Background:
Despite advances in the treatment of rheumatoid arthritis (RA) and the wide range of therapies available, there is a percentage of patients whose treatment presents a challenge for ...clinicians due to lack of response to multiple biologic and target-specific disease-modifying antirheumatic drugs (b/tsDMARDs).
Objective:
To develop and validate an algorithm to predict multiple failure to biological therapy in patients with RA.
Design:
Observational retrospective study involving subjects from a cohort of patients with RA receiving b/tsDMARDs.
Methods:
Based on the number of prior failures to b/tsDMARDs, patients were classified as either multi-refractory (MR) or non-refractory (NR). Patient characteristics were considered in the statistical analysis to design the predictive model, selecting those variables with a predictive capability. A decision algorithm known as ‘classification and regression tree’ (CART) was developed to create a prediction model of multi-drug resistance. Performance of the prediction algorithm was evaluated in an external independent cohort using area under the curve (AUC).
Results:
A total of 136 patients were included: 51 MR and 85 NR. The CART model was able to predict multiple failures to b/tsDMARDs using disease activity score-28 (DAS-28) values at 6 months after the start time of the initial b/tsDMARD, as well as DAS-28 improvement in the first 6 months and baseline DAS-28. The CART model showed a capability to correctly classify 94.1% NR and 87.5% MR patients with a sensitivity = 0.88, a specificity = 0.94, and an AUC = 0.89 (95% CI: 0.74–1.00). In the external validation cohort, 35 MR and 47 NR patients were included. The AUC value for the CART model in this cohort was 0.82 (95% CI: 0.73–0.9).
Conclusion:
Our model correctly classified NR and MR patients based on simple measurements available in routine clinical practice, which provides the possibility to characterize and individualize patient treatments during early stages.
To evaluate the long-term efficacy of once-daily baricitinib 4 mg or 2 mg in patients with active rheumatoid arthritis who had inadequate response (IR) to MTX, csDMARDs, or bDMARDs.
Data from three ...completed phase III studies, RA-BEAM (MTX-IR), RA-BUILD (csDMARD-IR), and RA-BEACON (bDMARD-IR), and one completed long-term extension study (RA-BEYOND) were analyzed up to 6.5 years (340 weeks RA-BEAM and 336 weeks RA-BUILD and RA-BEACON). Low disease activity (LDA) (Simplified Disease Activity Index SDAI ≤11), clinical remission (SDAI ≤3.3), and physical function (Health Assessment Questionnaire Disability Index HAQ-DI ≤0.5) were the main outcomes assessed. Completer and non-responder imputation (NRI) analyses were conducted on each population.
At week 340 or 336, LDA was achieved in 37%/83% of MTX-IR, 35%/83% of csDMARD-IR, and 23%/73% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. Remission was achieved in 20%/40% of MTX-IR, 13%/32% of csDMARD-IR, and 9%/30% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively. HAQ-DI ≤0.5 was reached in 31%/51% of MTX-IR, 25%/46% of csDMARD-IR, and 24%/38% of bDMARD-IR patients treated with baricitinib 4 mg, assessed by NRI/completer analyses, respectively.
Treatment with baricitinib 4 mg or 2 mg demonstrated efficacy up to 6.5 years with maintained LDA/remission results across SDAI, CDAI and DAS28-hsCRP consistent with previously reported data, and was well tolerated.
Palindromic rheumatism (PR) is a form of relapsing/remitting arthritis that may evolve to chronic rheumatic disease, mainly rheumatoid arthritis (RA). The exact nature of PR is unclear, as it may be ...considered a disease in itself, an abortive form of RA or just a pre-RA stage.
The authors review the most relevant epidemiological and clinical aspects of PR, especially the pathogenetic role of autoimmunity in PR, with most patients having a characteristic autoantibody profile similar to that observed in RA. The role of autoinflammation is also discussed. A literature review on the rate of RA progression and its prognostic factors was analyzed. Data on the efficacy of drug therapies used to treat PR are presented. PubMed was searched using the terms 'palindromic rheumatism' OR 'palindromic arthritis'.
PR is a disease entity with a close but unclear relationship with RA. In PR there is an unmet need, which is to clarify the clinical spectrum and elucidate the risk factors for evolution to RA. The role of autoimmunity and the autoinflammatory component should be investigated. Since most patients evolve to RA, PR may display a unique therapeutic opportunity to avoid this evolution.
Purpose
Tocilizumab is a humanized monoclonal antibody approved for rheumatoid arthritis treatment. In clinical practice, empirical dose-tapering strategies are implemented in patients showing ...sustained remission or low disease activity (LDA) to avoid overtreatment and reduce costs. Since rational adaptive-dosing algorithms taking the full pharmacokinetic (PK)/pharmacodynamic (PD) characteristics into account are currently lacking, we aimed to develop novel tapering strategies and compare them with currently used empirical ones.
Methods
Four strategies were simulated on a virtual population. In all of them, the same initial dose was administered every 28 days for six consecutive months. Then, different strategies were considered: (1) label-dosing; (2) mild empirical dose-tapering; (3) intense empirical dose-tapering; (4) therapeutic drug monitoring (TDM)-guided dose-tapering. The different strategies were evaluated on the proportion of patients who maintain remission/LDA 1 year after the intervention. Cost-savings of direct drug costs were also estimated as relative dose intensity.
Results
The overall proportion of simulated patients in remission/LDA after 1 year of the intervention was comparable between the mild empirical and the TDM-guided dose-tapering strategies, and much lower for the intense empirical dose-tapering strategy (80.3%, 78.2%, and 69.0%, respectively). Likewise, 1-year flare rates were lower for the mild empirical and TDM-guided tapering strategies. The relative dose intensity was lowest for the intense empirical dose-tapering, followed by the TDM-guided and the mild empirical dose-tapering approaches (61.2%, 71.0%, and 80.4%, respectively).
Conclusion
We demonstrated that the TDM-guided strategy using model-based algorithms performed similarly to mild empirical dose-tapering strategies in overall remission/LDA rates but is superior in cost-savings.
Patients with rheumatoid arthritis (RA) in clinical remission may have ultrasound-defined synovitis according to the presence of power Doppler (PD) signal. The objective was to describe the ...immunopathologic characteristics of ultrasound-defined synovitis compared with synovitis in patients with clinically active RA.
We included between 6 and 8 ultrasound-guided synovial biopsies per patient from 20 patients with RA in clinical remission (DAS28-ESR <2.6) with PD signal, 22 synovial tissue samples (ST) from patients with clinically active RA (swollen joint with confirmed inflammatory synovial fluid) as inflammatory controls, and 10 ST from non-inflammatory controls. Immunostaining for CD3 (T lymphocytes), CD20 (B lymphocytes), CD68 (macrophages), CD117 (mast cells), hsp47 (fibroblasts), bFGF and CXCL12 (angiogenic factors) was made and quantified by digital image analysis. The number of CD31 vessels/mm(2) was quantified.
RA patients in remission with PD signal had significantly reduced synovial T-cell, B-cell, mast cell and fibroblast density, but similar macrophage infiltration compared with patients with clinically active RA. Vascularity, bFGF and CXCL12 were partially reduced in RA patients in remission with PD signal compared to those with active RA, but were significantly higher compared with ST from non-inflammatory controls. During the 12-month follow up, 8/20 RA patients (40 %) lost remission: all had synovial hypertrophy grade ≥2 and significantly more synovial B cells and mast cells than patients maintaining remission.
Asymptomatic ultrasound-defined synovitis and clinically active arthritis differ in the degree of infiltrating lymphoid, mast cells and fibroblast density, but are similar with respect to macrophage infiltration. Persistently increased angiogenic factor expression and vascularity may explain the persistence of a PD signal.
Aims
Tocilizumab has a direct effect on inflammatory markers. Therefore, composite measures for disease activity assessment in rheumatoid arthritis (RA) using these inflammatory markers may not be ...suitable for tocilizumab treatment. We used a modelling approach to describe the tocilizumab exposure‐response relationship and to investigate the different dynamics of the individual components of the routinely used continuous composite measures.
Methods
Pharmacokinetic (PK), clinical and laboratory data were obtained from a prospective, observational, single‐centre study involving 35 subjects with RA treated with intravenous tocilizumab. A population PK/pharmacodynamic analysis was performed using nonlinear mixed effects models.
Results
The population for model development comprised 1086, 1083 and 1082 observations calculated with the disease activity score based on 28 joint (DAS28) and the simplified and clinical disease activity scores (SDAI, CDAI). The tocilizumab exposure‐response relationship was described with an indirect‐response model. Two main groups of individual components were identified based on their different dynamics under tocilizumab treatment: (i) tender and swollen joint counts and patient and evaluator global assessment showed a slower decrease of their baseline value (half‐life: 4.6 weeks, RSE: 24%) and the need for higher serum drug concentration (EC50: 4.60 μg/mL, RSE: 103%, IIV: 359%) than (ii) C‐reactive protein and erythrocyte sedimentation rate (half‐life: 2.3 weeks, RSE 19%; EC50: 0.878 μg/mL, RSE: 41%, IIV: 238%).
Conclusion
Our study confirms a different dynamics of the individual components of the most frequently used continuous composite measures under tocilizumab treatment which should be taken into account to avoid misassessment of disease activity.
Objective
To compare long-term clinical, immunological, and radiographic outcomes between five sets of remission criteria (four clinical and one ultrasound (US)-based) in a cohort of RA patients in a ...clinical care setting.
Methods
RA patients in remission (DAS28-ESR <2.6) were selected. Hand US assessments were made, and serum levels of inflammation/angiogenesis biomarkers were determined at baseline. Changes in baseline treatment and radiographic progression, defined as the variation in the modified Sharp van der Heijde score (mSHS) at 5 years, were analyzed. Five concepts were used to define remission: DAS28-ESR<2.6, SDAI<3.3, CDAI<2.8, Boolean criteria and Power Doppler score (PD)=0.
Results
Eighty-seven patients with DAS28-ESR<2.6 were included. One-third fulfilled SDAI (33.3%), CDAI (31%), and Boolean (35.6%) remission criteria, and 25.3% had no PD signal in the US evaluation. 26 patients (29.9%) changed therapy, ranging from 13.6% (PD remission) to 33.3% (CDAI remission) (
p
=0.11). Serum levels of ANG (
p
=0.015) and TNFa (
p
=0.025) were significantly lower in patients with Boolean remission, whereas IL-18 levels were significantly lower in those with PD remission (
p
=0.049). Patients without PD in the US assessment had significantly-lower mSHS erosion progression (
p
=0.014) at 5 years.
Conclusions
Patients with established RA in DAS28-ESR remission had comparable clinical and radiographic outcomes in SDAI, CDAI, and Boolean definitions in a clinical care setting. US remission remained the closest to structural damage abrogation.
Key Points
•
This study provides real world data on long-term outcomes of five clinical and imaging remission criteria in rheumatoid arthritis.
•
DAS28-ESR remission criteria had comparable radiographic progression and clinical prognosis than more stringent criteria in clinical practice.
•
US-based remission was closest to structural damage abolishment.
The use of biologics has significantly changed the management of rheumatoid arthritis over the last decade, becoming the cornerstone treatment for many patients. The current therapeutic arsenal ...consists of just under 10 biologic agents, with four different mechanisms of action. Several studies have demonstrated a large interindividual pharmacokinetic variability, which translates to unpredictability in clinical response among individuals. The present review focuses on the pharmacokinetics and pharmacodynamics of biologic agents approved for rheumatoid arthritis. The literature relating to their concentration–effect relationship and the use of pharmacokinetic–pharmacodynamic modelling to optimize drug regimens is analysed. Due to the scarcity and complexity of these studies, the current dosing strategy is based on clinical indexes/aspects. In general, dose individualization for biologics should be implemented increasingly in clinical practice as there is a direct benefit for treated rheumatoid arthritis patients. Moreover, there is an indirect benefit in terms of cost‐effectiveness.
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