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ID PMID Title PublicationDate abstract
30853688 Clinical Characteristics of Relapsing Polychondritis: A Report of 8 Cases in Japan. 2019 May 16 OBJECTIVES: Relapsing polychondritis (RP) is a very rare autoimmune disorder characterized by recurrent episodes of inflammation and destruction of cartilaginous tissues. We examined the clinical characteristics, management, and outcomes of Japanese RP patients. METHODS: We identified 8 RP cases in our department between 2003 and 2017. Detailed clinical features, testing, treatment, and outcomes were recorded. RESULTS: The mean time from symptom onset to diagnosis was 9 months. Four cases presented with auricular chondritis and laryngotracheal involvement and 3 cases presented with a saddle nose deformity. Anti-type II collagen antibody was positive in 5 of 6 cases. Of 3 cases with associated diseases (rheumatoid arthritis, ulcerative colitis, and Sjögren's syndrome), 2 died of respiratory failure. CONCLUSIONS: When RP is diagnosed, early computed tomography or pulmonary function testing is essential to enable early treatment. Undiagnosed airway involvement can cause tracheobronchial wall fibrosis, leading to fixed stenosis.
30828336 Phosphorylated Platelet-Derived Growth Factor Receptor-Positive Cells With Anti-apoptotic 2019 Rheumatoid arthritis (RA) is an autoimmune disease caused by inflammation of the synovium and characterized by chronic polyarthritis that destroys bone and cartilage. Fibroblast-like synoviocytes (FLSs) in the synovium of patients with RA can promote cartilage and bone destruction by producing proteins such as matrix metalloproteinases and receptor activator of NF-κB ligand, thereby representing an important therapeutic target for RA. FLSs have several phenotypes depending on which cell surface proteins and adhesion factors are expressed. Identifying the cellular functions associated with different phenotypes and methods of controlling them are considered essential for developing therapeutic strategies for RA. In this study, synovial tissue was collected from patients with RA and control subjects who required surgery due to ligament injury or fracture. Immunohistological analysis was used to investigate the rates of positivity for phosphorylated platelet-derived growth factor receptor-αβ (pPDGFRαβ) and cadherin-11 (CDH11) expression, and apoptosis-related markers were assessed for each cell phenotype. Next, FLSs were isolated in vitro and stimulated with tumor necrosis factor-α (TNF-α) in addition to a combination of PDGF and transforming growth factor (2GF) to investigate pPDGFRαβ and CDH11 expression and the effects of the inhibition of TNF and cyclin-dependent kinase (CDK) 4/6 on FLSs. Immunohistological analysis showed a large percentage of pPDGFRαβ+CDH11- cells in the sub-lining layer (SL) of patients with RA. These cells exhibited increased B-cell lymphoma-2 expression, reduced TNF receptor-1 expression, resistance to cell death, and abnormal proliferation, suggesting a tendency to accumulate in the synovium. Further, in vitro 2GF stimulation of FLSs lowered, whereas 2GF + TNF stimulation increased the pPDGFRαβ/CDH11 ratio. Hypothesizing that FLSs stimulated with 2GF + TNF would accumulate in vivo in RA, we determined the therapeutic effects of TNF and CDK4/6 inhibitors. The TNF inhibitor lowered the pPDGFRαβ/CDH11 ratio, whereas the CDK4/6 inhibitor suppressed cell proliferation. However, a synergistic effect was not observed by combining both the drugs. We observed an increase in pPDGFRαβ+CDH11- cells in the SL of the RA synovium and accumulation of these cells in the synovium. We found that the TNF inhibitor suppressed FLS activity and the CDK4/6 inhibitor reduced cell proliferation.
31102202 Risk of Developing Additional Immune-Mediated Manifestations: A Retrospective Matched Coho 2019 Jul INTRODUCTION: Immune-mediated inflammatory diseases (IMIDs) cause significant impairment in quality of life. Although they share similar genetic factors, environmental precipitants, and pathophysiological mechanisms, there is little evidence on the risk of developing subsequent IMIDs after an initial IMID diagnosis. We sought to assess the risk of developing subsequent IMIDs among patients diagnosed with an initial IMID. METHODS: This retrospective matched cohort study used a large US commercial health insurance claims database (01/01/2006-09/30/2015). The risks of developing secondary IMIDs among patients aged 18-64 years with a diagnosis of one of nine IMIDs of interest (ankylosing spondylitis, celiac disease, hidradenitis suppurativa [HS], inflammatory bowel disease, lupus, psoriatic arthritis [PsA], psoriasis, rheumatoid arthritis, and uveitis) as identified from diagnosis codes on medical claims were compared with up to 1000 matched controls without the primary IMID using Cox proportional hazards models. RESULTS: Across the nine IMIDs of interest, there were 398,935 unique case patients matched to 256,795,796 non-unique control patients. Case patients with an initial IMID had higher risks of developing each, any one, and any two of the other eight secondary IMIDs compared to their matched controls. Hazard ratios [95% confidence intervals] for the risk of developing any one secondary IMID ranged from 5.4 [5.0, 5.8] (initial IMID: HS) to 62.2 [59.9, 64.6] (initial IMID: PsA), and hazard ratios for developing any two secondary IMIDs ranged from 3.0 [2.3, 3.8] (HS) to 75.2 [69.3, 81.7] (PsA). CONCLUSIONS: This study demonstrates that the risk of developing a second IMID is significantly higher for individuals who have already experienced a first IMID in a large and contemporary US claims database. Certain pairs of IMIDs co-occur more frequently than others. The risk of developing subsequent IMIDs may be an important consideration for clinicians when selecting treatment strategies. FUNDING: Abbvie.
31498064 QT and QT dispersion intervals in long-standing and moderately active rheumatoid arthritis 2020 May OBJECTIVES: To define the prevalence of prolonged QT interval and QT dispersion (QTd) in rheumatoid arthritis (RA) patients and in a control population. METHODS: QT interval corrected by Bazett's formula (QTc) was calculated from standard 12-lead ECGs in 963 subjects free of previous cardiovascular events (646 RA patients and 317 controls strictly matched for age, sex and cardiovascular risk factors). RESULTS: RA patients (59.6±9.6 years, 68.1% females) had a long mean disease duration (10.6 years) and moderate disease activity (DAS28=3.68±1.23). QTc was 5 msec longer in RA patients than in controls (412±9 vs. 407±28 msec, p=0.013). However, the prevalence of QTc prolongation in RA patients and controls was not significantly different (5.3% vs. 6.3%, p=0.50). On the contrary, RA patients had a significantly greater QTd (42±26 vs. 35±18 msec, p<0.001) and a higher prevalence of increased QTd (33.3% vs. 18.3%, p<0.001) than controls. Furthermore, RA was independently associated to increased QTd [OR(95%CI)= 2.21(1.58-3.08), p=0.0001]. In the RA population, male gender and older age were independently associated with a higher prevalence of prolonged QTd. CONCLUSIONS: In this cohort of long-standing and moderately active RA patients, RA showed longer QTc but similar prevalence of prolonged QTc and an increased QTd with a 1.8-fold higher prevalence of increased QTd than the control population. Further studies in larger prospective cohorts are warranted to investigate whether QTd prolongation predicts sudden cardiac death and other adverse cardiovascular outcomes in RA.
31875623 Discovery of IL-6 and Development of Anti-IL-6R Antibody. 2019 A series of our studies on IL-6 have revealed that it has a pleiotropic activity in various tissues and cells and its deregulated expression is responsible for several chronic inflammations and hemopoietic malignancies.Humanized antibody against 80kd IL-6R (Tocilizumab) has shown significant therapeutic effect in RA, JIA, Castleman's diseases and several other autoimmune inflammatory diseases, such as, giant cell arteritis, reactive arthritis, polymyalgia rheumatica and adult still's disease. Cytokine storm induced by CAR-T cell therapy has been shown to be controlled by Tocilizumab.Therapeutic effect of Tocilizumab confirmed that over and constitutive-production of IL-6 is responsible for the pathogenesis of autoimmune diseases.Then, the question to be asked is how is IL-6 production regulated. We identified a novel molecule called Arid5a which binds with the 3'-UTR of IL-6 mRNA and protects its degradation by competing with Regnase-1. Interestingly, this molecule is present in nuclei and inflammatory stimulation induced translocation of Arid5a from nuclei into cytoplasm and it competes with Regnase-1 for the protection of mRNA of IL-6.Our study indicates that Arid5a is one of the key molecules for inflammation as well as the development of septic shock.The results also suggest the therapeutic potential of anti-agonistic agents for Arid5a in the prevention of various inflammatory diseases and septic shock.
31342661 Machine Learning to Predict Anti-Tumor Necrosis Factor Drug Responses of Rheumatoid Arthri 2019 Dec OBJECTIVE: Accurate prediction of treatment responses in rheumatoid arthritis (RA) patients can provide valuable information on effective drug selection. Anti-tumor necrosis factor (anti-TNF) drugs are an important second-line treatment after methotrexate, the classic first-line treatment for RA. However, patient heterogeneity hinders identification of predictive biomarkers and accurate modeling of anti-TNF drug responses. This study was undertaken to investigate the usefulness of machine learning to assist in developing predictive models for treatment response. METHODS: Using data on patient demographics, baseline disease assessment, treatment, and single-nucleotide polymorphism (SNP) array from the Dialogue on Reverse Engineering Assessment and Methods (DREAM): Rheumatoid Arthritis Responder Challenge, we created a Gaussian process regression model to predict changes in the Disease Activity Score in 28 joints (DAS28) for the patients and to classify them into either the responder or the nonresponder group. This model was developed and cross-validated using data from 1,892 RA patients. It was evaluated using an independent data set from 680 patients. We examined the effectiveness of the similarity modeling and the contribution of individual features. RESULTS: In the cross-validation tests, our method predicted changes in DAS28 (ΔDAS28), with a correlation coefficient of 0.405. It correctly classified responses from 78% of patients. In the independent test, this method achieved a Pearson's correlation coefficient of 0.393 in predicting ΔDAS28. Gaussian process regression effectively remapped the feature space and identified subpopulations that do not respond well to anti-TNF treatments. Genetic SNP biomarkers showed small contributions in the prediction when added to the clinical models. This was the best-performing model in the DREAM Challenge. CONCLUSION: The model described here shows promise in guiding treatment decisions in clinical practice, based primarily on clinical profiles with additional genetic information.
31226411 Collection of antirheumatic medication data from both patients and rheumatologists shows s 2019 Oct OBJECTIVES: The objective of the study was to examine the agreement between patient- and rheumatologist-reported antirheumatic medication (ARM) use in the Ontario Best Practices Research Initiative. STUDY DESIGN AND SETTING: We included adult patients who enrolled on or after September 1st 2010 and compared ARM use where rheumatologist visits and interviews occurred within 60 days of each other. Kappa statistic was used to measure agreement. We calculated sensitivity, specificity, and positive and negative predictive value, considering patient-reported data as the gold standard. To examine factors associated with agreement, a hierarchical generalized linear model was used. A subset analysis was also completed to compare start and stop dates of ARM. RESULTS: Overall agreement for ARM was good with higher sensitivity and lower specificity for conventional synthetic disease-modifying antirheumatic drugs compared with biologic disease-modifying antirheumatic drugs. Increased Health Assessment Questionnaire pain index and 28 disease activity score-erythrocyte sedimentation rate (DAS28-ESR) were significantly associated with lower agreement. Reporting stop dates was higher (19.4%) for patient-reported data compared with rheumatologist-reported data (13.1%). CONCLUSION: ARM reports had strong agreement particularly for patients who have low disease activity and pain. ARM discontinuation was reported more frequently by patients, which may indicate that patients may be discontinuing use of their rheumatoid arthritis medications before consulting their rheumatologist.
31084369 Ro60 and Y RNAs: structure, functions, and roles in autoimmunity. 2019 Apr Ro60, also known as SS-A or TROVE2, is an evolutionarily conserved RNA-binding protein that is found in most animal cells, approximately 5% of sequenced prokaryotic genomes and some archaea. Ro60 is present in cells as both a free protein and as a component of a ribonucleoprotein complex, where its best-known partners are members of a class of noncoding RNAs called Y RNAs. Structural and biochemical analyses have revealed that Ro60 is a ring-shaped protein that binds Y RNAs on its outer surface. In addition to Y RNAs, Ro60 binds misfolded and aberrant noncoding RNAs in some animal cell nuclei. Although the fate of these defective Ro60-bound noncoding RNAs in animal cells is not well-defined, a bacterial Ro60 ortholog functions with 3' to 5' exoribonucleases to assist structured RNA degradation. Studies of Y RNAs have revealed that these RNAs regulate the subcellular localization of Ro60, tether Ro60 to effector proteins and regulate the access of other RNAs to its central cavity. As both mammalian cells and bacteria lacking Ro60 are sensitized to ultraviolet irradiation, Ro60 function may be important during exposure to some environmental stressors. Here we summarize the current knowledge regarding the functions of Ro60 and Y RNAs in animal cells and bacteria. Because the Ro60 RNP is a clinically important target of autoantibodies in patients with rheumatic diseases such as Sjogren's syndrome, systemic lupus erythematosus, and neonatal lupus, we also discuss potential roles for Ro60 RNPs in the initiation and pathogenesis of systemic autoimmune rheumatic disease.
31260299 Discovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyro 2019 Jul 25 A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivatives as potent, reversible BTK inhibitors. Compared to the previously described cinnoline scaffold compounds, the 4-aminoquinoline analogues showed significantly improved drug-like properties, especially in their aqueous solubility. The most potent compound, 25, displayed a stronger inhibitory effect on both BTK(WT) (IC(50) = 5.3 nM) and BTK(C481S) (IC(50) = 39 nM). In a rodent collagen-induced arthritis model, compound 25 efficiently reduced paw swelling without a loss in body weight. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.
31823140 Risk of non-melanoma skin cancer for rheumatoid arthritis patients receiving TNF antagonis 2020 Mar OBJECTIVE: Tumor necrosis factor inhibitors (anti-TNF) have become the standard treatment for rheumatoid arthritis (RA). However, evidence is inconsistent as to whether RA patients with anti-TNF are associated with an increased risk of non-melanoma skin cancer (NMSC) compared with those without anti-TNF. We performed a systematic review and meta-analysis to evaluate the risk of NMSC in patients with anti-TNF drugs compared with those without anti-TNF. METHODS: We did a systematic literature search with PubMed, EMBASE, and the Cochrane Library from inception to April 1, 2019. Prospective observational studies were eligible for inclusion if they included any of the approved anti-TNF drugs and reported the risk estimates and 95% confidence interval (95% CI) of NMSC associated with anti-TNF in RA patients. Pooled relative risks (RRs) and 95% CIs were calculated using a fixed-effects model. To assess the heterogeneity and risk of publication bias, we respectively conducted the subgroup and sensitivity analysis, funnel plot, Begg's and Egger's test. RESULTS: The present meta-analysis included six studies with 123,031 patients. Compared with RA patients without anti-TNF, patients with anti-TNF drugs were associated with an increased risk of NMSC (RR 1.28, 95% CI 1.19 to 1.38; I(2) = 45.6%, P = 0.056), especially squamous cell skin cancer (SCC) (RR 1.30, 95% CI 1.09 to 1.54; I(2) = 0%, P = 0.854), but not basal cell skin cancer (RR 1.13, 95% CI 0.97 to 1.31; I(2) = 0%, P = 0.555). Sensitivity and subgroup analysis confirmed the robustness of the primacy results. There was no evidence of publication bias with Begg's and Egger's test or by inspection of the funnel plot. CONCLUSIONS: These results suggest that RA patients treated with anti-TNF are at an increased risk of NMSC, especially SCC. However, this association in RA urgently needs the more clinical studies and basic researches to further validate.Key Points• Rheumatoid arthritis patients treated with tumor necrosis factor inhibitors are associated with a higher risk of non-melanoma skin cancer compared to those patients treated without tumor necrosis factor inhibitors. Hence, tumor necrosis factor inhibitors may be avoided in rheumatoid arthritis patients who are at high risk of non-melanoma skin cancer.• Of note, rheumatoid arthritis patients who were treated for tumor necrosis factor inhibitors compared with patients who were not treated for tumor necrosis factor inhibitors were at significantly increased risk of squamous cell skin cancer, but were not at increased risk of basal cell skin cancer. Therefore, use of tumor necrosis factor inhibitors in rheumatoid arthritis patients should be paid attention to the occurrence of squamous cell skin cancer.
32039040 Molecular Characterization of Circulating Microbiome Signatures in Rheumatoid Arthritis. 2019 Rheumatoid Arthritis (RA) has been increasingly associated with perturbations to the microbial communities that reside in and on the body (the microbiome), in both human and animal studies. To date, such studies have mainly focused on the microbial communities that inhabit the gut and oral cavity. Mounting evidence suggests that microbial DNA can be detected in the blood circulation using a range of molecular methods. This DNA may represent an untapped pool of biomarkers that have the potential to report on changes to the microbiome of distant sites (e.g., example, the gut and oral cavity). To this end, through amplification and sequencing of the bacterial 16S rRNA variable region four, we evaluated the presence and identity of microbial DNA in blood samples obtained from RA patients (both prior to and 3 months following the instigation of treatment) in comparison to a small number of healthy control subjects and samples obtained from patients with ankylosing spondylitis (AS) and psoriatic arthritis (PA). Bacterial-derived DNA was identified in the majority of our patient samples. Taxonomic classification revealed that the microbiome community in RA was distinct from AS, PA, and the healthy state. Through analysis of paired patient samples obtained prior to and 3 months following treatment (V0 vs. V3), we found the microbiome to be modulated by treatment, and in many cases, this shift reduced the distance between these samples and the healthy control samples, suggesting a partial normalization following treatment in some patients. This effect was especially evident in seronegative arthritis patients. Herein, we provide further evidence for the existence of a blood microbiome in health and identify specific taxa modulated in disease and following treatment. These blood-derived signatures may have significant utility as disease biomarkers and suggest this area warrants further investigation.
30980385 Forkhead box o3a suppresses lipopolysaccharide-stimulated proliferation and inflammation i 2019 Nov Fibroblast-like synoviocytes (FLS), synovial tissue-specific cells, are key effector cells during the pathogenesis of rheumatoid arthritis (RA). Our previous study has shown that tripartite motif-containing protein 3 (TRIM3) overexpression inhibits the proliferation and cytokine secretion of RA FLS. Experiments with gene knockout mice have suggested the important roles of forkhead box o3a (Foxo3a) in RA pathogenesis. The present study aimed to investigate the correlation between Foxo3a and TRIM3 during RA pathogenesis. The expression of Foxo3a and TRIM3 was reduced in RA synovial tissues in comparison to healthy controls, and Foxo3a messenger RNA (mRNA) expression in RA synovial tissues correlated positively with TRIM3 mRNA expression. We found that stimulation with lipopolysaccharide (LPS) caused the downregulation of Foxo3a and TRIM3 in FLS. Foxo3a or TRIM3 overexpression significantly attenuated the promoting effects of LPS on cell proliferation and the release of tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1β. In addition, Foxo3a suppressed the inhibitory effects of LPS on the mRNA and protein levels of TRIM3, as well as the activity of TRIM3 promoter. Foxo3a or TRIM3 overexpression attenuated collagen-induced arthritis in rats. Furthermore, knockdown of TRIM3 significantly suppressed the effects of Foxo3a overexpression on LPS-activated FLS. In summary, our findings suggested that Foxo3a exerted inhibitory effects on LPS-induced proliferation and inflammation through increasing TRIM3 transcription. The decreased expression of Foxo3a may contribute to the RA pathogenesis.
33086968 A report of three cases which required tibialis anterior tendon resection to recover delay 2020 Jan Delayed wound healing is one of the severe complications after total ankle arthroplasty (TAA). In particular, once tibialis anterior (TA) tendon is exposed from tendon sheath of extensor retinaculum, wound healing will be critically intractable. We report three cases (mean age: 75.3 years old) of delayed wound healing after TAA cured by resection of TA tendon in patients with rheumatoid arthritis (RA). All three cases underwent TAA through an anterior approach, with careful suture of extensor retinaculum in wound closure. Ankle joint was fixed with splint and avoid weight bearing for three weeks after surgery. Delayed wound healing with TA tendon exposure was observed, and initially treated by debridement, basic fibroblast growth factor spray, and negative pressure wound therapy, which all failed to obtain wound healing. Finally, complete resection of TA tendon led to rapid wound healing. In all cases, ankle dorsal flexion was compensated by other extensors, with maintained range of motion and muscle strength (manual muscle testing 3 to 4) compared to pre-operation at 1 year after TAA operation. Resection of TA tendon may be considered as one of the salvage treatment options of severe delayed wound healing in TAA with anterior approach, especially in elderly patients.
30729372 Effect of biologic disease-modifying anti-rheumatic drugs for patients with rheumatoid art 2019 May OBJECTIVES: We examined the effect of biologic disease-modifying anti-rheumatic drugs on the time to pregnancy in patients with rheumatoid arthritis who hope to become mothers. Additionally, we evaluated adverse pregnancy outcomes and risk factors of these drugs. METHOD: We retrospectively investigated 25 pregnancies of 19 patients who were taking disease-modifying anti-rheumatic drugs. In 15 pregnancies, patients continued biologic disease-modifying anti-rheumatic drugs until conception (group A). In 10 pregnancies, patients discontinued biologic disease-modifying anti-rheumatic drugs and conventional synthetic disease-modifying anti-rheumatic drugs at the time of planning to conceive (group B). We used tumor necrosis factor inhibitors (certolizumab pegol and etanercept) for group A patients. RESULTS: The mean time to pregnancy was shorter in group A than in group B (5.9 ± 3.8 vs 11.0 ± 6.5 months, P = 0.04). The mean birth weight of newborns was lighter in group B than in group A (2446.5 ± 352.4 vs 2969.4 ± 459.9 g, P = 0.007). There were no significant differences in the rates of preterm birth, light-for-date, and premature rupture of the membranes between the groups. In patients with preterm birth or light-for-date newborns, the mean dose of corticosteroids during pregnancy was significantly higher compared with that in those with full-term birth or non-light-for-date newborns (P = 0.02, P < 0.01, respectively). CONCLUSIONS: In patients with rheumatoid arthritis who hope to conceive, continuing biologic disease-modifying anti-rheumatic drugs at the time of conception could shorten the time to pregnancy. Using biologic disease-modifying anti-rheumatic drugs before pregnancy does not affect abortion, preterm birth, light-for-date, and premature rupture of the membranes.
29933327 Mobile Apps for Individuals With Rheumatoid Arthritis: A Systematic Review. 2019 Apr BACKGROUND: Mobile health applications (apps) have the potential to help individuals with chronic illnesses learn about, monitor, and manage their condition, but these apps are largely unexamined, with the state and direction of development unclear. OBJECTIVE: We performed a systematic review of publicly available apps, directed toward individuals with rheumatoid arthritis (RA); described their current features; and determined areas of unmet need. METHODS: We searched the iTunes and Google Play App Stores for the term "arthritis" and reviewed the descriptions of these apps for specific mentions of RA. Applications that met inclusion criteria were downloaded and reviewed. Using a set of quality measures identified from literature review, we assessed each app for 4 features: basic characteristics, content source, functionality, and security. Frequencies for each feature were recorded, and percentages were calculated. RESULTS: Twenty apps intended for use by RA patients were identified in December 2016. Fifty percent of apps (n = 10) offered only symptom tracking. Five (20%) provided only information about RA, and 5 (20%) engaged patients by providing both symptom tracking and educational information. Fewer than 50% of apps provided means to contact health care providers or link to an online community, and only 6 (30%) offered security protection for the user. CONCLUSIONS: Most current RA apps do not provide a comprehensive experience for individuals with RA. Areas for optimization include the implementation of smartphone accessibility features and secure methods of protecting individual health information.
31674891 Therapeutic Potentials of Adenosine Receptors: The State of The Art. 2019
30561229 Usability and safety of SB5 (an adalimumab biosimilar) prefilled syringe and autoinjector 2019 Mar OBJECTIVE: To demonstrate comparability between administration of the adalimumab biosimilar, SB5, via prefilled syringe (PFS) and autoinjector (AI) pen based on injection site pain, patient preference, and safety in rheumatoid arthritis (RA) patients. METHODS: In this phase 2, open-label study (NCT02565810; EudraCT Number 2014-004887-39), adult RA patients self-administered 40 mg SB5 subcutaneously via PFS at weeks 0 and 2, followed by AI at weeks 4, 6, 8, and 10. Patients rated injection site pain from 0 (no pain) to 10 (severe pain) using a visual numeric scale immediately and 15-30 min post-injection at weeks 0, 2, 4, and 6. Equivalence between PFS and AI was concluded if the 97.5% confidence interval (CI) of the difference in the injection site pain scores at weeks 2 and 6 was contained within the equivalence margin of ±5. Overall impression and preference for PFS and AI were also evaluated. Safety was assessed up to 20 weeks after the first injection. RESULTS: Of 49 patients enrolled, 48 completed the study. Mean injection site pain scores were equivalent between PFS and AI immediately (2.3 vs 2.0; 97.5% CI = -0.99-0.30) and 15-30 min post-injection (0.8 vs 0.7; 97.5% CI = -0.47-0.25). The overall impression of both devices was comparable. The overall preference of AI was higher than PFS. Treatment-emergent adverse events (TEAE) were mild-to-moderate. There were no severe or serious TEAEs reported during the study. CONCLUSIONS: In RA patients, SB5 showed equivalent injection site pain and comparable safety when administered via PFS and AI.
29448870 A new assessment tool for ulnar drift in patients with rheumatoid arthritis using pathophy 2019 Jan OBJECTIVES: To establish a new assessment tool for ulnar drift (UD) in rheumatoid arthritis (RA). METHODS: We established an observational cohort of 67 patients (134 rheumatoid hands) beginning in 2004. Fifty-two patients (100 hands) had follow-up in 2009 and 37 patients (63 hands) completed follow-up in 2015. UD was evaluated with the Fearnley classification and our scoring method, which assesses four parameters of the metacarpophalangeal joint. Cluster analysis using UD parameters divided hands into groups. Changes in UD over time, correlation of the Fearnley stage and cluster with a functional assessment, and reliability of the parameters were analyzed. RESULTS: UD increased and worsened over time according to the trend test. A dendrogram indicated five clusters would be appropriate. Both the Fearnley classification and cluster were associated with function; however, our method related to function more linearly (R-squared: 0.42). We found one type of hand in which bone destruction precedes the joint dislocation and one type in which joint dislocation progresses with little deviation during UD progression. CONCLUSION: Our UD evaluation appeared to be simple and related to function. Additionally, it enables dividing UD hands into five stages. Thus, our assessment should be beneficial compared to the Fearnley classification in considering treatments of UD.
30801994 Derivation and Validation of a Major Toxicity Risk Score Among Nonsteroidal Antiinflammato 2019 Aug OBJECTIVE: While nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used in rheumatology, they can cause major toxicity. Improving the risk/benefit ratio requires a more precise understanding of risk. This study was undertaken to derive and validate a risk score for major toxicity among NSAID users enrolled in a randomized controlled trial. METHODS: Patients enrolled in a randomized controlled trial who had known cardiovascular disease or risk factors as well as osteoarthritis or rheumatoid arthritis were divided into derivation and validation cohorts. Patients were randomized to receive celecoxib, naproxen, or ibuprofen at typical dosages. The risk score was designed to predict the 1-year occurrence of major toxicity among NSAID users, including major adverse cardiovascular events, acute kidney injury, significant gastrointestinal events, and mortality. Variables significantly associated with major toxicity were candidates for inclusion in the final regression model. After derived models were found to have a similar model fit in the validation set, the cohorts were combined, allowing calculation of a risk score. RESULTS: In the derivation cohort, significant variables included age, male sex, history of cardiovascular disease, hypertension, diabetes mellitus, tobacco use, statin use, elevated serum creatinine level, hematocrit level, and type of arthritis. The C-index was 0.73 in the validation cohort and 0.71 in the total cohort; the model was well calibrated. Of the total population with complete data (n = 23,735), 1,080 participants (4.6%) had a predicted 1-year risk of major toxicity of <1%, 16,273 (68.6%) had a predicted risk of 1-4%, and 6,382 (26.9%) had a predicted risk of >4%. CONCLUSION: The risk score accurately categorizes the 1-year risk of major toxicity among NSAID users and may be useful in identifying patients who can safely use these agents.
31818460 Combination of gp130-targeting and TNF-targeting small molecules in alleviating arthritis 2020 Feb 19 Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that is characterized by T helper 17 (Th17) cell- and osteoclast-induced joint destruction and inflammation. In RA, several cytokines (interleukin (IL)-1, 6,17, and tumor necrosis factor (TNF)) are involved in almost all aspects of articular inflammation and destruction. This study aimed to evaluate the combinatorial effect of TNF and IL-6 inhibitors on the differentiation and activation of Th17 cells and osteoclasts in the context of RA, and to identify the RA-related mechanisms through IL-6 signaling. Tetrahydropapaverine (THP) showed direct binding to TNF in screening-ELISA, and SPR and TNF-neutralization assays. In a previous study, the therapeutic effect of gp130-targeting LMT-28 was confirmed in RA. Combinatorial treatment with LMT-28 and THP reduced the arthritis index and showed protective effects against bone and cartilage destruction in CIA mice. The secretion levels of TNF, IL-6, and IL-1β significantly decreased upon combinatorial treatment with LMT-28 and THP. Further, the LMT-28 and THP combination suppressed the differentiation and activation of Th17 cells in mouse splenocytes and human PBMCs. In human RA-FLS, the LMT-28 and THP combination inhibited cell proliferation and downregulated IL-6 and/or TNF-mediated signaling relative to that observed upon independent treatment with LMT-28 or THP. Furthermore, the combination of LMT-28 and THP significantly inhibited the differentiation of mouse bone marrow monocytes (BMMs) into osteoclasts. In conclusion, the LMT-28 and THP combination can attenuate RA through the inhibition of Th17 differentiation and osteoclastogenesis, and suppression of IL-6 or TNF-induced signaling pathways. This combinatorial therapy could be used as a new strategy for the treatment of RA.