28-joint Disease Activity Score Research Articles

Does non-surgical periodontal treatment contribute to rheumatoid arthritis amelioration? Evidence based on an overview and meta-analysis.

The aim of the present study was to provide an overview evaluating the effects of non-surgical periodontal treatment in rheumatoid arthritis, focusing on 28-joint Disease Activity Score (DAS28), C-reactive protein, and erythrocyte sedimentation rate. Systematic reviews, with and without meta-analyses, comparing individuals who had undergone non-surgical periodontal treatment with those who had not, and assessing parameters before and after treatment, were included. Electronic searches were conducted in August 2023 and updated in August 2024 across four databases (PubMed, Scopus, Embase, and Web of Science) and gray literature, with no restriction on language or publication date. The study followed the 2020 PRISMA statement, and a protocol was registered in PROSPERO (CRD42023414714). A total of 10 systematic reviews were included: six with meta-analyses and four without meta-analyses. The number of articles included ranged from three to 31 studies. Non-surgical periodontal treatment resulted in a significant decrease in C-reactive protein, erythrocyte sedimentation rate, and DAS28. The follow-up period after treatment ranged from six to 24weeks. A meta-analysis was conducted, incorporating data from 18 primary studies identified in the systematic reviews and comparing the difference in DAS28 at baseline (n = 454) and up to three months (n = 449) after the non-surgical periodontal treatment. A significant reduction in DAS28 was observed (MD = -0.76; 95% CI = -1.07 to -0.44). Despite the heterogeneity of data related to rheumatoid arthritis and periodontitis status, non-surgical periodontal treatment can result in a decrease in the concentration of circulating inflammatory mediators and, consequently, in a reduction in DAS28 in rheumatoid arthritis.

Ivarmacitinib, a selective Janus kinase 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis and inadequate response to conventional synthetic DMARDs: results from a phase III randomised clinical trial

ObjectiveTo assess the efficacy/safety of ivarmacitinib, a selective Janus kinase (JAK) 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic disease-modifying...

Therapeutic serum level for adalimumab in rheumatoid arthritis: explorative analyses of data from a randomised phase III trial

ObjectivesThe objectives of this study are to identify a therapeutic serum level for adalimumab associated with remission and low disease activity in patients with rheumatoid arthritis.MethodsAssociations between serum adalimumab trough...

Remote patient-reported outcome measure triage score for monitoring disease activity and allocation of consultations in rheumatoid arthritis patients

Objective Currently, expedited by the coronavirus disease 2019 pandemic, there is high demand for allocating patients in a state of low disease activity to telehealth, ideally based on remote measurements. This cross-sectional study assesses the discriminative accuracy of the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire regarding high and low disease activity. Furthermore, we aimed to optimize this classification, developing a remote triage score based on RAID and other patient-reported outcome measures (PROMs). Method Data were acquired from an outpatient clinic cohort of chronic rheumatoid arthritis patients at a large trainee hospital in the Netherlands. Patients were divided into high and low disease categories, based on 28-joint Disease Activity Score–C-reactive protein. Least absolute shrinkage and selection operator logistic regression were performed, including RAID item scores and other PROMs. Receiver operating characteristics curves and areas under the curve (AUCs) were obtained, and cut-off scores were based on predefined criteria of 90% and 95% sensitivity. Results In total, 278 patients were analysed, of whom 77.2% were identified as having low disease activity. RAID results correlated with DAS28-CRP, showing good performance. The regression model included the RAID items pain and functional disability assessment, and the self-reported swollen joint count (SR-SJC). With an AUC of 0.88 (95% confidence interval 0.84–0.92), this model performed better than the RAID total score. Conclusion A remote triage score based on a composite score of pain, functional disability assessment, and SR-SJC can detect a sufficient proportion of patients with low disease activity who can be allocated to remote consultations.

Expression of lncRNAs NEAT1, PACERR, and GAS5 can be associated with disease activity in rheumatoid arthritis patients.

Long non-coding RNAs (lncRNAs) have long been considered molecular noise within the transcriptome, but over time it has been shown that they perform many important biological functions and are associated with various inflammatory and autoimmune diseases, including rheumatoid arthritis (RA). The aim of this study was to evaluate the association between circulating lncRNAs and RA activity. The study included 63 patients with well-established RA (median disease duration 12 years), 51.7 (13); mean (SD) aged, 88.9% women and 25 healthy controls (HCs) 51.8 (8.2) aged, 80% women. Quantitative real-time polymerase chain reaction was used to evaluate the plasma concentration levels of 6 lncRNAs: PACERR, NEAT1, HOTTIP, GAS5, MALAT1 and HIX003209. Among the tested molecules, 5 targets (PACERR, NEAT1, HOTTIP, GAS5 and HIX003209) had decreased concentration in RA patients compared to HCs. LncRNAs NEAT1, PACERR, and GAS5 showed differences between the severe disease activity group (the 28 joint disease activity score, DAS28>5.1) and HCs; (P = 0.02, P = 0.003 and P = 0.04, respectively). The multiple linear regression analysis indicated that GAS5 (P = 0.01) had the greatest impact on disease activity based on DAS28. Circulating plasma lncRNAs may be considered as supporting molecular markers associated with RA activity and may be useful in identifying disease exacerbation.

Understanding Ultrasound Power Doppler Synovitis at Clinically Quiescent Joints and Thermographic Joint Inflammation Assessment in Patients with Rheumatoid Arthritis.

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthritis. We aim to study subclinical PD synovitis and thermographic joint inflammation assessment in patients with RA. Methods: We compared (1) PD synovitis at clinically quiescent (non-swollen; non-tender) joints based on patients' disease activity and (2) thermography (hands/wrists) outcomes based on PD joint inflammation findings and patient's disease activity. Results: Among eighty RA patients (mean (SD) age 57.0 (12.6) years; 61 of whom (76.3%) were female), the wrists (62.7%), second metacarpophalangeal joints (MCPJs) (37.0%), third MCPJs (33.8%), fourth MCPJs (24.8%), and fifth MCPJs (20.9%) were the five joint sites most frequently displaying subclinical PD synovitis; with no statistically significance differences (p > 0.05) between patients with 28-joint disease activity score (DAS28) < 3.2 versus those with DAS28 ≥ 3.2. At these five joint sites bilaterally, (1) the total maximum (Total Tmax), total average (Total Tavg), and total minimum (Total Tmin) temperatures were significantly greater (p < 0.05) for Total PD (TPD) score >1 versus TPD score ≤ 1, while their area under the ROC curve (AUC) values in identifying TPD score >1 ranged from 0.789 to 0.810, and (2) Total Tmax, Total Tavg, Total Tmin, and TPD score were significantly greater (p < 0.05) for patients with DAS28 ≥ 3.2 versus those with DAS28 < 3.2. Conclusions: Our results would serve as useful background data in studies on RA monitoring strategies detecting subclinical PD synovitis. Thermographic temperatures were greater in patients with greater disease activity and can help discriminate ultrasound PD joint inflammation severity.

Contribution of inflammation markers and quantitative sensory testing (QST) indices of central sensitisation to rheumatoid arthritis pain.

Pain, the primary complaint in rheumatoid arthritis (RA), is multifaceted, and may be driven by inflammatory disease activity and central sensitisation. We aimed to ascertain what proportion of RA pain severity is explained by markers of inflammation and quantitative sensory testing (QST) indices of central sensitisation. This was a cross-sectional analysis of data from individuals with clinically active RA. Pain severity was assessed using numerical rating scales and inflammation via 28-joint Disease Activity Score (DAS28) and Ultrasound (Greyscale, Power Doppler). Pain sensitivity was assessed by 'static' (tibialis anterior or brachioradialis pressure pain detection threshold-PPT-TA/PPT-BR) and 'dynamic' (temporal summation-TS, conditioned pain modulation-CPM) QST. Bivariate associations used Spearman's correlation coefficients, and multivariable linear regression models determined relative contributions to pain severity. In bivariate analyses of N = 96 (age 65 ± 10y, 77% females) people with RA, pain severity was significantly associated with inflammation indices (r = 0.20 to 0.55), and CPM (r=-0.26). In multivariable models that included TS, CPM, age, sex, and body mass index, inflammation indices remained significantly associated with pain severity. Multivariable models explained 22 to 27% of pain variance. Heterogeneity was apparent for associations with pain between subscores for pain now, strongest or average over the past 4-weeks. In individuals with clinically active RA, markers of inflammatory disease activity best explain RA pain with only marginal contributions from QST indices of central sensitisation. Although inflammation plays a key role in the experience of RA pain, the greater proportion of pain severity remains unexplained by DAS28 and ultrasound indices of inflammation.

Elevated remnant cholesterol as a potential predictor for cardiovascular events in rheumatoid arthritis patients.

The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) remains inadequately defined. Consequently, this study aims to evaluate the predictive value of remnant cholesterol (RC) for assessing CVD risk in RA patients. Plasma RC levels were measured in 114 RA patients and 41 healthy controls, calculated as total cholesterol minus HDL-C and LDL-C. These levels were further analyzed using 1H-NMR lipid/metabolomics. Meanwhile, the 28-joint Disease Activity Score (DAS28) assessed RA activity. RC levels were significantly elevated in RA patients (19.0 mg/dl, p < 0.001) compared to healthy controls (14.5 mg/dl). Furthermore, RC levels were significantly elevated at 37.4 mg/dl in patients who experienced cardiovascular event (CVE) compared to 17.4 mg/dl in those without CVE (p < 0.001). To enhance the precision and reliability of RC measurements, RC concentrations were further validated using 1H-NMR spectroscopy. Additionally, a positive correlation was observed between RC levels and DAS28. Multivariate analysis identified RC as a significant predictor of CVE (odds ratio = 1.82, p = 0.013). ROC curve analysis revealed superior predictive capability of RC for CVE (AUC = 0.919, p < 0.001) compared to LDL-C (AUC = 0.669, p = 0.018), with a high sensitivity of 94.7% and a specificity of 82.1%. Elevated RC levels demonstrate greater accuracy in predicting CVE occurrence in RA patients compared to traditional measures such as LDL-C. These findings suggest that elevated RC levels may serve as a novel predictor for occurrence of CVE in RA patients, facilitating early intervention strategies based on the risk stratification.

Correlations between ultrafast power Doppler perfusion imaging variables and clinical disease activity in rheumatoid arthritis: potential applications for diagnosing and treating patients in deep clinical remission.

This study aimed to evaluate the ability of ultrafast power Doppler (PD) to assess disease activity in rheumatoid arthritis (RA) by examining the correlations between variables from ultrafast PD perfusion imaging and clinical measures of disease activity. Thirty-three RA patients underwent clinical assessments of disease activity and ultrasound scans of bilateral wrists using both ultrafast and conventional PD systems. A spatial singular value decomposition filter was applied to the ultrafast PD imaging. Singular vectors representing perfusion and fast flows were selected to produce perfusion images. All images were quantitatively analyzed with computer assistance and scored semiquantitatively (0-3) by a physician for synovial vascularity. The Pearson correlation coefficients between image variables and clinical indices were calculated. The correlation coefficients ranged from weakly to moderately positive between ultrafast PD variables and clinical indices (r=0.221-0.374, all P<0.05). The strongest correlations were observed for synovial PD brightness with the 28-joint Disease Activity Score based on C-Reactive Protein (DAS28-CRP) and the Simplified Disease Activity Index (SDAI). In patients within the deep clinical remission (dCR) subgroup, synovial PD brightness showed stronger correlations with DAS28-CRP, the Clinical Disease Activity Index, and SDAI (r=0.578-0.641, all P<0.001). The correlation coefficients between conventional PD variables and clinical indices were similar to those observed with ultrafast PD variables. Ultrafast PD imaging effectively extracts capillary blood signals and generates perfusion images. In the RA population, ultrafast PD variables exhibit weak-to-moderate correlations with clinical indices, with these correlations being notably stronger in dCR patients.

Effect of abatacept versus conventional synthetic disease modifying anti-rheumatic drugs on rheumatoid arthritis-associated interstitial lung disease.

To compare the effects of abatacept and conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the progression and development of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This multi-center retrospective study included RA patients receiving abatacept or csDMARDs who underwent at least two pulmonary function tests and/or chest high-resolution computed tomography (HRCT). We compared the following outcomes between the groups: progression of RA-ILD, development of new ILD in RA patients without ILD at baseline, 28-joint Disease Activity Score with the erythrocyte sedimentation rate (DAS28-ESR), and safety. Longitudinal changes were compared between the groups by using a generalized estimating equation. The study included 123 patients who were treated with abatacept (n = 59) or csDMARDs (n = 64). Nineteen (32.2%) and 38 (59.4%) patients treated with abatacept and csDMARDs, respectively, presented with RA-ILD at baseline. Newly developed ILD occurred in one patient receiving triple csDMARDs for 32 months. Among patients with RA-ILD at baseline, ILD progressed in 21.1% of cases treated with abatacept and 34.2% of cases treated with csDMARDs during a median 21-month follow-up. Longitudinal changes in forced vital capacity and diffusing capacity for carbon monoxide were comparable between the two groups. However, the abatacept group showed a more significant decrease in DAS28-ESR and glucocorticoid doses than csDMARDs group during the follow-up. The safety of both regimens was comparable. Abatacept and csDMARDs showed comparable effects on the development and stabilization of RA-ILD. Nevertheless, compared to csDMARDs, abatacept demonstrated a significant improvement in disease activity and led to reduced glucocorticoid use.

The Association between the Response to Rituximab with Sociodemographic Data and Disease Characteristics Among a Sample of Iraqi Patients with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Rituximab (RTX), a monoclonal antibody with anti-CD20 action, is now used as a treatment. Even with proper RTX use, some patients showed variations in response. Objective: To assess the association of different sociodemographic data and disease characteristics with RTX responsiveness in RA patients. Methods: A cross-sectional study was conducted in the Specialized Center of Rheumatology at Baghdad Teaching Hospital in Baghdad, Iraq. The study included 90 RA patients who received a 1000mg RTX intravenous infusion for at least six months. The collected sociodemographic data included age, gender, smoking status, body mass index (BMI), disease characteristics such as co-morbidities, and the use of previous biological agents. The activity of RA was assessed by the 28-joint Disease Activity Score (DAS28) and Clinical Disease Activity Index (CDAI). Results: Upon measuring the DAS28, the enrolled patients were divided into RTX responders (50 patients) and RTX non-responders (40 patients). Patients with a family history of RA were significantly higher in the RTX responders (21% versus 2% in the non-responders group). The responders had a significantly longer RA duration (p=0.030).The mean of CDAI and DAS28 were significantly higher in patients with no family history of RA than in those with a family history of RA. Conclusions: Disease duration, family history, and the use of previous biological agents could be considered as possible predictors of response to RTX, thereby saving time and treatment costs.

Correlation between Serum Levels of Factor I, CD59, Interferon-gamma, and Interleukin-6 with the Response to Rituximab in Iraqi Patients with Rheumatoid Arthritis

Background: Rituximab is a chimeric IgG1 kappa immunoglobulin that has been genetically modified to incorporate human constant region sequences together with murine light- and heavy-chain variable region sequences. People use it to treat rheumatoid arthritis and certain malignancies. Objective: The study aimed to assess the potential association between the serum levels of Factor I, CD59, interleukins (IL)-6, and interferon-gamma (IFN)-γ and the response to Rituximab treatment in Iraqi rheumatoid arthritis patients. Methods: A cross-sectional study was conducted at the rheumatology center at Baghdad Teaching Hospital. Ninety adult patients who have been diagnosed with rheumatoid arthritis and are receiving Rituximab intravenous infusions were included. The enrolled patients were divided into a responder group (45 patients) and a non-responder group (45 patients). The response to Rituximab was assessed according to the 28-joint Disease Activity Score (DAS28). Results: The serum levels of Factor I and CD59 were significantly higher in the non-responders group in comparison to the responders group. In addition, the serum IL-6 and IFN-γ levels were significantly elevated in the non-responders group in comparison to the responders group. The estimated marker serum levels showed a strong, significant correlation with the 6-month change in DAS28. Conclusions: In Rituximab nonresponder RA patients, serum levels of Factor I, CD59, Factor H, IL-6, and IFN-γ are higher, and they have good potential to be used in the assessment of the response to Rituximab therapy.

Comparing DAPSA, DAPSA28, and DAS28-CRP in Patients With Psoriatic Arthritis Initiating a First Tumor Necrosis Factor Inhibitor Across Nine European Countries.

Because 66/68 joint counts are not always performed in routine care, we aimed to determine which of the modified 28-joint disease activity index for psoriatic arthritis (DAPSA28) or 28-joint disease activity score with C-reactive protein (DAS28-CRP) should be preferred for monitoring disease activity in psoriatic arthritis (PsA) when the original DAPSA (66/68 joints) is not available. Prospectively collected real-world data of European bionaive patients with PsA initiating a first tumor necrosis factor inhibitor were pooled. Remission and response status were evaluated at 6 months by remission (DAPSA ≤ 4, DAPSA28 ≤ 4, and DAS28-CRP < 2.6), response (75% improvement for DAPSA and DAPSA28), and combined EULAR good/moderate responses for DAS28-CRP. Logistic regression analyses on multiple imputed data were used to identify baseline predictors. Remission and response cohorts included 3,159 and 1,866 patients, respectively. The 6-month proportions achieving remission/response were DAPSA (27%/44%), DAPSA28 (28%/44%), and DAS28-CRP (59%/80%). Of 14 possible baseline predictors, 11 predicted both DAPSA and DAPSA28 remission (8 of which also predicted their response, indicated by "*"): longer disease duration*, male sex*, and higher CRP* were positive, whereas older age*, higher body mass index*, patient fatigue*, and global, physician global, health assessment questionnaire score*, and tender and swollen* joint counts were negative predictors. Eight and five of these predicted DAS28-CRP remission and response, respectively. In patients with PsA, DAPSA28 should be preferred over DAS28-CRP as a substitute for DAPSA when 66/68 joint counts are not available because of the large overlap in remission and response status and in predictors between DAPSA and DAPSA28.

Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial

ObjectivesTo investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction...

Extensive study of CCN4, VCAM-1, MMP-3, and GM-CSF as reliable markers for disease activity in rheumatoid arthritis

BackgroundThe involvement of Wnt-1-induced secreted protein-1 (WISP1/CCN4) in several inflammatory reaction has recently been proposed. Nevertheless, this protein's involvement in rheumatoid arthritis (RA) remains debated. Associations between poorly diagnosed RA and several classical markers derived from demography and biochemistry have been reported. AimWe sought to investigate the reliability and effectiveness of serum concentrations of CCN4, vascular cell adhesion molecule-1 (VCAM-1), matrix melloprotenase-3 (MMP-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in monitoring and predicting RA and bone damage, and their correlation with RA disease course. MethodsThe study analyzed 128 patients with RA, comprising 68 newly diagnosed and 60 previously diagnosed patients, as well as 60 controls. Biomarker levels were measured with enzyme linked immuno-sorbent assays. Routine laboratory parameters such as serological, clinical, biochemical, and hematological parameters were additionally measured. Demography, anthropometry, and clinical symptom data were collected through interviews and a questionnaire. The joint disease activity score 28 (DAS28) was used to determine disease activity. ResultsConcentrations of four biomarkers were significantly higher in the RA group than the healthy controls. Elevated biomarker concentrations were also observed in patients with high, rather than moderate or low, DAS28-ESR activity status, except for monocyte count, hematocrit (%), and urea level. Furthermore, CCN4 level positively correlated with VCAM-1, MMP-3, and GM-CSF levels, DA-S28-CRP and DAS28-ESR. The levels of three predictive markers, CCN4, VCAM-1, and MMP-3, were elevated in non-treated patients, whereas GM-CSF level showed no difference. The highest area under the curve was 73.3% for CCN4, with 93.3% sensitivity and 64.7% specificity. ConclusionOur data suggest that CCN4 can be reliably used to indicate activity and therapeutic response associated with RA, thus facilitating earlier RA diagnosis.

Long-term sustainability of response to upadacitinib among patients with active rheumatoid arthritis refractory to biological treatments: results up to 5 years from SELECT-BEYOND

ObjectiveTo evaluate the long-term sustainability of response to the Janus kinase inhibitor upadacitinib among patients with rheumatoid arthritis and an inadequate response or intolerance to biological disease-modifying antirheumatic drugs (bDMARD-IR)...

Biological use influences the impact of inflammation on risk of major adverse cardiovascular events in rheumatoid arthritis

ObjectivesChronic inflammation promotes cardiovascular risk in rheumatoid arthritis (RA). Biological disease-modifying antirheumatic drugs (bDMARDs) improve disease activity and cardiovascular disease outcomes. We explored whether bDMARDs influence the impact of disease...

Diagnostic Value of Interleukin 6, Interleukin 12P70, Serum Amyloid A, and Procalcitonin for Rheumatoid Arthritis and Their Relationship With the Disease Activity

To observe the diagnostic value of four serum inflammatory biomarkers, including interleukin 6 (IL-6), interleukin 12P70 (IL-12P70), serum amyloid A (SAA), and procalcitonin (PCT), in rheumatoid arthritis (RA) and to analyze their relationship with the disease activity. The study included 60 RA patients admitted to the Department of Rheumatology at Anhui Provincial Hospital of Traditional Chinese Medicine between December 2022 and December 2023. Thirty healthy individuals from the hospital's physical examination center served as the control group. Serum levels of IL-6 and IL-12P70 were detected using flow cytometry. SAA levels were determined by immunoturbidimetry, and PCT levels were assessed by chemiluminescence. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anticyclic citrullinated peptide (ACCP) were detected using an automated biochemical analyzer. The 28-joint disease activity scores (DAS28-ESR) based on ESR were observed. Statistical analysis included t-tests, rank-sum tests, and Kruskal-Wallis H tests to compare the expression differences of the biomarkers among different groups. The diagnostic value of these biomarkers for RA was analyzed by ROC curve analysis. Spearman correlation analysis was performed to assess the relationships between the four inflammatory biomarkers and CRP, ESR, RF, ACCP, and DAS28-ESR. 1) The expression levels of SAA, IL-6, and IL-12P70 in the RA group were significantly higher than those in the control group (P<0.01). 2) ROC curve analysis showed that the area under the curve (AUC) for PCT was 0.611 (95% confidence interval [CI]: 0.488-0.735, P>0.05), for SAA, it was 0.819 (95% CI: 0.733-0.906, P<0.01), for IL-6, it was 0.875 (95% CI: 0.803-0.946, P<0.01), and for IL-12P70, it was 0.832 (95% CI: 0.746-0.917, P<0.01). The combined index of IL-6, IL-12P70, SAA, and PCT had an AUC of 0.973 (95% CI: 0.942-1.000, P<0.01). This indicates that the four inflammatory biomarkers can assist in the diagnosis of rheumatoid arthritis. 3) The expression levels of PCT and SAA varied significantly among the high, moderate, and low activity RA groups (P<0.01). 4) In RA patients, CRP was positively correlated with SAA (rs =0.75, P<0.01), and IL-6 (rs =0.52, P<0.01). ESR was positively correlated with SAA (rs =0.36, P<0.01). DAS28-ESR was positively correlated with PCT (rs =0.34, P=0.01), SAA (rs =0.51, P<0.01) and IL-6 (rs =0.33, P=0.01). The four inflammatory biomarkers (PCT, SAA, IL-6, and IL-12P70) are closely related to rheumatoid arthritis disease activity and can serve as serum indicators to assist in the diagnosis and assessment of RA.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.

Thesafety and efficacy of upadacitinib 15mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. Thesafety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n =277/309) that initially received ABA. Of patients on UPA15 in the LTE (n =547), 28.3% (n =155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in theAmerican College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in theHealth Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n =263/303, 86.8%; ABA to UPA15: n =273/309, 88.3%) showed similar responses to the total population. The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.

Pharmacokinetic-pharmacodynamic modelling and simulation of methotrexate dosing in patients with rheumatoid arthritis.

To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component. An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). Every 40 nmol/L increase in ery-MTX-PG3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.