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Objectives Around 30% of patients with RA have an inadequate response to MTX. We aimed to use routine clinical and biological data to build machine learning models predicting EULAR inadequate response to MTX and to identify simple predictive biomarkers. Methods Models were trained on RA patients fulfilling the 2010 ACR/EULAR criteria from the ESPOIR and Leiden EAC cohorts to predict the EULAR response at 9 months (± 6 months). Several models were compared on the training set using the AUROC. The best model was evaluated on an external validation cohort (tREACH). The model's predictions were explained using Shapley values to extract a biomarker of inadequate response. Results We included 493 therapeutic sequences from ESPOIR, 239 from EAC and 138 from tREACH. The model selected DAS28, Lymphocytes, Creatininemia, Leucocytes, AST, ALT, swollen joint count and corticosteroid co-treatment as predictors. The model reached an AUROC of 0.72 [95% CI (0.63, 0.80)] on the external validation set, where 70% of patients were responders to MTX. Patients predicted as inadequate responders had only 38% [95% CI (20%, 58%)] chance to respond and using the algorithm to decide to initiate MTX would decrease inadequate-response rate from 30% to 23% [95% CI: (17%, 29%)]. A biomarker was identified in patients with moderate or high activity (DAS28 > 3.2): patients with a lymphocyte count superior to 2000 cells/mm3 are significantly less likely to respond. Conclusion Our study highlights the usefulness of machine learning in unveiling subgroups of inadequate responders to MTX to guide new therapeutic strategies. Further work is needed to validate this approach.

Background:Health care is shifting toward a person-centered care (PCC) approach. For implementation of PCC, there may be a special role for nurse practitioners (NPs).Purpose:The aim of this study was to explore the patient-perceived levels of and needs for of PCC in inflammatory arthritis patients who visited the NP at the outpatient clinic of an academic hospital in the Netherlands.Methods:A cross-sectional study was performed. Disease characteristics were inventoried from the patient records. Patients filled out the PCCoc/rheum instrument, an instrument to measure patient perceived PCC, and a questionnaire based on the 14 life areas of the Self-Management Web, extended with areas including pain, fatigue, and night's rest. Participants were asked which life areas caused problems, and whether these problems were discussed. Mean values were calculated for normally distributed data and medians for nonnormally distributed data.Results:Most of the patients had well-controlled disease (86.1%). The mean score of the PCCoc/rheum was 55.3 (SD 8.1). Patients experienced most problems in life areas fatigue (37.3%) and pain (35.3%), these were also the life areas that were most often addressed at consultation. The life areas that gave problems and that were least addressed during consultation were intimate relationships & sexuality (66.7%) and household chores (58.8%).Conclusions:Despite an overall high level of patient perceived PCC delivered by NPs, patient with low disease activity frequently reported problems in life areas not addressed at consultation.Implications for practice:Implementation of the Self-Management Web and changing the focus of NP consultations may help to improve accommodating individual patient needs.

Objectives We investigated whether work participation is affected in patients with arthralgia during transition to RA. Arthralgia patients with symptom resolution and early RA patients at diagnosis were used as a reference. Methods Three groups of patients were studied: arthralgia patients converting to RA (n = 114), arthralgia patients with spontaneous symptom resolution (n = 57), and early RA patients (n = 617). Both presenteeism (i.e. working while sick, scale 0–10) and absenteeism (i.e. sick leave) were taken into account. Work ability 1 year prior to clinical arthritis was estimated (in absolute numbers). The course of work restriction over time was studied using linear mixed models (β coefficient; delta per month) within each patient group. Results One-year prior to the development of clinical arthritis, mean presenteeism was 7.0 (95% CI 5.8, 8.1) in patients with arthralgia, indicating 30% loss, and further worsened to 6.1 (95% CI 5.3, 6.6) at RA diagnosis, thus indicating 39% loss. In early RA patients, presenteeism improved over time after DMARD initiation (β 0.052 per month 95% CI 0.042, 0.061, P Conclusion In the months preceding RA, presenteeism was already apparent, and it worsened further during progression to clinical arthritis and diagnosis. This underlines the relevance of the symptomatic pre-RA phase for patients. The observed reversibility in arthralgia patients with symptom resolution may suggest that intervention in pre-RA could improve work participation.

Objectives Cross-sectional studies have shown that rheumatoid arthritis is more prevalent among people with a lower educational attainment. No longitudinal data are present on educational attainment in the at-risk phase of clinically suspect arthralgia (CSA). We therefore analysed the association between educational attainment and progression from CSA to inflammatory arthritis (IA), and performed mediation analysis with subclinical joint inflammation to elucidate pathways of this association. Methods A total of 521 consecutive patients presenting with CSA were followed for IA development during median 25 months. Educational attainment was defined as low (lower secondary vocational education), intermediate or high (college/university education). Subclinical inflammation in hand and foot joints was measured at presentation with contrast enhanced 1.5 T-MRI. Cox-regression was used to analyse IA development per educational attainment. A three-step mediation analysis evaluated whether subclinical joint inflammation was intermediary in the path between educational attainment and IA development, before and after age correction. Association between educational attainment and IA development was verified in an independent CSA cohort. Results Low educational attainment was associated with increased IA development (HR = 2.35, 95% CI = 1.27, 4.33, P = 0.006), independent of BMI and current smoking status (yes/no). Moreover, patients with a low educational attainment had higher levels of subclinical inflammation, which also was associated with IA development. Partial mediation effect of subclinical inflammation was observed in the relationship between education and IA development. Low educational attainment was also associated with increased IA development in the validation cohort (HR = 5.72, 95% CI = 1.36, 24.08, P = 0.017). Conclusion This is the first study providing evidence that lower educational attainment is associated with a higher risk of progressing from arthralgia to IA. This effect was partially mediated by subclinical joint inflammation.

ObjectivesScleritis represents a severe extra-articular manifestation of rheumatoid arthritis (RA). Recent clinical observations suggest a decreasing incidence of scleritis in RA, attributed to improved treatment options. Our study reports on the incidence and clinical characteristics of scleritis in RA observed in the biological era and reflects on our results in a historical perspective.MethodsWe performed a retrospective evaluation of all 1623 consecutive patients with RA diagnosed at the department of rheumatology between 2011 and 2021 at the Erasmus Medical Center to investigate the incidence of scleritis. We also reviewed clinical and laboratory data of all patients with scleritis and RA from the department of ophthalmology at our center. In addition, we reviewed the literature on this topic and discuss our results in view of changes over time.ResultsThe incidence of scleritis within recent series of patients with a diagnosis of RA in our tertiary center was 0,25% in 10 years (4 out of 1623; 2011-2021).The cumulative incidence of scleritis in RA based on literature review from the pre-biologic era varied from 0.7% per 8 years to 0,8% per 30 years. Manifestations and complications of scleritis remained unchanged over time, with scleral necrosis developing in more than 80% of cases and mortality of RA patients with scleritis remained similar to pre-biologic era (30% in 9 years after the onset of scleritis). The RA patients with scleritis often exhibited autoantibodies (rheumatoid factor and/or anti-citrullinated protein antibody) and erosive disease.ConclusionAlthough our recent series is characterized by a slightly lower incidence of scleritis in RA compared to the pre-biologic era, clinical presentation remained severe and similar to the pre-biologic era. Ophthalmologists and rheumatologists should be aware of scleritis as a severe extra-articular manifestation of RA.

Objective To investigate the negative predictive value (NPV) of musculoskeletal US (MSUS) in arthralgia patients at risk for developing inflammatory arthritis. Methods An MSUS examination of hands and feet was performed in arthralgia patients at risk for inflammatory arthritis in four independent cohorts. Patients were followed for one-year on the development of inflammatory arthritis. Subclinical synovitis was defined as greyscale ≥2 and/or power Doppler ≥1. NPVs were determined and compared with the prior risks of not developing inflammatory arthritis. Outcomes were pooled using meta-analyses and meta-regression analyses. In sensitivity analyses, MSUS imaging of tender joints only (rather than the full US protocol) was analysed and ACPA stratification applied. Results After 1 year 78, 82, 77 and 72% of patients in the four cohorts did not develop inflammatory arthritis. The NPV of a negative US was 86, 85, 82 and 90%, respectively. The meta-analysis showed a pooled non-inflammatory arthritis prevalence of 79% (95% CI 75%, 83%) and a pooled NPV of 86% (95% CI 81, 89%). Imaging tender joints only (as generally done in clinical practice) and ACPA stratification showed similar results. Conclusion A negative US result in arthralgia has a high NPV for not developing inflammatory arthritis, which is mainly due to the high a priori risk of not developing inflammatory arthritis. The added value of a negative US (

BACKGROUND Despite enormous clinical improvements, due to better management strategies and the availability of biologicals, immune-mediated inflammatory diseases (IMIDs) still have a significant impact on patients’ lives. To further reduce disease burden, provider- as well as patient-reported outcomes (PROs) should be taken into account during treatment and follow-up. Web-based collection of these outcomes generates valuable repeated measurements, which could be used (1) in daily clinical practice for patient-centered care, including shared decision-making; (2) for research purposes; and (3) as an essential step toward the implementation of value-based health care (VBHC). Our ultimate goal is that our health care delivery system is completely aligned with the principles of VBHC. For aforementioned reasons, we implemented the IMID registry. OBJECTIVE The IMID registry is a digital system for routine outcome measurement that mainly includes PROs to improve care for patients with IMIDs. METHODS The IMID registry is a longitudinal observational prospective cohort study within the departments of rheumatology, gastroenterology, dermatology, immunology, clinical pharmacy, and outpatient pharmacy of the Erasmus MC, the Netherlands. Patients with the following diseases are eligible for inclusion: inflammatory arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, uveitis, Behçet disease, sarcoidosis, and systemic vasculitis. Generic and disease-specific (patient-reported) outcomes, including adherence to medication, side effects, quality of life, work productivity, disease damage, and activity, are collected from patients and providers at fixed intervals before and during outpatient clinic visits. Data are collected and visualized through a data capture system, which is linked directly to the patients’ electronic health record, which not only facilitates a more holistic care approach, but also helps with shared decision-making. RESULTS The IMID registry is an ongoing cohort with no end date. Inclusion started in April 2018. From start until September 2022, a total of 1417 patients have been included from the participating departments. The mean age at inclusion was 46 (SD 16) years, and 56% of the patient population is female. The average percentage of filled out questionnaires at baseline is 84%, which drops to 72% after 1 year of follow-up. This decline may be due to the fact that the outcomes are not always discussed during the outpatient clinic visit or because the questionnaires were sometimes forgotten to set out. The registry is also used for research purposes and 92% of the patients with IMIDs gave informed consent to use their data for that. CONCLUSIONS The IMID registry is a web-based digital system that collects provider- and PROs. The collected outcomes are used to improve care for the individual patient with an IMID and facilitate shared decision-making, and they are also used for research purposes. The measurement of these outcomes is an essential step toward the implementation of VBHC. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/43230

We appreciate the interest in our paper by Haroon, et al . We presented the 2-year results of the TARA trial, in which we concluded that ‘financial arguments may influence the decision to taper tumour necrosis factor-inhibitors first’.1 Based on this conclusion, Haroon, et al decided to respond to that with their real-world data from a resource-poor country.2 Ideally, if patients with rheumatoid arthritis (RA) are in sustained remission, then medication is quickly tapered and possibly stopped to reduce healthcare costs. Disease modifying anti-rheumatic drug (DMARD)-free remission is suggested as a preferred ultimate target in a treat-to-target management approach; however, we previously showed, in a systematic literature review, that this outcome is achievable in only …

Objectives The objective of this study was to compare DMARD-free remission rates (DFRs) and sustained DFRs (SDFRs), defined as, respectively, DFR for ≥6 months and ≥1 year, after 2 and 5 years, between three clinical arthritis phenotypes: undifferentiated arthritis (UA), autoantibody-negative (RA−) and autoantibody-positive RA (RA+). Methods All UA (n = 130), RA− (n = 176) and RA+ (n = 331) patients from the tREACH trial, a stratified single-blinded trial with a treat-to-target approach, were included in the study. (S)DFR comparisons between phenotypes after 2 and 5 years were performed with logistic regression. Medication use and early and late flares (DAS ≥ 2.4), defined as at 12 months after reaching DMARD-free remission (DFR), respectively, were also compared. Cox proportional hazard models were used to evaluate potential predictors for (S)DFR. Results Over the study periods of 2 and 5 years, less DFR was seen in RA+ (17.2–25.7%), followed by RA− (28.4–42.1%) and UA patients (43.1–58.5%). This also applied for SDFR over the 2- and 5-year periods in these three clinical arthritis phenotypes (respectively, 7.6% and 21.4%; 20.5% and 38.1%; and 35.4% and 55.4%). A flare during tapering was seen in 22.7% of patients. Of the patients in DFR, 7.5% had an early flare and 3.4% a late flare. Also, more treatment intensifications occurred in RA+ compared with RA− and UA. We found that higher baseline DAS, ACPA positivity, higher BMI and smoking were negatively associated with (S)DFR, while clinical phenotype (reference RA+), short symptom duration ( Conclusion Long-term clinical outcomes differ between UA, RA– and RA+. These data reconfirm that RA can be subdivided into the aforementioned clinical phenotypes and that treatment might be best stratified upon these phenotypes, although validation is needed. Trial registration ISRCTN, https://www.isrctn.com/, ISRCTN26791028.

ObjectiveThe aim of the current study was to evaluate the 2-year cost-utility ratio between tapering conventional synthetic disease-modifying antirheumatic drugs (csDMARD) first followed by the tumour necrosis factor (TNF)-inhibitor, or vice versa, in patients with rheumatoid arthritis (RA).MethodsTwo-year data of the Tapering strategies in Rheumatoid Arthritis trial were used. Patients with RA, who used both a csDMARD and a TNF-inhibitor and had a well-controlled disease (disease activity score ≤2.4 and swollen joint count≤1) for at least 3 months, were randomised into gradual tapering the csDMARD first followed by the TNF-inhibitor, or vice versa. Quality-adjusted life years (QALYs) were derived from the European Quality of life questionnaire with 5 dimensions. Healthcare and productivity costs were calculated with data from patient records and questionnaires. The incremental cost-effectiveness ratio and the incremental net monetary benefit were used to assess cost effectiveness between both tapering strategies.Results94 patients started tapering their TNF-inhibitor first, while the other 95 tapered their csDMARD first. QALYs (SD) were, respectively, 1.64 (0.22) and 1.65 (0.22). Medication costs were significantly lower in the patients who tapered the TNF-inhibitor first, while indirect cost were higher due to more productivity loss (p=0.10). Therefore, total costs (SD) were €38 833 (€39 616) for tapering csDMARDs first, and €39 442 (€47 271) for tapering the TNF-inhibitor (p=0.88). For willingness-to-pay (WTP) levels €83 800 tapering the TNF-inhibitor first has the highest probability.ConclusionOur economic evaluation shows that costs are similar for both tapering strategies. Regardless of the WTP, tapering either the TNF-inhibitor or the csDMARD first is equally cost effective.Trial registration numberNTR2754.

Knowledge of pathophysiology of rheumatoid arthritis (RA) has improved over the past decades, which resulted in new treatment options and strategies that led to better clinical outcomes. At the same time, we have come to understand that RA is a heterogeneous disease on a clinical as well as a pathophysiological level. Despite this heterogeneity, current management recommendations still adopt a ‘one-size-fits-all’ treatment approach, where ideally individualised treatment, or personalised medicine, is preferred. The first step towards personalised medicine in RA would be to designate different treatment strategies to distinct clinical or molecular phenotypes of patients. This viewpoint discusses current evidence and elaborates on future possibilities for personalised medicine in RA.

Objectives According to guidelines, clinical arthritis is mandatory for diagnosing RA. However, in the absence of clinical synovitis, imaging-detected subclinical synovitis is increasingly used instead and is considered as a starting point for DMARD therapy. To search for evidence we studied the natural course of arthralgia patients with subclinical synovitis from three longitudinal cohorts and determined the frequencies of non-progression to clinically apparent inflammatory arthritis (IA) (i.e. ‘false positives’). Methods Subclinical synovitis in the hands or feet of arthralgia patients was visualized with US (two cohorts; definition: greyscale ≥2 and/or power Doppler ≥1) or MRI (one cohort; definition: synovitis score ≥1 by two readers). Patients were followed for 1 year on for IA development; two cohorts also had 3 year data. Analyses were stratified for ACPA. Results Subclinical synovitis at presentation was present in 36%, 41% and 31% in the three cohorts. Of the ACPA-positive arthralgia patients with subclinical synovitis, 54%, 44% and 68%, respectively, did not develop IA. These percentages were even higher in the ACPA-negative arthralgia patients: 66%, 85% and 89%, respectively. Similar results were seen after 3 years of follow-up. Conclusion Replacing clinical arthritis with subclinical synovitis to identify RA introduces a high false-positive rate (44–89%). These data suggest an overestimation regarding the value of ACPA positivity in combination with the presence of subclinical synovitis in patients with arthralgia, which harbours the risk of overtreatment if DMARDs are initiated in the absence of clinical arthritis.

Early diagnosis and management of patients with inflammatory arthritis (IA) are critical to improve long-term patient outcomes. Assessment of joint swelling at joint examination is the reference of IA identification; early access clinics are constructed to promote this early recognition. Due to the COVID-19 pandemic, the face-to-face capacity of such services is severely reduced.1 This raises the concern of a major step backward after the important progress that has been made in the past 15 years.1 Telemedicine has recently become rapidly implemented. Although probably a valuable alternative in the management of established rheumatoid arthritis (RA), there is also the fear that this might cause delay in the speed of diagnosis.2 A symptom that evidently raises suspicion for IA during remote evaluation is the presence of patient-reported swelling. This symptom is also included in triage tools.3 4 The accuracy of patient-reported swelling in comparison with joint examination has been extensively evaluated in established RA. Heterogeneous results are reported; correlation coefficients were higher when patient scored their swelling on mannequins (ρ: 0.31–0.67) than when determined with questions.5 Hypothetically, the accuracy of patient-reported joint swelling for first recognition of IA is different than for flare detection in patients with established RA. To promote evidence-based care in the era of telemedicine, we determined the accuracy of patient-reported joint swelling for actual presence of IA in persons suspected of …

With great interest, we read the recently published report by Greenwood et al in which the benefits of coprescription of methotrexate (MTX) with tumour necrosis factor (TNF) inhibitors were investigated in autoantibody-positive and autoantibody-negative rheumatoid arthritis (RA) patients. Greenwood et al found a longer TNF inhibitor survival time when the TNF inhibitor was combined with MTX, which only applied for autoantibody-positive RA patients and thus not for autoantibody-negative RA.1 We believe that this finding is of great interest, and relevant, because of its possible implications for treatment with biologics in clinical practice. Because validation is important, we studied this in our cohort. Within the Erasmus MC, an academic hospital in the Netherlands, we obtained real-world data concerning biological use from the local pharmacy database and patient records. We retrospectively included data from patients with RA who started a TNF inhibitor between 2000 and 2020. In total, …

Background We present a study protocol for a randomized, double-blind, placebo-controlled trial that investigates the hypothesis if intervention in the symptomatic phase preceding clinical arthritis (clinically suspect arthralgia (CSA)) is effective in preventing progression from subclinical inflammation to clinically apparent persistent arthritis. Currently, rheumatoid arthritis (RA) can be recognized and diagnosed when arthritis (joint swelling) has become detectable at physical examination. Importantly, at this time, the immune processes have already matured, chronicity is established, and patients require long-standing treatment with disease-modifying anti-rheumatic drugs. The TREAT EARLIER trial studies the hypothesis that intervention in the symptomatic phase preceding clinical arthritis is more often successful in permanent disease modification because of less matured underlying disease processes. Methods A two-level definition to identify patients that are prone to develop RA is used. First, patients should have CSA and recent-onset arthralgia ( Discussion This proof-of-concept study is the logical consequence of pre-work on the identification of patients with CSA with MRI-detected subclinical joint inflammation. It will test the hypothesis whether intervention in patients in this early phase with the cornerstone treatment of classified RA (methotrexate) hampers the development of persistent RA and reduce the disease burden of RA. Trial registration Dutch Trial Register NL4599 (NTR4853). Registered on 20 October 2014

ObjectivesTo evaluate the 2-year clinical effectiveness of two gradual tapering strategies. The first strategy consisted of tapering the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) first (i.e., methotrexate in ~90%), followed by the tumour necrosis factor inhibitor (TNF-inhibitor), the second strategy consisted of tapering the TNF-inhibitor first, followed by the csDMARD.MethodsThis multicentre single-blinded randomised controlled trial included patients with rheumatoid arthritis (RA) with well-controlled disease for ≥3 consecutive months, defined as a Disease Activity Score (DAS) measured in 44 joints ≤2.4 and a swollen joint count ≤1, which was achieved with a csDMARD and a TNF-inhibitor. Eligible patients were randomised into gradual tapering the csDMARD followed by the TNF-inhibitor, or vice versa. The primary outcome was the number of disease flares. Secondary outcomes were DMARD-free remission (DFR), DAS, functional ability (Health Assessment Questionnaire Disability Index (HAQ-DI)) and radiographic progression.Results189 patients were randomly assigned to tapering their csDMARD (n=94) or TNF-inhibitor (n=95) first. The cumulative flare rate after 24 months was, respectively, 61% (95% CI 50% to 71%) and 62% (95% CI 52% to 72%). The patients who tapered their csDMARD first were more often able to go through the entire tapering protocol and reached DFR more often than the group that tapered the TNF-inhibitor first (32% vs 20% (p=0.12) and 21% vs 10% (p=0.07), respectively). Mean DAS and HAQ-DI over time, and radiographic progression did not differ between groups (p=0.45, p=0.17, p=0.8, respectively).ConclusionThe order of tapering did not affect flare rates, DAS or HAQ-DI. DFR was achievable in 15% of patients with established RA, slightly more frequent in patients that first tapered csDMARDs. Because of similar effects from a clinical viewpoint, financial arguments may influence the decision to taper TNF-inhibitors first.

ObjectivesThe aim of this study is to evaluate the effectiveness of two tapering strategies after achieving controlled disease in patients with rheumatoid arthritis (RA), during 1 year of follow-up.MethodsIn this multicentre single-blinded (research nurses) randomised controlled trial, patients with RA were included who achieved controlled disease, defined as a Disease Activity Score (DAS) ≤ 2.4 and a Swollen Joint Count (SJC) ≤ 1, treated with both a conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and a TNF inhibitor. Eligible patients were randomised into gradual tapering csDMARDs or TNF inhibitors. Medication was tapered if the RA was still under control, by cutting the dosage into half, a quarter and thereafter it was stopped. Primary outcome was proportion of patients with a disease flare, defined as DAS > 2.4 and/or SJC > 1. Secondary outcomes were DAS, European Quality of Life-5 Dimensions (EQ5D) and functional ability (Health Assessment Questionnaire Disability Index [HAQ-DI]) after 1 year and over time.ResultsA total of 189 patients were randomly assigned to tapering csDMARDs (n = 94) or tapering anti-TNF (n = 95). The cumulative flare rates in the csDMARD and anti-TNF tapering group were, respectively, 33 % (95% CI,24% to 43 %) and 43 % (95% CI, 33% to 53 % (p = 0.17). Mean DAS, HAQ-DI and EQ-5D did not differ between tapering groups after 1 year and over time.ConclusionUp to 9 months, flare rates of tapering csDMARDs or TNF inhibitors were similar. After 1 year, a non-significant difference was found of 10 % favouring csDMARD tapering. Tapering TNF inhibitors was, therefore, not superior to tapering csDMARDs. From a societal perspective, it would be sensible to taper the TNF inhibitor first, because of possible cost reductions and less long-term side effects.Trial registration numberNTR2754

Background: Previous studies have shown that it is possible to taper DMARDs in RA patients with an inactive disease, but this is accompanied with a higher chance of disease flares. Current recommendations advise to taper DMARDs from a clinical viewpoint. However, data on the feasibility of tapering DMARDs from a patient’s perspective are sparse. Objectives: To determine the impact of flare after DMARD-tapering on patients quantifying the changes in patient relevant domains e.g. functional ability, fatigue, quality of life, and worker productivity, and to explore the duration of the effect. Methods: Data were used from all 113 patients that flared after tapering DMARDs in the TARA study, a multicenter randomised controlled trial in which patients in sustained remission (DAS Results: In total, 113 patients experienced a flare. Patients who had a flare had a less stable course of the outcomes over time, compared with patients without flare (Figure 1A-G). When comparing all time points to baseline, statistical significant differences were found for DAS44 (p Conclusion: Having a flare does affect patient reported outcomes. It affects DAS44, VAS general health, morning stiffness, functional ability, quality of life, and fatigue. This effect lasted for more than 6 months. Although we only found minor differences with baseline on group level, on the individual patient level this can still be of great importance. Disclosure of Interests: Elise van Mulligen: None declared, Angelique Weel: None declared, Martijn Kuijper: None declared, Johanna Hazes: None declared, Annette van der Helm - van Mil Grant/research support from: The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting grant, agreement No 714312) and from the Dutch Arthritis Foundation. The funding source had no role in the design and conduct of the study., Pascal de Jong: None declared

OBJECTIVE: The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients.METHODS: A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis.RESULTS: The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m2, ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folateCONCLUSIONS: A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX.

We appreciate the interest of Garcia and Abud-Mendoza in our article on tapering towards disease-modifying antirheumatic drug (DMARD)-free remission (DFR), and we would like to respond to the points that were brought up.1 2 Garcia and Abud-Mendoza1 proposed two ways to reduce the amount of flares during tapering of medication, namely (1) the (continuous) use of low-dose glucocorticoids (GCs) and (2) the use of ultrasound to detect subclinical synovitis before a flare occurs. Although the (continuous) use of low-dose GCs might help in tapering DMARDs, including biologicals, to lower dosages without experiencing a flare, it does not alter the DFR rates because, in our opinion, patients are only in DFR if they do not use any DMARD, including GCs. However, we believe that DFR is not a suitable treatment goal because only 15% of patients with rheumatoid arthritis (RA) …

ObjectiveTo identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA).MethodsIn U-Act-Early, 108 disease-modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) ResultsWithin 1 year, 56/108 (52%) patients in U-Act-Early showed IR to ‘MTX+’. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively.ConclusionHigher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up ‘MTX+’ in DMARD-naive patients with new-onset RA.Trial registrationNCT01034137; Post-results, ISRCTN26791028; Post-results.

Background: Randomised controlled trials (RCTs) are the gold standard to estimate treatment effects. When patients receive effective treatment over time they may reach the limit of a certain measurement scale. This phenomenon is known as censoring and leads to skewed distributions of the outcome variable with an excess of either low (floor effect) or high values (ceiling effect). Applying traditional methods such as linear mixed models to analyse these kind of longitudinal RCT data may result in bias of the regression coefficients. To deal with floor effects due to censoring, a tobit mixed model can be used. The objective of this study was to compare the results of longitudinal linear mixed model analyses with longitudinal tobit mixed model analyses. Methods: A simulation study was performed in which several situations of RCTs with floor effects were simulated. From the simulated datasets, which were set up to estimate the interaction between treatment and time, the regression coefficient for this interaction and for the overall treatment effect were estimated. Additionally, data from an empirical RCT were analysed with both methods. Results: Regarding the interaction between treatment and time, the results of the tobit mixed model analysis were the same as the true values in all conditions, while the linear mixed model analysis revealed highly underestimated regression coefficients. However, the overall treatment effect with an increasing number of follow-up measurements in combination with a strong floor effect showed that the estimates from the tobit mixed model were also not accurate. Conclusion: Tobit mixed model analysis should be used to estimate treatments effects in longitudinal RCTs with floor effects due to censoring. © 2018, Prex S.p.A. All rights reserved.

Recently, we identified baseline higher disease activity score assessing 28 joints, current smoking and no alcohol consumption as predictors of inadequate response (IR) to methotrexate (MTX), used with or without other conventional synthetic disease modifying anti-rheumatic drugs, here designated as ‘MTX+’, in new-onset rheumatoid arthritis (RA).1 For those with a predicted IR to ‘MTX+’, a more intensive treatment strategy could be initiated, if prediction would be reliable. Therefore, we investigated, within the same patient population, protein biomarkers for additive predictive value to these clinical predictors. A model was developed using data from patients with RA in the U-Act-Early trial (ClinicalTrials.gov number NCT01034137) treated with a step-up MTX strategy (n=106) and was validated in patients who received MTX therapy (n=80) in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH, ISRCTN26791028).2,3 IR to ‘MTX+’ therapy was defined as the need to initiate a biological within the first treatment year. In baseline serum, 85 proteins were analysed in 2014 using multiplex Luminex profiling; seven candidate proteins, identified by partial least square discriminant analyses, were remeasured in 2018. Clinical baseline characteristics of the patients in both studies are shown in table 1. Of the proteins identified in the development cohort, in the …

Fertility is impaired in women with rheumatoid arthritis (RA), whereas less is known about male fertility problems. Pregnancy outcome in patients with RA is slightly less favorable compared with the general population, especially in patients with active disease. Disease activity usually improves during pregnancy, but less than previously thought. Although several antirheumatic drugs are contraindicated in pregnancy, more treatment options are available. There is evidence on the safety of TNF inhibitors in pregnancy. Given the impact of active disease on fertility and pregnancy outcome, a treat-to-target strategy is recommended for patients who are pregnant or have a wish to conceive.

Objective To investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA1c) levels in rheumatoid arthritis (RA) patients. Methods The derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease-modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu1–5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA1c were compared by paired t-test. Associations of MTXGlu concentrations with changes in the level of HbA1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort. Results In the derivation cohort, the mean change in HbA1c level after 3 months of treatment was −1.9 mmoles/mole (−0.18%) (P = 0.001). Levels of HbA1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, −5.5 mmoles/mole (−0.50%) (P < 0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, –3.7 mmoles/mole (−0.34%) (P < 0.001), for the MTX treatment arm, −0.8 mmoles/mole (−0.08%) (P = 0.018), and for the HCQ treatment arm, −2.0 mmoles/mole (−0.19%) (P = 0.175). Increased levels of MTXGlu2 (β = −0.20, P = 0.005), MTXGlu3 (β = −0.31, P < 0.001), MTXGlu4 (β = −0.33, P < 0.001) after treatment, MTXGlu5 (β = −0.39, P < 0.001), and total MTXGlu (β = −0.29, P < 0.001) were associated with decreased levels of HBA1c. In the validation cohort, levels of HbA1c were decreased by 2.6 mmoles/mole (0.23%) (P < 0.001) after treatment, and MTXGlu3 was associated with decreased levels of HbA1c (β = −0.26, P = 0.018). Conclusion MTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA1c levels, and glucocorticoid treatment resulted in increased levels of HbA1c.

We are pleased about the interest in our article by Mishra et al and we would like to respond to their questions so that there can be no ambiguity.1 2 First of all, there is some clarification needed on the conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) that were used in combination with the TNF-inhibitors at baseline in the TApering strategies in Rheumatoid Arthritis (TARA) study. In table 1, we elaborate on the different combinations of csDMARDs that were used for each intervention arm separately. In the csDMARD tapering group, the methotrexate (MTX) was tapered, except for the three patients who did not use MTX. These patients gradually tapered leflunomide (n=1) and sulfasalazine (n=2). View this table: Table 1 Use of csDMARDs at baseline in the TARA study …

OBJECTIVE: To evaluate direct and indirect costs per quality adjusted life year (QALY) for different initial treatment strategies in very early RA.METHODS: The 1-year data of the treatment in the Rotterdam Early Arthritis Cohort trial were used. Patients with a high probability (>70%) according to their likelihood of progressing to persistent arthritis, based on the prediction model of Visser, were randomized into one of following initial treatment strategies: (A) initial triple DMARD therapy (iTDT) with glucocorticoids (GCs) intramuscular (n = 91); (B) iTDT with an oral GC tapering scheme (n = 93); and (C) initial MTX monotherapy (iMM) with GCs similar to B (n = 97). Data on QALYs, measured with the Dutch EuroQol, and direct and indirect cost were used. Direct costs are costs of treatment and medical consumption, whereas indirect costs are costs due to loss of productivity.RESULTS: Average QALYs (sd) for A, B and C were, respectively, 0.75 (0.12), 0.75 (0.10) and 0.73 (0.13) for Dutch EuroQol. Highest total costs per QALY (sd) were, respectively, €12748 (€18767), €10 380 (€15 608) and €17 408 (€21 828) for strategy A, B and C (P = 0.012, B vs C). Direct as well as indirect costs were higher with iMM (strategy C) compared with iTDT (strategy B). Higher direct costs were due to ∼40% more biologic usage over time. Higher indirect costs, on the other hand, were caused by more long-term sickness and reduction in contract hours. iTDT was >95% cost-effective across all willingness-to-pay thresholds compared with iMM.CONCLUSION: iTDT was more cost-effective and had better worker productivity compared with iMM.

Introduction: Patients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA(+) RA and differences in treatment outcome between these subpopulations suggest that ACPA(+) and ACPA(-) RA are different disease subsets. The identification of T-helper (Th) cells specifically recognizing citrullinated peptides, combined with the strong association between HLA-DRB1 and ACPA positivity, point toward a pathogenic role of Th cells in ACPA(+) RA. In this context we recently identified a potential pathogenic role for CCR6(+) Th cells in RA. Therefore, we examined whether Th cell population distributions differ by ACPA status. Methods: We performed a nested matched case-control study including 27 ACPA(+) and 27 ACPA-treatment-naive early RA patients matched for disease activity score in 44 joints, presence of rheumatoid factor, sex, age, duration of complaints and presence of erosions. CD4(+)CD45RO(+) (memory) Th cell distribution profiles from these patients were generated based on differential chemokine receptor expression and related with disease duration. Results: ACPA status was not related to differences in total CD4(+) T cell or memory Th cell proportions. However, ACPA(+) patients had significantly higher proportions of Th cells expressing the chemokine receptors CCR6 and CXCR3. Similar proportions of CCR4(+) and CCR10(+) Th cells were found. Within the CCR6(+) cell population, four Th subpopulations were distinguished based on differential chemokine receptor expression: Th17 (CCR4(+)CCR10(-)), Th17.1 (CXCR3(+)), Th22 (CCR4(+)CCR10(+)) and CCR4/CXCR3 double-positive (DP) cells. In particular, higher proportions of Th22 (p = 0.02), Th17.1 (p = 0.03) and CCR4/CXCR3 DP (p = 0.01) cells were present in ACPA(+) patients. In contrast, ACPA status was not associated with differences in Th1 (CCR6-CXCR3(+); p = 0.90), Th2 (CCR6(-)CCR4(+); p = 0.27) and T-regulatory (CD25(hi)FOXP3(+); p = 0.06) cell proportions. Interestingly, CCR6(+) Th cells were inversely correlated with disease duration in ACPA-patients (R-2 = -0.35; p < 0.01) but not in ACPA(+) (R-2 < 0.01; p = 0.94) patients. Conclusions: These findings demonstrate that increased peripheral blood CCR6(+) Th cells proportions distinguish ACPA(+) RA from ACPA(-) RA. This suggests that CCR6(+) Th cells are involved in the differences in disease severity and treatment outcome between ACPA(+) and ACPA(-) RA.

To investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA1c ) levels in rheumatoid arthritis (RA) patients.The derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease-modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu1-5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA1c were compared by paired t-test. Associations of MTXGlu concentrations with changes in the level of HbA1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort.In the derivation cohort, the mean change in HbA1c level after 3 months of treatment was -1.9 mmoles/mole (-0.18%) (P = 0.001). Levels of HbA1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, -5.5 mmoles/mole (-0.50%) (P0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, -3.7 mmoles/mole (-0.34%) (P0.001), for the MTX treatment arm, -0.8 mmoles/mole (-0.08%) (P = 0.018), and for the HCQ treatment arm, -2.0 mmoles/mole (-0.19%) (P = 0.175). Increased levels of MTXGlu2 (β = -0.20, P = 0.005), MTXGlu3 (β = -0.31, P0.001), MTXGlu4 (β = -0.33, P0.001) after treatment, MTXGlu5 (β = -0.39, P0.001), and total MTXGlu (β = -0.29, P0.001) were associated with decreased levels of HBA1c . In the validation cohort, levels of HbA1c were decreased by 2.6 mmoles/mole (0.23%) (P0.001) after treatment, and MTXGlu3 was associated with decreased levels of HbA1c (β = -0.26, P = 0.018).MTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA1c levels, and glucocorticoid treatment resulted in increased levels of HbA1c .

OBJECTIVE: To evaluate the therapeutic and economic consequences of various disease activity indices (DAIs) in RA according to 1987 and 2010 criteria.METHODS: Data on disease activity states from all sustained visits were assessed from all patients who participate in the treatment in the Rotterdam Early Arthritis Cohort (tREACH) study, a stratified randomized trial to evaluate different treatment strategies in patients with a symptom duration of RESULTS: DAIs perform similar in RA according to 1987 and 2010 criteria. A total of 1104 DASs per DAI were available from 296 patients. DAIs differ significantly, compared with DASs, in classifying a patient's disease state. Consequently, treatment intensifications occur more frequently with SDAI, CDAI and DAS-28 usage, compared with DAS. Tapering treatment occurs less frequently with SDAI and CDAI and more frequently with DAS-28 usage. Simulated annual median medication costs are significantly higher if DAS-28, SDAI and CDAI are used compared with DAS usage.CONCLUSION: Usage of various DAIs in a single patient leads to inconsistent disease state categorizations. Consequently, these inconsistencies significantly influence therapeutic decisions and accompanying costs. As DAI usage is imperative to uphold current European League Against Rheumatology (EULAR) treatment recommendations, physicians should consider these therapeutic and economic consequences before choosing a particular DAI.

OBJECTIVE: To investigate if erythrocyte-methotrexate-polyglutamate (MTX-PG) concentrations in patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events.METHODS: We used a longitudinal study design with two cohorts. The derivation cohort included 102 and the validation cohort included 285 patients with RA on MTX. We measured erythrocyte-MTX-PG with 1-5 glutamate residues at 3 months, 6 months and 9 months after MTX start with a liquid chromatography (LC)-mass spectrometry (MS)/MS assay. Outcomes were disease activity score in 28 joints (DAS28) and adverse events. Longitudinal associations of MTX-PG concentrations after 3 months, 6 months and 9 months with DAS28 were tested with a linear mixed model adjusted for age, gender, baseline DAS28, MTX dose and comedication.RESULTS: In the derivation cohort, mean DAS28 decreased from 4.26 (SE=0.14) at baseline to 2.72 (SE=0.13) after 9 months. Thirty per cent of patients in the derivation cohort experienced more than three adverse events after 3 months, which decreased to 18% after 9 months. In the validation cohort, DAS28 and adverse events were comparable with the derivation cohort. In the derivation cohort, MTX-PG1 (ß=-0.005), MTX-PG2 (ß=-0.022), MTX-PG3 (β=-0.007) and total MTX-PG (ß=-0.004) were associated (pCONCLUSIONS: In this first longitudinal study, we showed that an increase in erythrocyte-MTX-PG concentration was associated with a decreased DAS28 over 9 months in two cohorts, and is therefore a potential tool for therapeutic drug monitoring of MTX in RA.

Introduction Genetic and disease-related factors give rise to a wide spectrum of glucocorticoid (GC) sensitivity in rheumatoid arthritis (RA). In clinical practice, GC treatment is not adapted to these differences in GC sensitivity. In vitro assessment of GC sensitivity before the start of therapy could allow more individualized GC therapy. The aim of the study was to investigate the association between in vitro and in vivo GC sensitivity in RA. Methods Thirty-eight early and 37 established RA patients were prospectively studied. In vitro GC sensitivity was assessed with dexamethasone-induced effects on interleukin-2 (IL-2) and glucocorticoid-induced leucine zipper (GILZ) messenger RNA expression in peripheral blood mononuclear cells (PBMCs). A whole-cell dexamethasone-binding assay was used to measure number and affinity (1/KD) of glucocorticoid receptors (GRs). In vivo GC sensitivity was determined by measuring the disease activity score (DAS) and health assessment questionnaire disability index (HAQ-DI) score before and after 2 weeks of standardized GC treatment. Results GR number was positively correlated with improvement in DAS. IL-2-EC50 and GILZ-EC50 values both had weak near-significant correlations with clinical improvement in DAS in intramuscularly treated patients only. HAQ responders had lower GILZ-EC50 values and higher GR number and KD. Conclusions Baseline cellular in vitro glucocorticoid sensitivity is modestly associated with in vivo improvement in DAS and HAQ-DI score after GC bridging therapy in RA. Further studies are needed to evaluate whether in vitro GC sensitivity may support the development of tailor-made GC therapy in RA.