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ID PMID Title PublicationDate abstract
31132731 The roles of synovial hyperplasia, angiogenesis and osteoclastogenesis in the protective e 2019 Aug Apigenin (API) is a plant flavone that is known to exert a protective effect in rheumatoid arthritis (RA), which is a chronic autoimmune disease. However, the molecular mechanism for API's protective effect against RA is still unclear. Here, a collagen-induced arthritis (CIA) mouse model was used to assess the protective effect of API on RA. Histomorphological studies, immunohistochemistry, RT-PCR, and western blot were conducted to elucidate the roles of synovial hyperplasia, angiogenesis, and osteoclastogenesis in the protective effect of API on RA. Fibroblast-like synoviocytes (FLSs) were isolated to measure the effect of API on FLS proliferation and apoptosis. API exhibited a significant protective effect in CIA mice in a dose- and time-dependent manner. An increase in apoptosis and decrease in proliferation were observed after the API treatment in FLSs, suggesting that API might inhibit synovial hyperplasia. Moreover, CIA angiogenesis was repressed by API via down-regulation of VEGF and VEGFR. Furthermore, API regulated the osteoclastogenesis-associated RANKL/RANK/OPG system in CIA mice. Therefore, API inhibits CIA by repressing synovial hyperplasia, angiogenesis, and osteoclastogenesis. This suggested that API might be a putative low toxicity candidate drug for RA treatment.
29799667 Subsequent Cardiovascular Events Among Patients With Rheumatoid Arthritis, Psoriatic Arthr 2019 Apr OBJECTIVE: To examine disease-modifying antirheumatic drug (DMARD) treatments and estimate the risk of a subsequent cardiovascular (CV) event following an initial CV event in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or psoriasis. METHODS: We analyzed data from MarketScan claims databases (January 1, 2006 to June 30, 2015) for adults with RA, PsA, or psoriasis and an initial/index CV event (acute myocardial infarction, stroke, or coronary revascularization) while receiving DMARDs (tumor necrosis factor inhibitor [TNFi] biologic DMARDs [bDMARDs], conventional synthetic DMARDs [csDMARDs], or non-TNFi bDMARDs). We studied DMARD treatment patterns following the index event and rates of subsequent CV events. We used Cox regression to investigate predictors of DMARD discontinuation and risk factors for subsequent CV events. RESULTS: Among 10,254 patients, 15.3% discontinued and 15.5% switched DMARD therapy after the index CV event. Independent predictors of DMARD discontinuation included a psoriasis diagnosis, renal disease, hypertension, heart failure, diabetes mellitus, older age, and baseline csDMARD or non-TNFi bDMARD use (versus TNFi bDMARDs). Rates per 1,000 patient-years of subsequent events were 75.2 (95% confidence interval [95% CI] 54.4-96.0) for patients taking TNFi bDMARDs, 83.6 (95% CI 53.3-113.9) for csDMARDs, and 122.4 (95% CI 60.6-184.3) for non-TNFi bDMARDs. A diagnosis of RA (versus psoriasis) and heart failure at baseline, but not a DMARD pattern after the index event, were independently associated with an increased risk of subsequent CV event. CONCLUSION: In this large nationwide study, nearly one-third of patients with RA, PsA, or psoriasis switched or discontinued DMARD therapy following a CV event. There was no association between DMARD class and the risk of a subsequent CV event.
31776092 Bone marrow-derived mesenchymal stem cells-secreted exosomal microRNA-192-5p delays inflam 2020 Jan BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease closely correlated to synovial tissue inflammation. Exosomes are known to transfer microRNAs (miRNAs) between cells and have been validated as the vehicles for delivery of therapeutic molecules. AIM AND SCOPE: The current study was set to examine the functional values of bone marrow-derived mesenchymal stem cells (BMSCs)-secreted exosomal miR-192-5p (exo-miR-192-5p) on inflammation in RA. METHODS: Following the screening of differentially expressed genes in RA and miRNA-mRNA target prediction, BMSCs were infected with lentivirus expressing miR-192-5p to obtain miR-192-5p-overexpressed exosomes. To study the effect of exo-miR-192-5p on the expression of ras-related C3 botulinum toxin substrate 2 (RAC2), collagen-induced arthritis (CIA) rat models were established, and the clinical and histopathological changes were evaluated in the rats injected with exosomes. Subsequently, the expression patterns of pro-inflammatory factors were determined by ELISA. RESULTS: miR-192-5p was found to be down-regulated, while RAC2 was up-regulated in RA samples. Bioinformatics prediction revealed that the up-regulated RAC2 in RA may be regulated by miR-192-5p, which was further confirmed by dual luciferase reporter gene assay. The clinical arthritic scores, joint destruction, and inflammatory response were reduced after the injection of exosomes in rats with CIA targeting RAC2, and the treatment efficacy was even better with miR-192-5p-overexpressed exosomes. CONCLUSION: Our study established that the BMSCs-secreted exosomal miR-192-5p can delay the event of the inflammatory response in RA and may represent a possible therapeutic strategy for the treatment of RA.
31526593 Definition and construct validation of clinically relevant cutoffs on the Flare Assessment 2020 Apr OBJECTIVE: The Flare Assessment in Rheumatoid Arthritis (FLARE-RA) questionnaire was devised for the detection of flares in patients with RA. We aimed to define construct validity and cut-off(s) for the FLARE-RA questionnaire. METHODS: This cross-sectional study included adult patients with prevalent RA (2010 ACR/EULAR criteria) attending outpatient rheumatology clinics in France (n = 138), Denmark (n = 253), USA (n = 75), and Argentina (n = 105). Flare occurrence over the past 3 months was assessed with the FLARE-RA questionnaire scoring from 0 (no flare) to 10 (maximum flare). The cut-offs for the FLARE-RA score were defined using the following anchor items obtained at the same encounter: (1) Patient report of flare; (2) DAS28-CRP > 3.2; (3) Change of anti-rheumatic treatment, based on the area under the receiver operating characteristic curve (AUC) and distance to (0,1). RESULTS: Four hundred seventy four patients with RA duration ≥2 years (mean age 58.6 years, 74.9% female) were included in the main analysis. The discrimination for the FLARE-RA cut-offs was acceptable-to-excellent: AUC for the global FLARE-RA score ranged from 0.71 to 0.92. The cut-offs for the FLARE-RA score were lower using "patient report of flare" than DAS28-CRP and "change of anti-rheumatic treatment". Proposed FLARE-RA cut-offs for clinical detection and change of anti-rheumatic treatment are 2 and 5, respectively, for patients with RA duration 2-5 years, and 2 and 3.5, respectively, for patients with RA duration >5 years. CONCLUSIONS: Proposed FLARE-RA cut-offs have acceptable discriminative capacity across the tested anchor items and are expected to aid in early recognition and timely management of RA flares.
30897288 Exenatide ameliorates inflammatory response in human rheumatoid arthritis fibroblast-like 2019 Jul Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology characterized by degradation of cartilage and bone, accompanied by unimpeded proliferation of synoviocytes of altered phenotype. In the present study, we investigated the involvement of the glucagon-like peptide 1 (GLP-1) receptor on human fibroblast-like synoviocytes (FLS) in the pathogenesis of RA using the selective GLP-1 agonist exenatide, a licensed drug used for the treatment of type 2 diabetes. Our results indicate that exenatide may play a role in regulating tumor necrosis factor-α-induced mitochondrial dysfunction by increasing mitochondrial membrane potential, oxidative stress by reducing the production of reactive oxygen species, the expression of NADPH oxidase 4, expression of matrix metalloproteinase (MMP)-3 and MMP-13, release of proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, monocyte chemoattractant protein-1, and high-mobility group protein 1, as well as activation of the p38/nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α/nuclear factor κB signaling pathway in primary human RA FLS. These positive results indicate that exenatide may have potential as a therapeutic agent for the treatment and prevention of RA. © 2019 IUBMB Life, 9999(9999):1-9, 2019.
31208237 Mavrilimumab: a unique insight and update on the current status in the treatment of rheuma 2019 Jul Introduction: Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease, which affects joints and extra-articular structures. Nowadays, the armamentarium of therapeutic options is progressively expanding and embraces several mechanisms of action: TNF inhibition, B-cell depletion, T-cell co-stimulation inhibition, IL-6 blockade, and JAK-inhibition. Granulocyte-Monocyte-Colony-Stimulating-Factor (GM-CSF) is a mediator acting as a cytokine with a proven pathogenetic role in RA, providing a potential alternative target for the management of the disease. Mavrilimumab is a monoclonal antibody against GM-CSF receptor, which has been successfully tested in RA patients. Areas covered: Beginning with a description of the preclinical evidence and the rationale for GM-CSF blockade in RA, this review will provide a wide overview of mavrilimumab efficacy and safety profile by analyzing phase I/II RCTs conducted in patients with moderate to severe RA. Expert opinion: According to the promising results from phase I-II RCTs, mavrilimumab could be considered as an additional therapeutic option for RA patients multi-resistant to the available targeted drugs. However, the optimal dose and the profile of this new drug should be confirmed in phase III RCTs before the marketing.
31530199 Gadolinium-conjugated CB86: a novel TSPO-targeting MRI contrast agent for imaging of rheum 2020 Apr TSPO is up-regulated in activated macrophages, and serves as an attractive target for macrophages molecular imaging and therapy. MRI may be an ideal technique in the clinical management of RA due to its excellent spatial resolution. In the present study, a novel TSPO-targeting MRI contrast agent was developed by conjugating a novel TSPO ligand CB86 with gadolinium chelate to visualise inflamed regions in RA mice model. A novel TSPO ligand CB86 was linked to DTPAA, followed by chelation with gadolinium to obtain MRI targeted contrast agent CB86-DTPA-Gd. CB86-DTPA-Gd was characterised by MRI relaxivity, cell cytotoxicity, cell specificity and in vitro stability analysis. The distribution and MRI intensity was evaluated in RA rat model. Synthesis of CB86-DTPA-Gd was completed successfully with MRI relaxivity of 11.05/mM/sec (9.4 T, 25 °C). CB86-DTPA-Gd exhibited a good stability in human serum, high RAW264.7 cells specificity and no cytotoxicity in RAW264.7 cells. The biodistribution and MRI studies showed that the accumulation and signal intensity of CB86-DTPA-Gd in the right RA ankles was higher and stronger than those of Gd‑DTPA. This study demonstrates that CB86-DTPA-Gd can identify phagocytic active macrophages in the synovial joints, and has potential as a promising targeting MRI contrast agent for imaging of peripheral inflammation.
32199713 The microbiome and rheumatoid arthritis. 2019 Dec Rheumatoid Arthritis (RA) is a severe, chronic autoimmune disease that affects 1% of the world's population. Familial risk contributes 50% of the risk of seropositive RA, with strongest risks seen in first-degree relatives. Smoking increases the risk of developing anti-citrullinated peptide antibody (ACPA)(+) RA, particularly in individuals with high-risk RA-susceptibility alleles. Other contributory environmental risks including particulate exposure, periodontal disease, bronchiectasis, diet, obesity and the oral contraceptive impact respiratory, oral, intestinal and genital tract mucosal sites. Furthermore, the first signs of autoimmunity may appear at mucosal sites e.g. sputum ACPA-IgA and IgG. While oral and faecal dysbiosis are well described, there is no consistent single bacterial species that appears to drive RA. Animal and human data suggest a model in which multiple environmental influences impact mucosal immune function through the host genetics through enhanced mucosal permeability and the traffic of pro-inflammatory PAMPs and the amplification of autoimmune responses. In some cases, autoimmunity may be driven by cross-reactivity, or mimicry, to pathogen-specific antigens, particularly where the host immune system fails to support their rapid control and elimination.
30894209 Hypoxia-induced miR-191-C/EBPβ signaling regulates cell proliferation and apoptosis of fi 2019 Mar 20 BACKGROUND: Hypoxia plays an important role in the proliferation of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), leading to pathology of RA. This study was conducted to evaluate hypoxia-induced microRNAs (hypoxamiR) in RA-FLS and its role in the function of RA-FLS. METHODS: RA-FLS were cultured under normoxia (21% O(2)) or hypoxia (3% O(2)) condition, followed by a microRNA (miRNA) array analysis. The upregulation of miR-191 by hypoxia was confirmed in RA-FLS and FLS from osteoarthritis (OA) patients by quantitative real-time polymerase chain reaction (RT-PCR). Transfection of miR-191 mimic and inhibitor was used to investigate the function of miR-191 in RA-FLS. The functional targets of miR-191 were predicted by bioinfomatics and then validated by reporter gene assay. RESULTS: A subset of miRNAs was identified to be induced by hypoxia including miR-191. The upregulation of miR-191 was found to be specific in hypoxic RA-FLS, compared to hypoxic OA-FLS. We observed that miR-191 in RA-FLS increased cellular proliferation via promoting G(1)/S transition of the cell cycle and suppressed cell apoptosis induced by cell starvation. Bioinformatical analysis and experimental assays identified CCAAT/enhancer binding protein β (C/EBPβ) as a target gene of miR-191 in RA-FLS. Enforced expression of C/EBPβ rescued the cellular phenotypes induced by miR-191. In addition, an inverse correlation between the C/EBPβ level and hypoxia stimulation was found in RA-FLS, and overexpression of C/EBPβ could partly rescue the hypoxia-induced cell proliferation. CONCLUSION: We demonstrated the miR-191-C/EBPβ signaling pathway mediating the hypoxia-induced cell proliferation in RA.
31251449 Assessing the development and treatment of rheumatoid arthritis using multiparametric phot 2019 Nov Rheumatoid arthritis (RA), characterized by polyarthritis, is a chronic, systemic and inflammatory autoimmune disease. In this study, we developed a dual-modality multiparametric photoacoustic and ultrasound imaging technique, and successfully derived multiple parameters such as relative concentration of total hemoglobin (C(HbT) ), ratio of angiogenesis, joint size and area of synovia to assess the development and treatment of RA. We established a model of adjuvant arthritis using a total number of 15 rats and randomly divided them into three groups: (a) targeted group in which the rats received targeted antirheumatic drugs; (b) nontargeted group in which the rats were treated with nontargeted antirheumatic drugs; (c) control group. We longitudinally monitored the joints of the rats in all three groups for up to 20 days and carried out quantitative analysis to evaluate the development and treatment of RA based on the derived parameters. The results suggest that the proposed dual-modality imaging technique is able to assess the effectiveness of the RA treatment using quantitative hemodynamic and morphological parameters. To show the clinical feasibility of this technique, we performed in vivo joint studies of health volunteers to visualize both structures and inside hemodynamics of the distal interphalangeal joint.
31441345 Revisit of autoimmunity to glucose-6-phosphate isomerase in experimental and rheumatoid ar 2020 Mar Rheumatoid arthritis (RA) is an inflammatory disorder characterized by synovial inflammation in multiple joints. Autoantibodies (Abs) are the hallmark of RA, and as disease-specific and diagnostic markers, rheumatoid factor and anti-citrullinated protein antibody (ACPA) are produced pre-clinically, but their pathogenic roles in RA remain elusive. In this review, we focus on one of the candidate autoantigens in RA; glucose-6-phosphate isomerase (GPI). The arthritogenic role of GPI has been confirmed in two different mouse models: the K/BxN- and GPI-induced arthritis models. Both anti-GPI Abs and citrullinated-GPI peptide Abs have been detected in human RA. Studies conducted in these rodent models have confirmed that the pathogenesis of arthritis involves the localization of autoantigens not only in the joints but also in the circulation. In this review, we revisit and summarize the arthritogenic relevance of GPI in animal RA models and in human RA, and extend the discussion to joint-specific inflammation.
31159650 Changing hospitalization trends for systemic lupus erythematosus and rheumatoid arthritis 2019 Jun OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic, multisystemic, immune-mediated disorder associated with a substantial hospitalization risk. As a comparatively rare disease, there is a sparsity of research examining the burden of hospital admission in the contemporary era. We aim to describe national trends in hospitalization rates in England between 1998 and 2015 for SLE, using rheumatoid arthritis (RA) and general population rates as comparison cohorts for benchmarking. METHODS: Hospital admission rates, emergency and day-case admission rates, length of stay and bed days used were calculated using finished consultant episodes from Hospital Episode Statistics data. Cochran-Armitage tests and linear regression quantified the significance and magnitude of change over time. RESULTS: SLE admissions increased from 8.97 to 9.04 per 100,000 (p < 0.001) between 1998 and 2015. By comparison, RA admissions rose from 71.0 to 171.6 per 100,000 (p < 0.001) and all-cause admissions rose from 24,500 to 34,500 per 100,000 (p < 0.001). Emergency admissions decreased both for SLE (2.6 to 1.2 per 100,000) and RA (12.8 to 4.4 per 100,000) despite all-cause emergency admissions increasing from 9400 to 10,300 per 100,000. SLE and RA day cases increased, whilst median length of stay decreased. Despite increasing admissions, total bed days for SLE and RA fell by 60% and 90%, respectively. CONCLUSIONS: Whilst all-cause emergency admissions rose in the general population, those for SLE fell. Length of stay and bed days reduced and day cases increased, probably reflecting changing therapeutic strategies. This potentially large reduction in resource utilization warrants consideration when assessing the impact of new therapies.
31471012 Rheumatoid arthritis disease activity and the risk of aseptic arthroplasty loosening. 2020 Apr OBJECTIVES: To assess the influence of rheumatoid arthritis (RA) disease activity (DA) on the risk of aseptic loosening after total hip/knee arthroplasty (THA/TKA). METHODS: We identified RA patients who underwent THA/TKA and determined their DA using the simplified disease activity index (SDAI). The risk of aseptic loosening was estimated using radiographic signs of component loosening (RCL). We performed Cox regression to estimate RCL based on SDAI, adjusting for therapy. We also investigated a cohort of 2:1 matched osteoarthritis (OA) patients as a control group without systemic inflammation. RESULTS: We identified 49 RA patients with a history of THA/TKA, of whom 18 (36.7%) showed RCL. SDAI over time was significantly higher in patients with RCL (median; 25th and 75th percentile: 10.8 months; 8.6 and 15.8; vs 7.0 months; 2.7 and 15.5;p = 0.043). In the regression model, each unit of mean SDAI over time significantly increased the risk of RCL (HR 1.125, 95% CI 1.021-1.241;p = 0.018). Patients treated with biological had a lower risk of RCL than those treated with traditional DMARDs (HR 0.192, 95% CI 0.042-0.891;p = 0.035). In the 88 matched OA patients, the RCL rate was significantly lower than in the RA group (13.6%;p = 0.002). CONCLUSION: Higher inflammatory DA increases the risk for radiographic loosening after THA/TKA in patients with RA. The significantly lower risk in patients with OA further underlines the potential role of inflammatory DA. In the context of treating RA to target, the presence of an arthroplasty might be considered as an indication for more stringent control of DA.
31393192 Persistent anemia and hypoalbuminemia in rheumatoid arthritis patients with low serum trii 2020 Jul Objectives: To determine the clinical characteristics of rheumatoid arthritis (RA) patients with low serum triiodothyronine (T3) levels.Methods: We evaluated serum free T3 (fT3), free T4, and thyroid-stimulating hormone (TSH) levels in 338 RA patients. After excluding patients taking anti-thyroid drugs or having anti-thyroid antibodies, we compared the clinical characteristics of the RA patients with low fT3 to those with normal/high fT3, before and after RA treatment.Results: Six percent of RA patients had low fT3 levels. Patients with low fT3 were older and had higher disease activity scores (DAS28), higher Steinbrocker stage, higher health assessment questionnaire scores, lower body mass index, and lower hemoglobin and albumin levels compared with normal/high-fT3 patients. After RA treatment, fT3 levels normalized in half of the low-fT3 patients and remained low in the other half. Although DAS28 scores were similarly improved in both subgroups of the low-fT3 patients, anemia and hypoalbuminemia did not normalize in the persistently low-fT3 subgroup.Conclusion: Low serum fT3 levels represent the profound wasting seen in RA patients that is characterized by anemia and hypoalbuminemia and that cannot be evaluated by DAS28 scores alone.
30321923 Ankle fusion after failed ankle replacement in rheumatic and non-rheumatic patients. 2019 Oct BACKGROUND: With longer follow-up, survival rate of total ankle replacements (TAR) diminishes. It is therefore important to have a reliable fall-back option in case of failed TAR. Revision arthroplasty is often impossible because of loss of bonestock or infection. Conversion to ankle fusion is then indicated. We investigated the clinical, radiographic and patient reported results for fusion after failed TAR in a consecutive group of patients. We concentrated on the influence of inflammatory joint disease (IJD) on union rate. METHODS: Patient files and radiographic images of 46 consecutive patients (47 ankles) were reviewed. There were 22 patients with IJD. Fixation methods included; anterior plating, blade plate fixation, intramedullary nailing, compression screws and external fixation. Foot and Ankle Outcome Score (FAOS) and Foot and Ankle Ability Measure (FAAM) were used to determine patient related outcomes. RESULTS: Forty out of 47 ankles (85%) Fused. Union rate in the non-IJD group (96%) was significantly higher compared to the IJD-group (73%, p=0.04). Revisions and complications were more frequent in the IJD group, but numbers were too small to detect a significant difference. Mean PROM scores were: FAOS-symptoms; 68.5, FAOS-pain; 70.3, FAOS-QoL; 43.7, FAOS-ADL; 68.1 and FAAM-ADL; 52.1, with no significant difference between IJD and non-IJD patients. CONCLUSIONS: IJD-patients have a higher nonunion rate after ankle fusion for failed TAR. However, patient reported outcome is not significantly different between the two groups. LEVEL OF EVIDENCE: IV, retrospective cohort.
31123977 Differing X-ray patterns in seronegative and seropositive rheumatoid arthritis. 2019 Sep INTRODUCTION: Anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) status are important predictors for rheumatoid arthritis (RA) erosivity. Qualitative differences on hand/feet radiographs have been described, indicating more carpal fusion in seronegative RA. This study explores these differences further using the total Sharp/van der Heijde score (TSS), digital X-ray radiogrammetry (DXR), and qualitative description. METHODS AND MATERIALS: Matched seronegative (ACPA negative, RF negative, snRA) and seropositive (ACPA, RF > 3xULN, spRA) were examined. TSS scores both for erosions and joint space narrowing (JSN) were registered separately and compared for both groups. Joint compartments and single joints were compared, using a heat map. The degree of carpal fusion was quantified 0-5. DXR measurements (bone mineral density, cortical thickness, bone width, metacarpal index) were determined for each hand separately. Finally, selected radiographs were examined unblinded to search for non-quantifiable differences. RESULTS: A total of 56 snRA and 57 spRA patients were examined. spRA patients had more erosions and joint space narrowing. Erosion load differed significantly between spRA and snRA in the foot and metacarpophalangeal joint, but not in the wrist or proximal interphalangeal joint compartments. Intracompartmental differences were greater in spRA. JSN scores were greater in spRA, in all compartments except wrist. Carpal fusion and DXR scores did not differ between the groups. The qualitative comparison showed that snRA patients displayed periarticular ossifications, carpal shortening, and sparing of the CMC joints, whereas spRA patients had more CMC damage and less shortening. CONCLUSION: X-ray manifestations in snRA and spRA are qualitatively and quantitatively different. This suggests pathophysiological differences between the two forms. Key Points • Seronegative and seropositive RA display qualitatively and quantitatively different X-ray patterns, suggesting differences in the underlying pathophysiological process. This is the first time that this has been shown in a systematic, quantitative fashion.
31076944 The effect of concomitant hand osteoarthritis on pain and disease activity in patients wit 2019 Oct INTRODUCTION: Pain is a core complaint among rheumatoid arthritis (RA) patients, and persistent pain requires treatment adjustments according to current strategies. We aimed to quantify the impact of hand osteoarthritis (OA) on health status and residual pain in patients with RA. METHODS: This cross-sectional survey compared RA patients with and without osteoarthritis of the hand. The main outcome was pain intensity. Other measurements included disease activity scores (the Disease Activity Score 28-joints; the Simplified Disease Activity Index, SDAI; the Clinical Disease Activity Index, CDAI), functional disability and self-reported quality of life, and the proportion of patients with residual pain (Patient Acceptable Symptom State, PASS). RESULTS: Eighty-one patients were analyzed, including 39 with RA and OA and 42 with RA only. The patients were mainly women (94%), with a median disease duration of 13 years. This group also reported a higher intensity of pain (visual analogue scale, VAS 70 mm vs. 30 mm; p = 0.003), higher disease activity (3.89 vs. 2.88; p = 0.001), and greater functional disability irrespective of treatment and comorbidities. A strong correlation (r(2) = 0.69; p < 0.001) between pain and disease activity was observed, although no differences in pain were observed between groups according to disease activity categories. Patients with RA and OA had a higher proportion of residual pain (59% vs. 29%; p = 0.006) even in the absence of clinical inflammation. CONCLUSION: The coexistence of RA and hand OA is associated with distorted disease activity measurements in RA. Osteoarthritis contributes to persistent pain and greater disability in patients with RA.
31429794 Efficacy and safety of intravenous golimumab plus methotrexate in patients with rheumatoid 2019 Aug 20 OBJECTIVE: To evaluate the safety and efficacy of intravenous golimumab + methotrexate (MTX) in patients with active rheumatoid arthritis (RA) aged < 65 years and those ≥ 65 years who were enrolled in the GO-FURTHER study. METHODS: In the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, patients with active RA were randomized to intravenous (IV) golimumab 2 mg/kg + MTX or placebo + MTX at weeks 0 and 4, then every 8 weeks thereafter (with crossover to golimumab at week 16 [early escape] or week 24 [per-protocol]). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology (ACR) 20/50/70 response criteria. Efficacy and adverse events (AEs) were monitored through 2 years. Efficacy and AEs were summarized for patients aged < 65 years or ≥ 65 years; AEs were also summarized for patients < or ≥ 70 years and patients < or ≥ 75 years. RESULTS: In GO-FURTHER, 592 patients were randomized to receive placebo (n = 197) or golimumab (n = 395), 515 were aged < 65 years and 77 were ≥ 65 years. At week 24, ACR20 response rates were greater for golimumab + MTX patients compared with placebo + MTX for patients < 65 years (61.6% vs 31.3%, p < 0.001) and those ≥ 65 years (69.5% vs 33.3%; p < 0.01). Infections were the most common AE through week 112 (51.6% in patients < 65 years; 55.3% in patients ≥ 65 years); upper respiratory infections were the most common infection in patients < 65 years (13.2%) and those ≥ 65 years (11.8%). Serious AEs occurred in 17.7% in patients < 65 years and 25.0% of patients ≥ 65 years and included malignancies, pneumonia, fractures, acute pancreatitis, cellulitis, and bacterial arthritis. CONCLUSIONS: In GO-FURTHER, ACR response rates were similar between patients < 65 years and patients ≥ 65 years within each treatment group. AEs in elderly patients were similar to the known safety profile of IV golimumab. Immunosenescence is known to increase the risk of infections in the elderly. Elderly patients had a numerically higher incidence of serious infections. Six malignancies occurred in golimumab-treated patients, all in patients < 65 years. TRIAL REGISTRATION: clinicaltrials.gov: NCT00973479 . Registered September 9, 2009.
31030958 Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid 2019 Jul Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response.
31178440 Budget impact of introducing tofacitinib to the public hospital formulary in Hong Kong, 20 2019 Jun INTRODUCTION: As the first approved oral kinase inhibitor, tofacitinib is effective and well-tolerated, but more expensive than conventional treatments for uncontrolled rheumatoid arthritis. Public formulary listing typically exerts a positive impact on the uptake of new drugs. We aimed to assess the budgetary impact of introducing tofacitinib into the Hospital Authority Drug Formulary as a fully subsidised drug in Hong Kong. METHODS: We applied a population-based budget impact model to trace the number of eligible patients receiving biologics or tofacitinib treatment, then estimated the 5-year healthcare expenditure on rheumatoid arthritis treatments, with or without tofacitinib (2017-2021). We used linear regression to estimate the number of target patients and compound annual growth rate to estimate market share. Competing treatments included abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, and tofacitinib. Retail price was used for drug costs, valued in Hong Kong dollars (HK$) in 2017 and discounted at 4% per year. RESULTS: The annual treatment cost of tofacitinib was HK$74 214 per patient, and the costs of biologics ranged from HK$64 350 to HK$115 700. Without tofacitinib, the annual government health expenditures for rheumatoid arthritis treatment were estimated to increase from HK$147.9 million (2017) to HK$190.6 million (2021). The introduction of tofacitinib to the formulary would reduce healthcare expenditures by 17.3% to 20.3% per year, with cumulative savings of HK$192.8 million; this change was estimated to provide consistent savings (HK$66.4 million to HK$196.8 million) in all tested scenarios. CONCLUSION: Introduction of tofacitinib to the formulary will provide 5-year savings, given the current drug price and patient volume.