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ID PMID Title PublicationDate abstract
33879745 Medicare beneficiary panel characteristics associated with high Part D biologic disease-mo 2021 Apr 23 The aim of this study was to investigate beneficiary panel characteristics associated with rheumatologists' prescribing of biologic DMARDs (bDMARDs) for older adults.In this retrospective observational study, we used Medicare Public Use Files (PUFs) to identify rheumatologists who met criteria for high-prescribing, defined as bDMARD prescription constituting ≥20% of their DMARD claims for beneficiaries ≥65 years of age. We first used descriptive analysis then multivariable regression model to test the association of high prescribing of bDMARDs with rheumatologists' panel size and beneficiary characteristics. In particular, we quantified the proportion of panel beneficiaries ≥75 years of age to assess how caring for an older panel correlate with prescribing of bDMARDs.We identified 3197 unique rheumatologists, of whom 405 (13%) met criteria for high prescribing of bDMARDs for Medicare beneficiaries ≥65 years of age. The high-prescribers provided care to 12% of study older adults, and yet accounted for 21% of bDMARD prescriptions for them. High prescribing of bDMARDs was associated with smaller panel size, and their beneficiaries were more likely to be non-black, ≥75 years of age, non-dual eligible, have diagnosis of CHF, however, less likely to have CKD.Rheumatologists differ in their prescribing of bDMARDs for older adults, and those caring for more beneficiaries ≥75 years of age are more likely to be high-prescribers. Older adults are more prone to the side-effects of bDMARDs and further investigation is warranted to understand drivers of differential prescribing behaviors to optimize use of these high-risk and high-cost medications.
32813284 Adaptation of American College of Rheumatology Rheumatoid Arthritis Disease Activity and F 2021 Dec OBJECTIVE: To provide guidance on the implementation of recommended American College of Rheumatology (ACR) rheumatoid arthritis (RA) disease activity and functional status assessment measures in telehealth settings. METHODS: An expert panel was assembled from the recently convened ACR RA disease activity and functional status measures working groups to summarize strategies for implementation of ACR-recommended RA disease activity (the Clinical Disease Activity Index [CDAI], Disease Activity Score in 28 joints using the erythrocyte sedimentation rate or the C-reactive protein level [DAS28-ESR/CRP], Patient Activity Scale II [PAS-II], Simplified Disease Activity Index [SDAI], and Routine Assessment of Patient Index Data 3 [RAPID3]) and functional status (the Health Assessment Questionnaire II [HAQ-II], Multidimensional Health Assessment Questionnaire [MDHAQ], and PROMIS physical function 10-item short form [PROMIS PF-10]) measures in telehealth settings. RESULTS: Measures composed of patient-reported items (disease activity: PAS-II, RAPID3; functional status: HAQ-II, MDHAQ, PROMIS PF-10) require minimal modification for use in telehealth settings. Measures requiring formal joint counts (the CDAI, DAS28-ESR/CRP, and SDAI) can be calculated using patient-reported swollen and tender joint counts. When the feasibility of laboratory testing is limited, the CDAI can be used in place of the SDAI, and scoring modifications of the DAS28-ESR/CRP without the acute-phase reactant are available. Assessment of the validity of these modifications is limited. Implementation of these measures can be facilitated by electronic health record collection, mobile applications, and provider/staff administration during telehealth visits. CONCLUSION: The ACR-recommended RA disease activity and functional status measures can be adapted for use in telehealth settings to support high-quality clinical care. Research is needed to better understand how telehealth settings may impact the validity of these measures.
33555152 Long-term methotrexate use in rheumatoid arthritis patients: real-world data from the MART 2021 Apr BACKGROUND: The MARTE study investigated the demographic, clinical, and therapeutic characteristics of rheumatoid arthritis (RA) patients ongoing methotrexate (MTX) treatment for longer than 8 years. METHODS: This cross-sectional, observational study considered 587 RA patients from 67 Rheumatology Units across Italy. Data collected included demographic, clinical, and therapeutic characteristics, focusing on MTX prescription patterns (route of administration, dosing regimens, treatment duration, and discontinuation). RESULTS: As initial therapy, 90.6% of patients received one conventional synthetic Disease Modifying Anti Rheumatic Drug (csDMARD), with treatment started within the first 3 months from diagnosis in half of the patients. MTX was the first csDMARD in 46.2% of patients. The prevalent route of administration at diagnosis was the intramuscular (60.5%), while at study entry (baseline) 57.6% were receiving subcutaneous MTX. Patients who required a higher MTX dose at study entry were those who received a significantly lower starting MTX dose (P<0.001). Significantly higher MTX doses were currently required in men (P<0.001), current smokers (P=0.013), and overweight patients (P=0.028), whereas patients on oral therapy received significantly lower doses of MTX (P<0.001). CONCLUSIONS: The MARTE study confirms once again the potential of the proper use of MTX in the treatment of RA. Data from our study suggest that a higher dose of MTX should be used since the first stages in overweight patients, men, and smokers.
32702188 Variability in Glucocorticoid Prescribing for Rheumatoid Arthritis and the Influence of Pr 2021 Nov OBJECTIVE: Glucocorticoids are recommended for short-term use in rheumatoid arthritis (RA), but many patients continue receiving long-term therapy. We evaluated the variability in glucocorticoid prescribing across rheumatologists to inform interventions to limit long-term glucocorticoid use to the lowest dose necessary. METHODS: Two cohorts were created using Medicare data from 2006 to 2015. Using cohort 1 (RA patients receiving disease-modifying antirheumatic drugs [DMARDs]), we calculated each rheumatologist's "provider preference" for glucocorticoids (frequency of use compared to other providers), using the ratio of observed to expected number of patients receiving glucocorticoids to account for case mix. In cohort 2 (RA patients receiving stable DMARD therapy), we evaluated whether provider preference for glucocorticoids could independently predict use of ≥5 mg/day of glucocorticoids 6-9 months after initiation of DMARD therapy. RESULTS: Using cohort 1 (1,272,644 yearly observations; 385,597 patients), we calculated provider preference among 6,875 rheumatologists (28,936 yearly observations). Provider preference was highly variable, with physicians at the lowest and upper quartiles prescribing glucocorticoids 33% less often to 31% more often (25th and 75th percentiles, respectively) than expected. In cohort 2 (155,539 patients receiving stable DMARD therapy), provider preference was strongly associated with glucocorticoid use ≥5 mg/day at 6-9 months, with a predicted probability of use of 22% (95% confidence interval [95% CI] 21.7-22.7) versus 11% (95% CI 10.2-10.9) for a patient seeing a provider in the highest versus lowest quintile of preference. CONCLUSION: Glucocorticoid prescribing for RA varies greatly among rheumatologists, and provider preference is one of the strongest predictors of a patient's long-term glucocorticoid use. These findings raise quality of care concerns and highlight the need for stronger evidence to guide RA treatment.
33595870 Methotrexate Triglutamate as a Determinant of Clinical Response in Mexican Patients With R 2021 Aug Methotrexate is the gold standard treatment in rheumatoid arthritis. Once absorbed, it is internalized in cells, where glutamate residues are added to produce polyglutamated forms, which are responsible for the effect of methotrexate. The aim of the current study is to determine the relationship between methotrexate triglutamate concentrations and the clinical evolution in rheumatoid arthritis patients, as well as to characterize the variability in both features to propose strategies for low-dose methotrexate optimization. The quantification of methotrexate triglutamate concentration in red blood cells was performed through ultra-performance liquid chromatography coupled with mass spectrometry. Polymorphisms of genes involved in the formation of polyglutamates were determined by real-time polymerase chain reaction. A multivariate regression was performed to determine the covariates involved in the variability of methotrexate triglutamate concentrations and a population pharmacokinetics model was developed through nonlinear mixed-effects modeling. Disease activity score changed according to methotrexate triglutamate concentrations; patients with good response to treatment had higher concentrations than moderate or nonresponding patients. The methotrexate triglutamate concentrations were related to time under treatment, dose, red blood cells, and body mass index. A 1-compartment open model was selected to estimate the pharmacokinetic parameters; the typical total clearance (L/day) was determined as 1.45 * (body mass index/28 kg/m(2) ) * (red blood cells/4.6 × 10(6) cells/μL) and the volume of distribution was 52.4 L, with an absorption rate of 0.0346/day and a fraction metabolized of 1.03%. Through the application of the model, the initial dose of methotrexate is proposed on the basis of stochastic simulations and considering methotrexate triglutamate concentrations found in responders patients.
34585327 Autologous ATG-free hematopoietic stem cell transplantation for refractory autoimmune rheu 2022 Mar Autologous hematopoietic stem cell transplantation (HSCT) has been recognized as treatment alternative for patients with severe, refractory autoimmune rheumatic diseases (ARDs). Usually, anti-thymocyte globulin (ATG)-containing conditioning regimens are employed; however, ATG is unavailable in some developing nations. We report our 15-year clinical experience autografting patients with ARDs with an ATG-free conditioning regimen and a brief assessment of patient-reported outcomes post-HSCT. All patients had active disease and were resistant to multiple lines of treatment. Event-free survival (EFS) was assessed using the Kaplan-Meier method. Eight patients underwent autologous HSCT. Diagnoses included juvenile idiopathic arthritis (n = 3), systemic lupus erythematosus (n = 2), systemic sclerosis (n = 2), and rheumatoid arthritis (n = 1). Median time from diagnosis to HSCT was 3 years (0.75-19). Hematological recovery was documented in all recipients, and 4 patients (50%) completed the procedure in a completely ambulatory setting. Five (62.5%) patients achieved complete response and 3 (37.5%) partial response. The median EFS was 7 months (95% CI, 4.97-9.02), and the 1-year EFS rate was 21.9% (95% CI, 18.25-25.76). Transplant-related mortality was 0%, and 1 recipient died 8 years post-HSCT due to chronic kidney disease. Six (75%) patients presented steroid dosage reduction post-HSCT, and 2 (25%) perceived improvement in functionality despite having relapsed. HSCT is a viable treatment alternative for selected patients with severe therapy-resistant ARDs, as an improvement in disease management and quality of life was documented. The need remains to elucidate the characteristics of the optimal HSCT candidate, as well as the adequate conditioning regimen when ATG is not available. Key Points • Despite advances in the treatment of autoimmune rheumatic diseases, some patients remain refractory. In this context, autologous hematopoietic stem cell transplantation (HSCT) rises as a viable alternative. • Of 8 HSCT recipients with autoimmune rheumatic diseases, 5 (62.5%) patients achieved complete response and 3 (37.5%) partial response, with a 1-year event-free survival of 21.9%. • Transplant-related mortality was 0%, with 4 (50%) patients autografted in a completely outpatient setting. • Even when relapse presented, patients reported an improvement in functionality and quality of life; also, a better response to DMARDs and a reduction in steroid dependency post-HSCT were documented.
35095831 CD209/CD14(+) Dendritic Cells Characterization in Rheumatoid and Psoriatic Arthritis Patie 2021 Dendritic cells (DC) have a key role in the initiation and progression of inflammatory arthritis (IA). In this study, we identified a DC population that derive from monocytes, characterized as CD209/CD14(+) DC, expressing classical DC markers (HLADR, CD11c) and the Mo-DC marker (CD209), while also retaining the monocytic marker CD14. This CD209/CD14(+) DC population is present in the circulation of Healthy Control (HC), with increased frequency in Rheumatoid Arthritis (RA) and Psoriatic arthritic (PsA) patients. We demonstrate, for the first time, that circulatory IA CD209/CD14(+) DC express more cytokines (IL1β/IL6/IL12/TNFα) and display a unique chemokine receptor expression and co-expression profiles compared to HC. We demonstrated that CD209/CD14(+) DC are enriched in the inflamed joint where they display a unique inflammatory and maturation phenotype, with increased CD40 and CD80 and co-expression of specific chemokine receptors, displaying unique patterns between PsA and RA. We developed a new protocol of magnetic isolation and expansion for CD209(+) DC from blood and identified transcriptional differences involved in endocytosis/antigen presentation between RA and PsA CD209(+) DC. In addition, we observed that culture of healthy CD209(+) DC with IA synovial fluid (SF), but not Osteoarthritis (OA) SF, was sufficient to induce the development of CD209/CD14(+) DC, leading to a poly-mature DC phenotype. In addition, differential effects were observed in terms of chemokine receptor and chemokine expression, with healthy CD209(+) DC displaying increased expression/co-expression of CCR6, CCR7, CXCR3, CXCR4 and CXCR5 when cultured with RA SF, while an increase in the chemokines CCR3, CXCL10 and CXCL11 was observed when cultured with PsA SF. This effect may be mediated in part by the observed differential increase in chemokines expressed in RA vs PsA SF. Finally, we observed that the JAK/STAT pathway, but not the NF-κB pathway (driven by TNFα), regulated CD209/CD14(+) DC function in terms of activation, inflammatory state, and migratory capacity. In conclusion, we identified a novel CD209/CD14(+) DC population, which is active in the circulation of RA and PsA, an effect potentiated once they enter the joint. Furthermore, we demonstrated that JAK/STAT inhibition can be used as a therapeutic strategy to decrease the inflammatory state of the pathogenic CD209/CD14(+) DC.
34819488 Use of Monoclonal Antibodies Therapy for Treatment of Mild to Moderate COVID-19 in 4 Patie 2021 Nov 25 BACKGROUND The use of monoclonal antibodies therapy (MAT) in early mild to moderate Coronavirus disease 2019 (COVID-19) has gained importance in recent times. However, there is limited information on the safety and efficacy of MAT in treating COVID-19 in patients with underlying rheumatologic diseases. Patients with rheumatologic diseases are usually on long-term corticosteroids and immunosuppressive therapy, which increases their risk for progressing to more severe forms of COVID-19. We report a case series of 4 patients with rheumatologic diseases who were treated with MAT for COVID-19. MATERIAL AND METHODS A retrospective observational study was conducted in our institution on patients with underlying rheumatological disorders who received MAT as per the EUA protocol of the FDA. RESULTS Two of the 4 patients were on immunosuppresive therapy at the time of receiving MAT. They recovered from COVID-19 without any adverse outcomes. No flare of underlying rheumatologic disease was noted. CONCLUSIONS MAT was observed to be a safe and effective therapy in 4 patients with rheumatological illnesses and COVID-19 treated at our hospital.
34015588 Navigation-based analysis of associations between intraoperative joint gap and mediolatera 2021 Jun BACKGROUND: No data have demonstrated how joint gap measured under a distraction force is actually associated with mediolateral laxity evaluated under a varus-valgus force during total knee arthroplasty (TKA). This study aimed to investigate the correlations between them using a navigation system. METHODS: A total of 113 primary navigated TKAs were included. After bone resection and soft-tissue balancing, the component gap was measured with a distraction force of 60 N and 80 N for both the medial and lateral compartment (i.e. a total of 120 N and 160 N) at 0°, 10°, 30°, 60°, 90°, and 120° knee flexion. After the final prosthetic implantation and capsule closure, mediolateral laxity under a maximum varus-valgus stress was recorded with image-free navigation at each knee flexion angle. The correlation between joint gap laxity (total differences between component gap and insert thickness in the medial and lateral compartment) and mediolateral laxity was analyzed using Spearman's rank correlation coefficient. RESULTS: The joint gap laxity under both distraction forces showed significant positive correlations with mediolateral laxity at 10°, 30°, 60°, and 90° flexion, whereas no correlation was observed at extension and 120° flexion. The correlations were stronger in gap measurement under 80 N than 60 N at all examined ranges. In patients with body mass indexes (BMIs) ≥ 30 kg/m(2), the correlation became non-significant. CONCLUSION: Intraoperative joint gap laxity was associated with mediolateral laxity after TKA, especially at mid-flexion angles. The factors weakening the correlations were a lower applied distraction force for gap measurement and a larger BMI.
32963355 A shedding soluble form of interleukin-17 receptor D exacerbates collagen-induced arthrit 2021 Aug Rheumatoid arthritis (RA) is exacerbated by TNF-alpha signaling. However, it remains unclear whether TNF-α-activated TNFR1 and TNFR2 are regulated by extracellular factors. Here, we showed that soluble glycosylated interleukin-17 receptor D (sIL-17RD), which was produced by proteolytic cleavage, enhanced TNF-α-induced RA. We revealed that IL-17RD shedding was induced by the proteolytic enzyme TACE and enhanced by TNF-α expression in macrophages. Intriguingly, sIL-17RD was elevated in the sera of arthritic mice and rats. Recombinant sIL-17RD significantly enhanced the TNF-α-induced proinflammatory response by promoting TNF-α-TNFR-sIL-17RD complex formation and receptor clustering, leading to the accelerated development of collagen-induced arthritis. Our observations revealed that ectodomain shedding of IL-17RD occurred in RA to boost the TNF-α-induced inflammatory response. Targeting sIL-17RD may provide a new strategy for the therapy of RA.
34453079 Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheuma 2021 Aug 27 The presence or absence of autoantibodies against citrullinated proteins (ACPAs) distinguishes two main groups of rheumatoid arthritis (RA) patients with different etiologies, prognoses, disease severities, and, presumably, disease pathogenesis. The heterogeneous responses of RA patients to various biologics, even among ACPA-positive patients, emphasize the need for further stratification of the patients. We used high-density protein array technology for fingerprinting of ACPA reactivity. Identification of the proteome recognized by ACPAs may be a step to stratify RA patients according to immune reactivity. Pooled plasma samples from 10 anti-CCP-negative and 15 anti-CCP-positive RA patients were assessed for ACPA content using a modified protein microarray containing 1631 different natively folded proteins citrullinated in situ by protein arginine deiminases (PADs) 2 and PAD4. IgG antibodies from anti-CCP-positive RA plasma showed high-intensity binding to 87 proteins citrullinated by PAD2 and 99 proteins citrullinated by PAD4 without binding significantly to the corresponding native proteins. Curiously, the binding of IgG antibodies in anti-CCP-negative plasma was also enhanced by PAD2- and PAD4-mediated citrullination of 29 and 26 proteins, respectively. For only four proteins, significantly more ACPA binding occurred after citrullination with PAD2 compared to citrullination with PAD4, while the opposite was true for one protein. We demonstrate that PAD2 and PAD4 are equally efficient in generating citrullinated autoantigens recognized by ACPAs. Patterns of proteins recognized by ACPAs may serve as a future diagnostic tool for further subtyping of RA patients.
34201243 Irinotecan (CPT-11) Canonical Anti-Cancer Drug Can also Modulate Antiviral and Pro-Inflamm 2021 Jun 8 Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O'nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1β was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1β treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.
33611869 Preferences of inflammatory arthritis patients for biological disease-modifying antirheuma 2021 Aug 30 BACKGROUND/AIM: To evaluate treatment adherence and predictors of drug discontinuation among patients with inflammatory arthritis receiving bDMARDs within the first 100 days after the announcement of the COVID-19 pandemic. MATERIALS AND METHODS: A total of 1871 patients recorded in TReasure registry for whom advanced therapy was prescribed for rheumatoid arthritis (RA) or spondyloarthritis (SpA) within the 3 months (6–9 months for rituximab) before the declaration of COVID-19 pandemic were evaluated, and 1394 (74.5%) responded to the phone survey. Patients’ data regarding demographic, clinical characteristics and disease activity before the pandemic were recorded. The patients were inquired about the diagnosis of COVID-19, the rate of continuation on bDMARDs, the reasons for treatment discontinuation, if any, and the current general disease activity (visual analog scale, [VAS]). RESULTS: A total of 1394 patients (493 RA [47.3% on anti-TNF] patients and 901 SpA [90.0% on anti-TNF] patients) were included in the study. Overall, 2.8% of the patients had symptoms suggesting COVID-19, and 2 (0.15%) patients had PCR-confirmed COVID-19. Overall, 18.1% of all patients (13.8% of the RA and 20.5% of the SpA; p = 0.003) discontinued their bDMARDs. In the SpA group, the patients who discontinued bDMARDs were younger (40 [21–73] vs. 44 years [20–79]; p = 0.005) and had higher general disease activity; however, no difference was relevant for RA patients. CONCLUSION: Although the COVID-19 was quite uncommon in the first 100 days of the pandemic, nearly one-fifth of the patients discontinued bDMARDs within this period. The long-term effects of the pandemic should be monitored.
33661799 Superb Microvascular Imaging in Assessment of Synovitis and Tenosynovitis in Juvenile Idio 2021 Mar 1 The aim of this study is to evaluate the diagnostic utility of superb microvascular imaging (SMI) in assessment of synovitis/tenosynovitis in juvenile idiopathic arthritis in comparison to power Doppler ultrasound. Thirty juvenile idiopathic arthritis cases with active clinical findings and ultrasound features of effusion and/or tenosynovitis were further imaged with power Doppler and SMI. For classification of synovial inflammation, a semiquantitative scale (4 points) adopted by Outcome Measures in Rheumatology was used.A total of 35 knee, 2 hip, 2 ankle, 2 wrist, 2 elbow joints, and 6 flexor hallucis longus/tibialis posterior tenosynovitis were assessed. In knee joint, power Doppler and SMI scales were the same for 23 (65.7%) joints, SMI upgraded scale from 0 to 2 in single joint (2.9%); 1 to 2 (14.3%) in 5 joints; and 2 to 3 (17.1%) in 6 joints. For other joints, power Doppler and SMI scales were the same for 5 (62.5%) joints. Superb microvascular imaging upgraded scale from 1 to 2 (25%) in 2 joints and 1 to 3 (12.5%) in a single joint. For flexor hallucis longus/tibialis posterior tenosynovitis, power Doppler and SMI scales were the same for two cases (33.3%). Superb microvascular imaging upgraded scale from 0 to 2 in two cases (33.3%); and 2 to 3 (33.3%) in 2 cases. There was no case of SMI scale downgraded compared with power Doppler scale.Superb microvascular imaging is a feasible technique in the assessment of synovial inflammation and tenosynovitis in juvenile idiopathic arthritis. Superb microvascular imaging has higher sensitivity compared with power Doppler ultrasound in depiction of increased vascularity.
33452180 Patient-reported outcomes data in patients with psoriatic arthritis from a randomised tria 2021 Jan OBJECTIVES: We examined patient-reported outcomes (PROs) in The Study of Etanercept And Methotrexate in Patients with Psoriatic Arthritis (PsA); a 48-week, phase 3, randomised controlled trial that compared outcomes with methotrexate (MTX) monotherapy, etanercept monotherapy, and MTX+ etanercept in patients with PsA. METHODS: Efficacy endpoints included: mean changes from baseline and proportion of patients who reported improvements≥minimal clinically important difference (MCID) at week 24 in treatment groups for Health Assessment Questionnaire-Disability Index, Patient Global Assessment (PtGA), Patient Global Assessment of Joint Pain (PtGAJP) and Medical Outcomes Study Short Form-36 Questionnaire (SF-36) Physical Component Summary (PCS), and Mental Component Summary, and eight domain scores. PROs were analysed as reported (observed), without multiplicity adjustment; therefore, p values are descriptive. RESULTS: At week 24, patients receiving etanercept monotherapy or MTX+ etanercept combination reported greater improvements (p≤0.05) in PtGA, PtGAJP and SF-36 PCS scores compared with those receiving MTX monotherapy. Compared with MTX monotherapy, higher proportions of patients receiving etanercept monotherapy and combination therapy reported improvements≥MCID in PtGA (etanercept vs MTX, p=0.005) and PtGAJP (MTX +etanercept vs MTX, p=0.038). Across PROs, proportions of patients reporting scores≥age and gender-matched normative values at week 24 ranged from 20.8% to 51.0% with MTX monotherapy, 30.9% to 48.8% with etanercept monotherapy, and 30.6% to 52.3% with MTX+ etanercept combination. CONCLUSIONS: Patients receiving etanercept monotherapy or MTX+ etanercept reported greater improvements from baseline in several PROs compared with those receiving MTX monotherapy. PROs should be incorporated in discussions between patients and clinicians regarding their treatment choices as they can help determine which treatments are more beneficial in patients with PsA.
33973403 Cardiovascular Safety of Hydroxychloroquine in US Veterans With Rheumatoid Arthritis. 2021 Sep OBJECTIVE: Hydroxychloroquine (HCQ) may prolong the QT interval, a risk factor for torsade de pointes, a potentially fatal ventricular arrhythmia. This study was undertaken to examine the cardiovascular safety of HCQ in patients with rheumatoid arthritis (RA). METHODS: We conducted an active comparator safety study of HCQ in a propensity score-matched cohort of 8,852 US veterans newly diagnosed as having RA between October 1, 2001 and December 31, 2017. Patients were started on HCQ (n = 4,426) or another nonbiologic disease-modifying antirheumatic drug (DMARD; n = 4,426) after RA diagnosis, up to December 31, 2018, and followed up for 12 months after therapy initiation, up to December 31, 2019. RESULTS: Patients had a mean ± SD age of 64 ± 12 years, 14% were women, and 28% were African American. The treatment groups were balanced with regard to 87 baseline characteristics. There were 3 long QT syndrome events (0.03%), 2 of which occurred in patients receiving HCQ. Of the 56 arrhythmia-related hospitalizations (0.63%), 30 occurred in patients in the HCQ group (hazard ratio [HR] associated with HCQ 1.16 [95% confidence interval (95% CI) 0.68-1.95]). All-cause mortality occurred in 144 (3.25%) and 136 (3.07%) of the patients in the HCQ and non-HCQ groups, respectively (HR associated with HCQ 1.06 [95% CI, 0.84-1.34]). During the first 30 days of follow-up, there were no long QT syndrome events, 2 arrhythmia-related hospitalizations (none in the HCQ group), and 13 deaths (6 in the HCQ group). CONCLUSION: Our findings indicate that the incidence of long QT syndrome and arrhythmia-related hospitalization is low in patients with RA during the first year after the initiation of HCQ or another nonbiologic DMARD. We found no evidence that HCQ therapy is associated with a higher risk of adverse cardiovascular events or death.
33879239 IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 l 2021 Apr 20 BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.
34226947 In the era of disease-modifying antirheumatic drugs, how close are we to treating rheumato 2021 Nov We wanted to see how close we could get to our goal of treating rheumatoid arthritis (RA) without the use of glucocorticoids (GCs) in the disease-modifying antirheumatic drugs (DMARDs) era using real-life data. Established in 2017, the TReasure database is a web-based, prospective, observational cohort for Turkey. As of May 2019, there were 2,690 RA patients recorded as receiving biologic and targeted synthetic DMARDs (bDMARDs and tsDMARDs) therapy. At the start of the bDMARDs or tsDMARDs, patients with follow-up visits of at least 3 months were registered. At the time of registration and the last visit, doses of GCs were recorded and it was determined if the target dose of ≤ 7.5 mg was achieved. During registration and follow-up, 23.4% of the patients did not receive GCs and 76.5% of the patients received GCs at any time. GCs could be stopped after 59 (25-116) months in 28.4% of these patients, but 71.6% of patients were still using GC. The target GC dose could not be achieved in 18.2% of these patients (n = 352). The rate of continuing to use GC was significantly higher in women, in the elderly, those with rheumatoid factor (RF) positive, with higher Visual Analog Scale (VAS) pain and Disease Activity Score (DAS)-28. The initial GC dose of ≥ 7.5 mg/day was found to be crucial in not reaching the GC target dose (p < 0.001, OR 39.0 (24.1-63.2)). The initial GC dose of ≥ 7.5 mg/day, female gender, age, RF positivity, high DAS28, and VAS pain level were all highly related for GC continuation. Despite the use of DMARDs, our data revealed that we are still far from achieving our goal of treating RA without using steroids.
33982895 Interleukin-34 Reprograms Glycolytic and Osteoclastic Rheumatoid Arthritis Macrophages via 2021 Nov OBJECTIVE: In rheumatoid arthritis (RA), elevated serum interleukin-34 (IL-34) levels are linked with increased disease severity. IL-34 binds to 2 receptors, macrophage colony-stimulating factor receptor (M-CSFR) and syndecan 1, which are coexpressed in RA macrophages. Expression of both IL-34 and syndecan 1 is strikingly elevated in the RA synovium, yet their mechanisms of action remain undefined. This study was undertaken to investigate the mechanism of action of IL-34 in RA. METHODS: To characterize the significance of IL-34 in immunometabolism, its mechanism of action was elucidated in joint macrophages, fibroblasts, and T effector cells using RA and preclinical models. RESULTS: Intriguingly, syndecan 1 activated IL-34-induced M-CSFR phosphorylation and reprogrammed RA naive cells into distinctive CD14+CD86+GLUT1+ M34 macrophages that expressed elevated levels of IL-1β, CXCL8, and CCL2. In murine M34 macrophages, the inflammatory phenotype was accompanied by potentiated glycolytic activity, exhibited by transcriptional up-regulation of GLUT1, c-Myc, and hypoxia-inducible factor 1α (HIF-1α) and amplified pyruvate and l-lactate secretion. Local expression of IL-34 provoked arthritis by expanding the glycolytic F4/80-positive, inducible nitric oxide synthase (iNOS)-positive macrophage population, which in turn attracted fibroblasts and polarized Th1/Th17 cells. The cross-talk between murine M34 macrophages and Th1/Th17 cells broadened the inflammatory and metabolic phenotypes, resulting in the expansion of IL-34 pathogenicity. Consequently, IL-34-instigated joint inflammation was alleviated in RAG(-/-) mice compared to wild-type mice. Syndecan 1 deficiency attenuated IL-34-induced arthritis by interfering with joint glycolytic M34 macrophage and osteoclast remodeling. Similarly, inhibition of glycolysis by 2-deoxy-d-glucose reversed the joint swelling and metabolic rewiring triggered by IL-34 via HIF-1α and c-Myc induction. CONCLUSION: IL-34 is a novel endogenous factor that remodels hypermetabolic M34 macrophages and facilitates their cross-regulation with T effector cells to advance inflammatory bone destruction in RA.
33188421 Tuberculosis risk with biologics by screening-guided preventive strategy in rheumatoid art 2021 Jun 18 OBJECTIVES: We aimed to compare tuberculosis (TB) risk during biologics treatment between patients with RA who did (prophylaxis) and did not (non-prophylaxis) undergo chemoprophylaxis following pre-biologic latent TB screening in Korea of an intermediate TB burden. METHODS: Using the 2002-16 Korea National Health Insurance database, we conducted a cohort study examining TB risk, defined by International Classification of Diseases Tenth Revision codes plus anti-TB drugs, among RA patients initiating a biologic drug with and without chemoprophylaxis after screening triage for latent TB. To control baseline confounding, we used propensity score-based fine stratification (PSS) and weighting. Cox proportional hazards models estimated hazard ratios and 95% CIs comparing TB risk between the prophylaxis vs non-prophylaxis groups. RESULTS: The PSS-weighted study cohort (mean age 57.0 years; 81.3% female) included 2249 and 7225 RA patients in the prophylaxis and non-prophylaxis groups, respectively. During 2.42 years of biologics treatment, 118 patients developed TB with the incidence rate per 100 person-years of 0.33 in the prophylaxis and 0.63 in the non-prophylaxis groups. The PSS-weighted hazard ratio (95% CI) for TB associated with the prophylaxis was 0.52 (0.32, 0.86). During the follow-up time, the incidence rate of TB remained consistently low in the prophylaxis group but it was highest in the first year, then time-dependently declined in the non-prophylaxis group. CONCLUSION: This population-based cohort study warns that the current screening-based preventive strategy generates a substantially higher TB risk after biologics initiation among screening-negative patients compared with screening-positive patients receiving chemoprophylaxis, when the background TB burden is not low.