6 Domestic life capture a broader spectrum of the construct than the corresponding summated items from the SF36-Physical Function sub-scale and the corresponding items of the World Health Organization Disability Assessment Schedule 2.0. This study illustrates the potential of building quantitative measurement by aggregating ICF categories and their qualifier ratings into meaningful domains.
31316519 Rheumatoid Synovial Fluids Regulate the Immunomodulatory Potential of Adipose-Derived Mese 2019 Introduction: Adipose-derived mesenchymal stem cells (ADSC) have been shown to have remarkable immune-modulating effects. However, their efficacy in clinical trials has yet to be fully demonstrated. This could be due to a lack of a proper inflammatory environment in vivo that primes ADSC. Here, we define how the articular microenvironment of rheumatoid arthritis (RA) patients modulates the therapeutic efficiency of ADSC. Methods: Synovial fluids (SF) were collected from 8 RA patients, 2 Spondyloarthritis patients and one control synovial fluid from a patient undergoing traumatic-related surgery. SF inflammatory status was determined by routine analysis and quantification of pro-inflammatory cytokines. ADSC were first treated with SF and ADSC proliferation and gene expression of immunomodulatory factors was evaluated. In order to determine the mechanisms underlying the effect of SF on ADSC, tumor necrosis factor (TNF), interleukin-6 (IL-6), and NF-κB neutralization assays were performed. To evaluate the effect of SF on ADSC functions, ADSC were pre-treated with SF and then co-cultured with either macrophages or T cells. The modulation of their phenotype was assessed by flow cytometry. Results: Pro-inflammatory RASF maintained the proliferative capacity of ADSC and upregulated the gene expression of cyclooxygenase-2 (COX2), indoleamine-1,2-dioxygenase (IDO), interleukin-6 (IL-6), tumor-necrosis factor stimulated gene 6 (TSG6), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and programmed death-ligand 1 (PD-L1), all factors involved in ADSC immunomodulatory potential. The RASF-induced gene expression was mainly mediated by TNF alone or in combination with IL-6 and signaled through the NF-κB pathway. Conditioning ADSC with pro-inflammatory RASF enhanced their ability to induce CD4(+)Foxp3(+)CD25(high) regulatory T cells (Tregs) and inhibit pro-inflammatory markers CD40 and CD80 in activated macrophages. Conclusions: Inflammatory synovial fluids from RA patients had the capacity to modulate ADSC response, to induce Tregs and modulate the phenotype of macrophages. The clinical use of ADSC in affected joints should take into account the influence of the local articular environment on their potential. Having a sufficient pro-inflammatory microenvironment will determine whether optimal immunoregulatory response should be expected. Direct ADSC intra-articular delivery to patients could be a potential strategy to properly prime their immunomodulatory potential and enhance their clinical benefits.
31079001 Triptolide suppresses human synoviocyte MH7A cells mobility and maintains redox balance by 2019 Jul Triptolide (TPL), the main active ingredient in Tripterygium glycosides, has been reported to exert anti-inflammation and anti-tumor effects. The present study was designed to investigate the effects of TPL on rheumatoid arthritis (RA) and explore the underlying mechanisms. By using human synoviocyte MH7A cells, TPL was proven to significantly impede migration and invasion of MH7A cells, and also inhibited MMP-2 and MMP-9 expression. Moreover, TPL was found to increase SOD, CAT, GSH-Px activities while decrease MDA activity, indicating that TPL maintained redox balance in MH7A cells. TPL could down-regulate the number of LC3(+) puncta, Beclin1 expression and LC3 II/I ratio in a concentration-dependent manner, indicating that TPL inhibited autophagy in MH7A cells. Activation of autophagy was found to counteract the effects of TPL on MH7A cells while inhibition of autophagy had the opposite effects. Our data demonstrated that TPL suppressed cell mobility and maintained redox balance through inhibiting autophagy in MH7A cells. Finally, our data revealed that TPL increased p-AKT/AKT ratio significantly and inhibition of PI3K/AKT signaling pathway activated autophagy in MH7A cells, suggesting that TPL suppressed autophagy through activating AKT signaling pathway in MH7A cells. Taken together, our present study revealed that TPL inhibited cell mobility and maintained redox balance in human synoviocyte MH7A cells through autophagy inhibition. Our findings suggested the potential clinical application of TPL on RA treatment.
30183595 Efficacy and safety of certolizumab pegol in combination with methotrexate in methotrexate 2019 Mar OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. METHODS: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed. RESULTS: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed. CONCLUSIONS: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.
31043095 Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjecto 2019 May BACKGROUND: The anti-interleukin-6 receptor antibody tocilizumab is approved for subcutaneous injection using a prefilled syringe (PFS). We report results from a bioequivalence study in healthy subjects and a user-handling study in patients with rheumatoid arthritis (RA) using an autoinjector (AI) for tocilizumab. METHODS: A randomized crossover study in healthy subjects (N = 161) examined the bioequivalence, safety, and tolerability of tocilizumab after a single subcutaneous injection by AI versus PFS. A nonrandomized observational, real-life human factors study in RA patients (N = 54) assessed user (RA patients, caregivers, health care providers) ability to administer tocilizumab effectively by AI. RESULTS: Bioequivalence criteria for tocilizumab AI versus PFS were met for key pharmacokinetic parameters. Safety was comparable between devices and consistent with the established tocilizumab profile. In the real-life human factors study, the proportion of users who successfully performed all essential tasks required to operate the AI to deliver the full dose was 92.3% at first assessment and 98.1% at second assessment, with no safety concerns. CONCLUSIONS: Tocilizumab administration by AI was bioequivalent to administration by PFS. Intended users were successful in performing the tasks required to administer tocilizumab by AI. No new safety signals were observed in either study. CLINICAL TRIAL REGISTRATION: NCT02678988, NCT02682823.
31748230 Impaired ATM activation in B cells is associated with bone resorption in rheumatoid arthri 2019 Nov 20 Patients with rheumatoid arthritis (RA) may display atypical CD21(-/lo) B cells in their blood, but the implication of this observation remains unclear. We report here that the group of patients with RA and elevated frequencies of CD21(-/lo) B cells shows decreased ataxia telangiectasia-mutated (ATM) expression and activation in B cells compared with other patients with RA and healthy donor controls. In agreement with ATM involvement in the regulation of V(D)J recombination, patients with RA who show defective ATM function displayed a skewed B cell receptor (BCR) Igκ repertoire, which resembled that of patients with ataxia telangiectasia (AT). This repertoire was characterized by increased Jκ1 and decreased upstream Vκ gene segment usage, suggesting improper secondary recombination processes and selection. In addition, altered ATM function in B cells was associated with decreased osteoprotegerin and increased receptor activator of nuclear factor κB ligand (RANKL) production. These changes favor bone loss and correlated with a higher prevalence of erosive disease in patients with RA who show impaired ATM function. Using a humanized mouse model, we also show that ATM inhibition in vivo induces an altered Igκ repertoire and RANKL production by immature B cells in the bone marrow, leading to decreased bone density. We conclude that dysregulated ATM function in B cells promotes bone erosion and the emergence of circulating CD21(-/lo) B cells, thereby contributing to RA pathophysiology.