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.

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.

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.

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.

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.

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.

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.

Effectiveness and safety over 3 years after the 2-year U-Act-Early trial of the strategies initiating tocilizumab and/or methotrexate.

OBJECTIVES: U-Act-Early was a 2-year, randomized placebo controlled, double-blind trial, in which DMARD-naïve early RA patients were treated to the target of sustained remission (SR). Two strategies initiating tocilizumab (TCZ), with and without methotrexate (MTX), were more effective than a strategy initiating MTX. The aim of the current study was to determine longer-term effectiveness in daily clinical practice. METHODS: At the end of U-Act-Early, patients were included in a 3-year post-trial follow-up (PTFU), in which treatment was according to standard care and data were collected every 3 months during the first year and every 6 months thereafter. Primary end point was disease activity score assessing 28 joints (DAS28) over time. Mixed effects models were used to compare effectiveness between initial strategy groups, correcting for relevant confounders. Between the groups as randomized, proportions of patients were tested for DMARD use, SR and radiographic progression of joint damage. RESULTS: Of patients starting U-Act-Early, 226/317 (71%) participated in the PTFU. Over the total 5 years, mean DAS28 was similar between groups (P > 0.20). During U-Act-Early, biologic DMARD use decreased in both TCZ initiation groups and increased in the MTX initiation group, but during follow-up this trend did not continue. SR was achieved at least once in 99% of patients. Of the 226 patients, only 30% had any radiographic progression over 5 years, without significant differences between the groups. CONCLUSION: Although in the short-term the strategies initiating TCZ yielded the most clinical benefit, in the longer-term differences in important clinical outcomes between the strategies disappeared, probably due to continuation of the treat-to-target principle.

Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-II treat-to-target trials.

OBJECTIVES: Methotrexate (MTX), often combined with low moderately dosed prednisone, is still the cornerstone of initial treatment for early rheumatoid arthritis (RA). It is not known how this strategy compares with initial treatment with a biological. We therefore compared the effectiveness of tocilizumab (TCZ), or TCZ plus MTX (TCZ+MTX) with MTX plus 10 mg prednisone (MTX+pred), all initiated within a treat-to-target treatment strategy in early RA. METHODS: Using individual patient data of two trials, we indirectly compared tight-controlled treat-to-target strategies initiating TCZ (n=103), TCZ+MTX (n=106) or MTX+pred (n=117), using initiation of MTX (n=227) as reference. Primary outcome was Disease Activity Score assessing 28 joints (DAS28) over 24 months. To assess the influence of acute phase reactants (APRs), a disease activity composite outcome score without APR (ie, modification of the Clinical Disease Activity Index (m-CDAI)) was analysed. Secondary outcomes were remission (several definitions), physical function and radiographic progression. Multilevel models were used to account for clustering within trials and patients over time, correcting for relevant confounders. RESULTS: DAS28 over 24 months was lower for TCZ+MTX than for MTX+Pred (mean difference: -0.62 (95% CI -1.14 to -0.10)). Remission was more often achieved in TCZ+MTX and in TCZ versus MTX+pred (p=0.02/0.05, respectively). Excluding APRs from the disease activity outcome score, TCZ-based strategies showed a slightly higher m-CDAI compared with MTX+pred, but this was not statistically significant. Other outcomes were also not statistically significantly different between the strategies. CONCLUSIONS: In patients with early RA, although TCZ-based strategies resulted in better DAS28 and remission rates compared with MTX+pred, at least part of these effects may be due to a specific effect of TCZ on APRs.

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial.

BACKGROUND: For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS: We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS: Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING: Roche Nederland BV.

Progression of structural damage is not related to rituximab serum levels in rheumatoid arthritis patients.

OBJECTIVE: The most cost-effective dosing regimen for rituximab treatment in RA is currently unknown. The objective of this study is to determine whether low rituximab serum levels are associated with progression of structural damage in RA patients. METHODS: Sixty-two RA patients were treated with rituximab in three different centres. Structural damage was assessed on radiographs of hands and feet before and 1 year after therapy using the Sharp-van der Heijde scoring method (SHS). Patients were divided into progressors vs non-progressors based on different cut-off values. Rituximab serum levels were measured by sandwich ELISA after 4 and 12 weeks (Leiden University Medical Center and University Medical Centre, Utrecht cohorts) or 4 and 16 weeks (Academic Medical Center/University of Amsterdam cohort). RESULTS: There was no difference in rituximab levels between progressors and non-progressors 4 weeks and 12 or 16 weeks after initiation of treatment in the different cohorts. There was also no correlation between rituximab levels at week 4 or week 12 or 16 and change in SHS score after 1 year. CONCLUSION: Low rituximab serum levels are not associated with progression of structural damage in RA patients. The results do not support the use of dosages higher than 2 × 1000 mg rituximab to inhibit progression of joint destruction.

Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial.

BACKGROUND: Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. OBJECTIVE: To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. DESIGN: A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) SETTING: 7 hospitals in the Netherlands. PATIENTS: 236 patients with early RA (duration <1 year). INTERVENTION: Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. MEASUREMENTS: The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. RESULTS: Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. LIMITATION: A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. CONCLUSION: Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. PRIMARY FUNDING SOURCE: Catharijne Foundation.

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.

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).

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).

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).

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.

Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients.

OBJECTIVE: To analyze the relationship between the type I interferon (IFN) signature and clinical response to rituximab in rheumatoid arthritis (RA) patients. METHODS: Twenty RA patients were treated with rituximab (cohort 1). Clinical response was defined as a decrease in the Disease Activity Score evaluated in 28 joints (DAS28) and as a response according to the European League Against Rheumatism (EULAR) criteria at week 12 and week 24. The presence of an IFN signature was analyzed in peripheral blood mononuclear cells by measuring the expression levels of 3 IFN response genes by quantitative polymerase chain reaction analysis. After comparison with the findings in healthy controls, patients were classified as having an IFN high or an IFN low signature. The data were confirmed in a second independent cohort (n = 31). Serum IFNα bioactivity was analyzed using a reporter assay. RESULTS: In cohort 1, there was a better clinical response to rituximab in the IFN low signature group. Consistent with these findings, patients with an IFN low signature had a significantly greater reduction in the DAS28 and more often achieved a EULAR response at weeks 12 and 24 as compared with the patients with an IFN high signature in cohort 2 versus cohort 1. The pooled data showed a significantly stronger decrease in the DAS28 in IFN low signature patients at weeks 12 and 24 as compared with the IFN high signature group and a more frequent EULAR response at week 12. Accordingly, serum IFNα bioactivity at baseline was inversely associated with the clinical response, although this result did not reach statistical significance. CONCLUSION: The type I IFN signature negatively predicts the clinical response to rituximab treatment in patients with RA. This finding supports the notion that IFN signaling plays a role in the immunopathology of RA.