Concomitant prednisone may alleviate methotrexate side-effects in rheumatoid arthritis patients.

OBJECTIVES: To evaluate whether addition of low-moderate dose prednisone to methotrexate (MTX) treatment can alleviate common MTX side-effects in rheumatoid arthritis (RA) patients. METHODS: We performed a post-hoc analysis of the CAMERA-II trial which randomized (1:1) 236 early DMARD and prednisone naive RA patients to treatment with MTX + prednisone 10 mg daily, or MTX monotherapy during two years. MTX dose was increased using a treat-to-target approach. We used Generalized Estimating Equations to model the occurrence of common MTX side-effects and of any adverse event over time, controlling for disease activity and MTX dose over time and other possible predictors of adverse events. To assess whether a possible effect was prednisone-specific, we performed the same analysis in the U-ACT-EARLY trial, in which the addition of tocilizumab (TCZ) to MTX was compared to MTX monotherapy in a comparable setting. RESULTS: MTX side-effects were reported at 5.9% of visits in the prednisone-MTX group, compared to 11.2% in the MTX monotherapy group. After controlling for MTX dose and disease activity over time, treatment duration, age, sex, and baseline transaminase levels, addition of prednisone significantly decreased the occurrence of MTX side-effects (OR: 0.54, CI: 0.38-0.77, p = 0.001). Specifically, the occurrence of nausea (OR 0.46, CI: 0.26-0.83, p = 0.009)) and elevated ALT/AST (OR 0.29, CI: 0.17-0.49, p < 0.001) was decreased. There was a trend towards fewer overall adverse events in the prednisone-MTX arm (OR: 0.89, CI: 0.72-1.11, p = 0.30). No difference in MTX side-effects was found between TCZ-MTX and MTX monotherapy in U-ACT-EARLY (OR 1.05, CI: 0.61-1.80, p = 0.87). CONCLUSION: Addition of 10 mg prednisone daily to MTX treatment in RA patients may ameliorate MTX side-effects, specifically nausea and elevated ALT/AST.

What is the best target in a treat-to-target strategy in rheumatoid arthritis? Results from a systematic review and meta-regression analysis.

OBJECTIVES: A treat-to-target (T2T) strategy has been shown to be superior to usual care in rheumatoid arthritis (RA), but the optimal target remains unknown. Targets are based on a disease activity measure (eg, Disease Activity Score-28 (DAS28), Simplified Disease Activity Indices/Clinical Disease Activity Indices (SDAI/CDAI), and a cut-off such as remission or low disease activity (LDA). Our aim was to compare the effect of different targets on clinical and radiographic outcomes. METHODS: Cochrane, Embase and (pre)MEDLINE databases were searched (1 June 2022) for randomised controlled trials and cohort studies after 2003 that applied T2T in RA patients for ≥12 months. Data were extracted from individual T2T study arms; risk of bias was assessed with the Cochrane Collaboration tool. Using meta-regression, we evaluated the effect of the target used on clinical and radiographic outcomes, correcting for heterogeneity between and within studies. RESULTS: 115 treatment arms were used in the meta-regression analyses. Aiming for SDAI/CDAI-LDA was statistically superior to targeting DAS-LDA regarding DAS-remission and SDAI/CDAI/Boolean-remission outcomes over 1-3 years. Aiming for SDAI/CDAI-LDA was also significantly superior to DAS-remission regarding both SDAI/CDAI/Boolean-remission (over 1-3 years) and mean SDAI/CDAI (over 1 year). Targeting DAS-remission rather than DAS-LDA only improved the percentage of patients in DAS-remission, and only statistically significantly after 2-3 years of T2T. No differences were observed in Health Assessment Questionnaire and radiographic progression. CONCLUSIONS: Targeting SDAI/CDAI-LDA, and to a lesser extent DAS-remission, may be superior to targeting DAS-LDA regarding several clinical outcomes. However, due to the risk of residual confounding and the lack of data on (over)treatment and safety, future studies should aim to directly and comprehensively compare targets. PROSPERO REGISTRATION NUMBER: CRD42021249015.

A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis.

AIMS: In immune-mediated inflammatory diseases (IMIDs), early symptom control is a key therapeutic goal. Methotrexate (MTX) is the first-line treatment across IMIDs. However, MTX is underutilized and suboptimally dosed, partly due to the inability of making individualized treatment decisions through therapeutic drug monitoring (TDM). To implement TDM in clinical practice, establishing a relationship between drug concentration and disease activity is paramount. In this meta-analysis, we investigated the relationship between concentrations of MTX polyglutamates (MTX-PG) in erythrocytes and efficacy as well as toxicity across IMIDs. METHODS: Studies analysing MTX-PG in relation to disease activity and/or toxicity were included for inflammatory arthritis (rheumatoid [RA] and juvenile idiopathic arthritis [JIA]), inflammatory bowel disease (Crohn's and ulcerative colitis) and dermatitis (psoriasis and atopic dermatitis). Meta-analyses were performed resulting in several summary effect measures: regression coefficient (ß), correlation coefficient and mean difference (of MTX-PG in responders vs. nonresponders) for IMIDs separately and collectively. RESULTS: Twenty-five studies were included. In RA and JIA, higher MTX-PG was significantly associated with lower disease activity at 3 months (ß: -0.002; 95% confidence interval [CI]: -0.004 to -0.001) and after 4 months of MTX use (ß: -0.003; 95% CI: -0.005 to -0.002). Similarly, higher MTX-PG correlated with lower disease activity in psoriasis (R: -0.82; 95% CI: -0.976 to -0.102). Higher MTX-PG was observed in RA, JIA and psoriasis responders (mean difference: 5.2 nmol/L MTX-PGtotal ; P < .01). CONCLUSION: We showed that higher concentrations of erythrocyte MTX-PG were associated with lower disease activity in RA, JIA and psoriasis. These findings are an important step towards implementation of TDM for MTX treatment across IMIDs.

TOFA-PREDICT study protocol: a stratification trial to determine key immunological factors predicting tofacitinib efficacy and drug-free remission in psoriatic arthritis (PsA).

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease that affects up to 30% of patients with psoriasis. Current challenges in clinical care and research include personalised treatment, understanding the divergence of therapy response and unravelling the multifactorial pathophysiology of this complex disease. Moreover, there is an urgent clinical need to predict, assess and understand the cellular and molecular pathways underlying the response to disease-modifying antirheumatic drugs (DMARDs). The TOFA-PREDICT clinical trial addresses this need. Our primary objective is to determine key immunological factors predicting tofacitinib efficacy and drug-free remission in PsA. METHODS AND ANALYSIS: In this investigator-initiated, phase III, multicentre, open-label, four-arm randomised controlled trial, we plan to integrate clinical, molecular and imaging parameters of 160 patients with PsA. DMARD-naïve patients are randomised to methotrexate or tofacitinib. Additionally, patients who are non-responsive to conventional synthetic (cs)DMARDs continue their current csDMARD and are randomised to etanercept or tofacitinib. This results in four arms each with 40 patients. Patients are followed for 1 year. Treatment response is defined as minimal disease activity at week 16. Clinical data, biosamples and images are collected at baseline, 4 weeks and 16 weeks; at treatment failure (treatment switch) and 52 weeks. For the first 80 patients, we will use a systems medicine approach to assess multiomics biomarkers and develop a prediction model for treatment response. Subsequently, data from the second 80 patients will be used for validation. ETHICS AND DISSEMINATION: The study was approved by the Medical Research Ethics Committee in Utrecht, Netherlands, is registered in the European Clinical Trials Database and is carried out in accordance with the Declaration of Helsinki. The study's progress is monitored by Julius Clinical, a science-driven contract research organisation. TRIAL REGISTRATION NUMBER: EudraCT: 2017-003900-28.

Prediction Aided Tapering In rheumatoid arthritis patients treated with biOlogicals (PATIO): protocol for a randomized controlled trial.

BACKGROUND: Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis (RA) but are expensive and increase the risk of infection. Therefore, in patients with a stable low level of disease activity or remission, tapering bDMARDs should be considered. Although tapering does not seem to affect long-term disease control, (short-lived) flares are frequent during the tapering process. We have previously developed and externally validated a dynamic flare prediction model for use as a decision aid during stepwise tapering of bDMARDs to reduce the risk of a flare during this process. METHODS: In this investigator-initiated, multicenter, open-label, randomized (1:1) controlled trial, we will assess the effect of incorporating flare risk predictions into a bDMARD tapering strategy. One hundred sixty RA patients treated with a bDMARD with stable low disease activity will be recruited. In the control group, the bDMARD will be tapered according to "disease activity guided dose optimization" (DGDO). In the intervention group, the bDMARD will be tapered according to a strategy that combines DGDO with the dynamic flare prediction model, where the next bDMARD tapering step is not taken in case of a high risk of flare. Patients will be randomized 1:1 to the control or intervention group. The primary outcome is the number of flares per patient (DAS28-CRP increase > 1.2, or DAS28-CRP increase > 0.6 with a current DAS28-CRP ≥ 2.9) during the 18-month follow-up period. Secondary outcomes include the number of patients with a major flare (flare duration ≥ 12 weeks), bDMARD dose reduction, adverse events, disease activity (DAS28-CRP) and patient-reported outcomes such as quality of life and functional disability. Health Care Utilization and Work Productivity will also be assessed. DISCUSSION: This will be the first clinical trial to evaluate the benefit of applying a dynamic flare prediction model as a decision aid during bDMARD tapering. Reducing the risk of flaring during tapering may enhance the safety and (cost)effectiveness of bDMARD treatment. Furthermore, this study pioneers the field of implementing predictive algorithms in clinical practice. TRIAL REGISTRATION: Dutch Trial Register number NL9798, registered 18 October 2021, https://www.trialregister.nl/trial/9798 . The study has received ethical review board approval (number NL74537.041.20).

Using real-world data to dynamically predict flares during tapering of biological DMARDs in rheumatoid arthritis: development, validation, and potential impact of prediction-aided decisions.

BACKGROUND: Biological disease-modifying antirheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis. However, as bDMARDs may also lead to adverse events and are expensive, tapering them is of great clinical interest. Tapering according to disease activity-guided dose optimization (DGDO) does not seem to affect long term remission rates, but flares are frequent during this process. Our objective was to develop a model for the prediction of flares during bDMARD tapering using data from routine care and to evaluate its potential clinical impact. METHODS: We used a joint latent class model to repeatedly predict the probability of a flare occurring within the next 3 months. The model was developed using longitudinal data on disease activity (DAS28) and other routine care data from two clinics. Predictive accuracy was assessed in cross-validation and external validation was performed with data from the DRESS (Dose REduction Strategy of Subcutaneous tumor necrosis factor inhibitors) trial. Additionally, we simulated the reduction in number of flares and bDMARD dose when implementing the model as a decision aid during bDMARD tapering in the DRESS trial. RESULTS: Data from 279 bDMARD courses were used for model development. The final model included two latent DAS28-trajectories, bDMARD type and dose, disease duration, and seropositivity. The area under the curve of the final model was 0.76 (0.69-0.83) in cross-validation and 0.68 (0.62-0.73) in external validation. In simulation of prediction-aided decisions, the mean number of flares over 18 months decreased from 1.21 (0.99-1.43) to 0.75 (0.54-0.96). The reduction in he bDMARD dose was mostly maintained, increasing from 54 to 64% of full dose. CONCLUSIONS: We developed a dynamic flare prediction model, exclusively based on data typically available in routine care. Our results show that using this model to aid decisions during bDMARD tapering may significantly reduce the number of flares while maintaining most of the bDMARD dose reduction. TRIAL REGISTRATION: The clinical impact of the prediction model is currently under investigation in the PATIO randomized controlled trial (Dutch Trial Register number NL9798).

Classification of rheumatoid arthritis into active or inactive with a modified Disease Activity score, for future use as a treat-to-target tool, with a HandScan score replacing joint counts.

OBJECTIVES: To establish the value of a modified Disease Activity score with Optical Spectral Transmission score (DAS-OST) without joint counts but with a HandScan score, versus that of DAS28, to classify rheumatoid arthritis (RA) as active versus inactive, with as reference standard the rheumatologist's clinical classification. METHODS: RA patients with at least one HandScan and DAS28 measurement performed at the same visit were included. Data was extracted from medical records, as was the clinical interpretation as active or inactive RA by the rheumatologist. Logistic regression analyses were performed to calculate areas under the receiver operating characteristics (AU-ROC) curves. The clinical interpretation was used as reference standard in all analyses, and disease activity measures were used as predictor variables. The performance of predictor variables (AU-ROCs) was compared. RESULTS: The data of 1505 RA patients were used for analyses. The highest AU-ROC of 0.88 (95%CI 0.85-0.90) was shown for DAS28; AU-ROC of DAS-OST was 0.78 (95%CI 0.75-0.81), difference 0.10, p<0.01. CONCLUSIONS: Compared to DAS28, DAS-OST classified RA statistically significantly less well as active versus inactive, when using the clinical classification as reference standard. However, a DAS-modification without joint scores might have a place in strategies limiting routine outpatients' visits to the rheumatologist.

Efficacy of Tocilizumab Monotherapy Versus Tocilizumab and Methotrexate Combination Therapy in the Prevention of Radiographic Progression in Rheumatoid Arthritis: An Analysis Using Individual Patient Data From Multiple Clinical Trials.

OBJECTIVE: To compare the effects of preventing radiographic progression (in its 3 components) of tocilizumab (TCZ) monotherapy with those of TCZ and methotrexate (MTX) in combination therapy (TCZ + MTX), and to evaluate possible effect modifiers in this model. METHODS: Randomized trials that compared TCZ monotherapy to TCZ + MTX combination therapy for differences in radiographic progression were analyzed on an individual patient data level using mixed-effects models, and data were collected from 820 subjects with either early rheumatoid arthritis (RA) or established RA. Outcomes were classified as the absence of radiographic progression after 2 years (i.e., preventing radiographic progression) as measured by total Sharp/van der Heijde score (SHS), erosion score, and joint space narrowing (JSN) score. Effect modification by baseline joint damage, disease duration, and Disease Activity Score in 28 joints (DAS28) was studied. RESULTS: Overall, TCZ + MTX combination therapy was more effective in preventing radiographic progression compared to TCZ monotherapy, which was measured by total SHS score. However, in patients with early RA who had more joint damage compared to those with less joint damage at baseline (relative risk [RR] 1.02 versus RR 0.91, respectively) or in patients with a lower DAS28 score compared to those with a higher DAS28 score (RR 1.04 versus RR 0.92, respectively) at baseline, this advantage disappeared. In patients with established RA, the advantage of TCZ + MTX versus TCZ alone in the prevention of radiographic progression disappeared with a longer disease duration at baseline (RR 1.04 versus 0.83). Results of erosion scores as an outcome were in line with these findings, though findings for JSN scores were less clear. CONCLUSION: Combination therapy with TCZ + MTX is more effective in preventing radiographic progression compared to TCZ monotherapy, but the effectiveness of TCZ monotherapy may approximate the effectiveness of TCZ + MTX in patients with early RA who have more joint damage and/or a lower DAS28 at baseline and in patients with established RA who have longer disease duration.

Development and Validation of Rheumatoid Arthritis Disease Activity Indices Including HandScan (Optical Spectral Transmission) Scores.

OBJECTIVE: To develop and validate a composite rheumatoid arthritis (RA) disease activity index using optical spectral transmission (OST) scores obtained with the HandScan, replacing tender and swollen joint counts. METHODS: RA patients from a single center routinely undergoing HandScan measurements with at least 1 concurrent OST score and Disease Activity Score in 28 joints (DAS28) were included. Data were extracted from medical records. Linear regression analyses with the DAS28 as the outcome were performed to create a disease activity index (DAS-OST). OST score, erythrocyte sedimentation rate (ESR), and patient global assessment (PtGA) visual analog scale (VAS), sex, age, disease duration, and rheumatoid factor status were evaluated as independent variables. Final models were derived based on the statistical significance of coefficients and model fit. Of the data, two-thirds were used for development and one-third for validation; external validation was performed in a cohort from another center. Agreement between DAS-OST and DAS28 was assessed using the Bland-Altman plot method and intraclass correlation coefficient (ICC). Diagnostic value of the DAS-OST was determined for established definitions of remission, low disease activity (LDA), and high disease activity (HDA). RESULTS: Data of 3,358 observations from 1,505 unique RA patients were extracted. DAS-OST was defined as: -0.44 + OST × 0.03 + male × -0.11 + LN(ESR) × 0.77 + PtGA VAS × 0.03. The ICCs between DAS-OST and DAS28 were 0.88 (95% confidence interval [95% CI] 0.87-0.90) and 0.82 (95% CI 0.75-0.86) and measurement errors were 0.58 and 0.87 in internal and external validation, respectively. Sensitivity for remission, LDA, and HDA was 79%, 91%, and 43%, respectively, and specificity was 92%, 80%, and 96% in external validation. CONCLUSION: Using the HandScan, RA disease activity can be accurately estimated if combined with ESR, PtGA VAS, and sex into a disease activity index (DAS-OST).

Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α.

OBJECTIVE: SSc is a complex disease characterized by vascular abnormalities and inflammation culminating in hypoxia and excessive fibrosis. Previously, we identified chemokine (C-X-C motif) ligand 4 (CXCL4) as a novel predictive biomarker in SSc. Although CXCL4 is well-studied, the mechanisms driving its production are unclear. The aim of this study was to elucidate the mechanisms leading to CXCL4 production. METHODS: Plasmacytoid dendritic cells (pDCs) from 97 healthy controls and 70 SSc patients were cultured in the presence of hypoxia or atmospheric oxygen level and/or stimulated with several toll-like receptor (TLR) agonists. Further, pro-inflammatory cytokine production, CXCL4, hypoxia-inducible factor (HIF) -1α and HIF-2α gene and protein expression were assessed using ELISA, Luminex, qPCR, FACS and western blot assays. RESULTS: CXCL4 release was potentiated only when pDCs were simultaneously exposed to hypoxia and TLR9 agonist (P < 0.0001). Here, we demonstrated that CXCL4 production is dependent on the overproduction of mitochondrial reactive oxygen species (mtROS) (P = 0.0079) leading to stabilization of HIF-2α (P = 0.029). In addition, we show that hypoxia is fundamental for CXCL4 production by umbilical cord CD34 derived pDCs. CONCLUSION: TLR-mediated activation of immune cells in the presence of hypoxia underpins the pathogenic production of CXCL4 in SSc. Blocking either mtROS or HIF-2α pathways may therapeutically attenuate the contribution of CXCL4 to SSc and other inflammatory diseases driven by CXCL4.

Utility of the HandScan in monitoring disease activity and prediction of clinical response in rheumatoid arthritis patients: an explorative study.

OBJECTIVES: The aims were to determine the ability of the HandScan [assessing inflammation in hand and wrist joints using optical spectral transmission (OST)] to measure RA disease activity longitudinally, compared with DAS28, and to determine whether short-term (i.e. 1 month) changes in the OST score can predict treatment response at 3 or 6 months. METHODS: Participants visited the outpatient clinic before the start of (additional) RA medication and 1, 3 and 6 months thereafter. Disease activity was monitored at each visit with the HandScan and DAS28 in parallel. A mixed effects model with DAS28 as the outcome variable with a random intercept at patient level, visit month and DAS28 one visit earlier was used to evaluate whether changes in the OST score are related to changes in DAS28. Binary logistic regression was used to test the predictive value of short-term changes in the OST score together with the baseline OST score for achievement of treatment response (EULAR or ACR criteria). All models were adjusted for RA stage (early or established). RESULTS: In total, 64 RA patients were included. One unit change in OST score was found to be related to an average DAS28 change of 0.03 (95% CI: 0.01, 0.06, P = 0.03). When adding OST score as a variable in the longitudinal model, the ability of the model to estimate DAS28 (i.e. explained variance) increased by 2%, to 59%. Neither baseline OST score nor short-term change in OST score was predictive for treatment response at 3 or 6 months. CONCLUSION: A longitudinal association of OST score with DAS28 exists, although explained variance is low. The predictive ability of short-term changes in HandScan for treatment response is limited.

COVID-19 related thrombi in ascending and descending thoracic aorta with peripheral embolization: a case report.

BACKGROUND: COVID-19 (severe acute respiratory syndrome coronavirus 2) infected patients have increased risk for thrombotic events, which initially may have been under recognized. The existence of cardiovascular emboli can be directly life threatening when obstructing the blood flow to vital organs such as the brain or other parts of the body. The exact mechanism for this hypercoagulable state in COVID-19 patients yet remains to be elucidated. CASE SUMMARY: A 72-year-old man critically ill with COVID-19 was diagnosed with a free-floating and mural thrombus in the thoracic aorta. Subsequent distal embolization to the limbs led to ischaemia and necrosis of the right foot. Treatment with heparin and anticoagulants reduced thrombus load in the ascending and thoracic aorta. DISCUSSION: One-third of COVID-19 patients show major thrombotic events, mostly pulmonary emboli. The endothelial expression of angiotensin-converting enzyme-2 receptors makes it feasible that in patients with viraemia direct viral-toxicity to the endothelium of also the large arteries results in local thrombus formation. Up to date, prophylactic anticoagulants are recommended in all patients that are hospitalized with COVID-19 infections to prevent venous and arterial thrombotic complications.

Non-adherence in difficult-to-treat rheumatoid arthritis from the perspectives of patients and rheumatologists: a concept mapping study.

OBJECTIVES: Treatment non-adherence is more frequent among difficult-to-treat (D2T) than among non-D2T RA patients. Perceptions of non-adherence may differ. We aimed to thematically structure and prioritize barriers to (i.e. causes and reasons for non-adherence) and facilitators of optimal adherence from the patients' and rheumatologists' perspectives. METHODS: Patients' perceptions were identified in semi-structured in-depth interviews. Experts selected representative statements regarding 40 barriers and 40 facilitators. Twenty D2T and 20 non-D2T RA patients sorted these statements during two card-sorting tasks: first, by order of content similarity and, second, content applicability. Additionally, 20 rheumatologists sorted the statements by order of content applicability to the general RA population. The similarity sorting was used as input for hierarchical cluster analysis. The applicability sorting was analysed using descriptive statistics, prioritized and the results compared between D2T RA patients, non-D2T RA patients and rheumatologists. RESULTS: Nine clusters of barriers were identified, related to the healthcare system, treatment safety/efficacy, treatment regimen and patient behaviour. D2T RA patients prioritized adverse events and doubts about effectiveness as the most important barriers. Doubts about effectiveness were more important to D2T than to non-D2T RA patients (P = 0.02). Seven clusters of facilitators were identified, related to the healthcare system and directly to the patient. All RA patients and rheumatologists prioritized a good relationship with the healthcare professional and treatment information as the most helpful facilitators. CONCLUSIONS: D2T RA patients, non-D2T RA patients and rheumatologists prioritized perceptions of non-adherence largely similarly. The structured overviews of barriers and facilitators provided in this study may guide improvement of adherence.

Healthcare utilization and economic burden of difficult-to-treat rheumatoid arthritis: a cost-of-illness study.

OBJECTIVES: To determine the impact of difficult-to-treat rheumatoid arthritis (D2T RA) on (costs related to) healthcare utilization, other resource use and work productivity. METHODS: Data regarding healthcare utilization, other resource use and work productivity of 52 D2T (according to the EULAR definition) and 100 non-D2T RA patients were collected via a questionnaire and an electronic patient record review during a study visit. Annual costs were calculated and compared between groups. Multivariable linear regression analysis was performed to assess whether having D2T RA was associated with higher costs. RESULTS: Mean (95% CI) annual total costs were €37 605 (€27 689 - €50 378) for D2T and €19 217 (€15 647 - €22 945) for non-D2T RA patients (P<0.001). D2T RA patients visited their rheumatologist more frequently, were more often admitted to day-care facilities, underwent more laboratory tests and used more drugs (specifically targeted synthetic DMARDs), compared with non-D2T RA patients (P<0.01). In D2T RA patients, the main contributors to total costs were informal help of family and friends (28%), drugs (26%) and loss of work productivity (16%). After adjustment for physical functioning (HAQ), having D2T RA was no longer statistically significantly associated with higher total costs. HAQ was the only independent determinant of higher costs in multivariable analysis. CONCLUSIONS: The economic burden of D2T RA is significantly higher than that of non-D2T RA, indicated by higher healthcare utilization and higher annual total costs. Functional disability is a key determinant of higher costs in RA.

Tissue-Resident Memory CD8+ T Cells From Skin Differentiate Psoriatic Arthritis From Psoriasis.

OBJECTIVE: To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA. METHODS: In-depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high-throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis. RESULTS: Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin-17A (IL-17A) and IL-22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin-homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue-resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up-regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22-like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function. CONCLUSION: Tissue-resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development.

Difficult-to-treat rheumatoid arthritis: contributing factors and burden of disease.

OBJECTIVES: Treatment of difficult-to-treat (D2T) RA patients is generally based on trial-and-error and can be challenging due to a myriad of contributing factors. We aimed to identify risk factors at RA onset, contributing factors and the burden of disease. METHODS: Consecutive RA patients were enrolled and categorized as D2T, according to the EULAR definition, or not (controls). Factors potentially contributing to D2T RA and burden of disease were assessed. Risk factors at RA onset and factors independently associated with D2T RA were identified by logistic regression. D2T RA subgroups were explored by cluster analysis. RESULTS: Fifty-two RA patients were classified as D2T and 100 as non-D2T. Lower socioeconomic status at RA onset was found as an independent risk factor for developing D2T RA [odds ratio (OR) 1.97 (95%CI 1.08-3.61)]. Several contributing factors were independently associated with D2T RA, occurring more frequently in D2T than in non-D2T patients: limited drug options because of adverse events (94% vs 57%) or comorbidities (69% vs 37%), mismatch in patient's and rheumatologist's wish to intensify treatment (37% vs 6%), concomitant fibromyalgia (38% vs 9%) and poorer coping (worse levels). Burden of disease was significantly higher in D2T RA patients. Three subgroups of D2T RA patients were identified: (i) 'non-adherent dissatisfied patients'; (ii) patients with 'pain syndromes and obesity'; (iii) patients closest to the concept of 'true refractory RA'. CONCLUSIONS: This comprehensive study on D2T RA shows multiple contributing factors, a high burden of disease and the heterogeneity of D2T RA. These findings suggest that these factors should be identified in daily practice in order to tailor therapeutic strategies further to the individual patient.

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.

Effect on Costs and Quality-adjusted Life-years of Treat-to-target Treatment Strategies Initiating Methotrexate, or Tocilizumab, or Their Combination in Early Rheumatoid Arthritis.

OBJECTIVE: Our study aimed to evaluate the cost effectiveness of initiating tocilizumab (TCZ) ± methotrexate (MTX) versus initiating MTX as treat-to-target treatment strategies over 5 years in early disease-modifying antirheumatic drug (DMARD)-naïve rheumatoid arthritis (RA). METHODS: Data on resource use were collected with questionnaires at baseline, 3, 6, 12, and 24 months, and yearly thereafter, and were converted to costs using Dutch reference prices. Quality-adjusted life-years (QALY) were calculated using the EQ5D5L, with utility based on Dutch tariff or estimated by the Health Assessment Questionnaire. To account for missing cost data and QALY data and for sample uncertainty, first bootstraps (10,000 samples) were obtained. Second, single imputation using chained equations nested within these bootstrap samples was performed. An economic evaluation was performed for TCZ + MTX and TCZ, compared to MTX, as initial treatment in a treat-to-target strategy from a healthcare and societal perspective over 5 years. Several sensitivity analyses were performed. RESULTS: Mean differences in QALY were small and not significant (TCZ + MTX vs MTX: 0.06, 95% CI -0.02 to 0.13; TCZ vs. MTX: -0.03, 95% CI -0.05 to 0.11). Limited savings in indirect nonhealthcare costs and productivity loss costs (for TCZ only) were observed, but these did not compensate for the higher medication costs. Sensitivity analyses did not materially change these findings, although lower-priced TCZ, or reserving TCZ as initial therapy for prognostically unfavorable RA patients, improved cost effectiveness considerably but did not individually lead to a strategy being cost effective. CONCLUSION: Based on our analyses, early initiation of TCZ + MTX is not cost effective compared to MTX initiation in a step-up treat-to-target treatment strategy over 5 years in early RA patients.

Validation of a Prognostic Multivariable Prediction Model for Insufficient Clinical Response to Methotrexate in Early Rheumatoid Arthritis and Its Clinical Application in Evidencio.

INTRODUCTION: Methotrexate (MTX) constitutes the first-line therapy in rheumatoid arthritis (RA), yet approximately 30% of the patients do not benefit from MTX. Recently, we reported a prognostic multivariable prediction model for insufficient clinical response to MTX at 3 months of treatment in the treatment in the Rotterdam Early Arthritis Cohort (tREACH), including baseline predictors: Disease activity score 28 (DAS28), Health Assessment Questionnaire (HAQ), erythrocyte folate, single-nucleotide polymorphisms (SNPs; ABCB1, ABCC3), smoking, and BMI. The purpose of the current study was (1) to externally validate the model and (2) to enhance the model's clinical applicability. METHODS: Erythrocyte folate and SNPs were assessed in 91 early disease-modifying antirheumatic drug (DMARD)-naïve RA patients starting MTX in the external validation cohort (U-Act-Early). Insufficient response (DAS28 > 3.2) was determined after 3 months and non-response after 6 months of therapy. The previously developed prediction model was considered successfully validated in the U-Act-Early (validation cohort) if the area under the curve (AUC) of the receiver operating characteristic (ROC) was not significantly lower than in the tREACH (derivation cohort). RESULTS: The AUCs in U-Act-Early at three and 6 months were 0.75 (95% CI 0.64-0.85) and 0.71 (95% CI 0.60-0.82) respectively, similar to the tREACH. Baseline DAS28 > 5.1 and HAQ > 0.6 were the strongest predictors. The model was simplified by excluding the SNPs, while still classifying 73% correctly. Furthermore, interaction terms between BMI and HAQ and BMI and erythrocyte folate significantly improved the model increasing correct classification to 75%. Results were successfully implemented in Evidencio online platform assisting clinicians in shared decision-making to intensify treatment when appropriate. CONCLUSIONS: We successfully externally validated our recently reported prediction model for MTX non-response and enhanced its clinical application thus enabling its evaluation in a clinical trial. TRIAL REGISTRATION: The U-Act-Early is registered at ClinicalTrials.gov. number: NCT01034137. tREACH is registered retrospectively at ISRCTN registry, number: ISRCTN26791028 at 23 August 2007.

Effectiveness of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease-modifying antirheumatic drugs (TOPIRA): study protocol for a pragmatic trial.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. METHODS: In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. DISCUSSION: This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. TRIAL REGISTRATION: This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set.