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Introduction: Drug-free remission (DFR) and its maintenance have been defined as the most desirable outcome for rheumatoid arthritis (RA) patients. DFR is linked to resolution of arthritis-related symptoms and restoration of normal functioning. However, there is currently no consensus if an optimal strategy, upon the initiation of treatment to the proper drugs withdrawal, is enough to induce it, or whether it is a predetermined condition related to patients' intrinsic characteristics. Areas covered: This review focuses on two key concepts around DFR. First, we analyze patients' intrinsic factors that may increase the chance of DFR, regardless of therapeutic choices. Second, we discuss on the evidence that it can be induced thanks to adequate, extrinsic disease management. Finally, we provide a glimpse into consequences of drugs discontinuation .Expert opinion: The early initiation of DMARD and the subsequent strict monitoring and drug adjustments are of primary importance to allow patients to achieve DFR, irrespective of initial treatment strategy. Once remission is obtained and maintained, it is possible to gradually taper and discontinue drugs with no dramatic consequences on the disease course. Among those who stop medication, ACPA-negative patients more often maintain the remission. Thus, DFR might depend on a combination of intrinsic and extrinsic factors.

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.

Objectives Our study aims to describe the association between SLE and sexual function, analysing demographic variables, comorbidities and other disease-related factors. As an exploratory objective, the impact of asking about sexual function during outpatient consultation was evaluated. Methods From 2018 to 2019, we invited sexually active men diagnosed with SLE to complete questionnaires that evaluated their sexual function and quality of life. Additionally, patients were asked if they believed they had sexual dysfunction, whether they would be interested in receiving specialized sexual care, and if they considered SLE to be detrimental to their sexual function. Epidemiological and disease-related data were retrieved from the patients’ clinical records. Results We included 124 men with SLE. Twenty-two (18%) patients answered positively when asked if they believed they had sexual dysfunction. These patients had lower overall erectile function scores and lower physical function scores than those who did not consider they had sexual dysfunction. In the multivariable analysis, factors that were associated with better sexual function were high physical function (B = 0.126, p = .031), lower BMI (B = 0.53, p = .010) and the patient’s perception of normal sexual function (B = 13.0, p < .001). Comorbidities associated with worse sexual function were type 2 diabetes (B = −8.1, p = .017) and a history of thrombosis (B = −5.12, p = .019). Conclusion Sexual function of male patients with SLE is impaired, independently of disease activity, chronic disease damage or pharmacological treatment. A simple question about perception of sexual function in the outpatient clinic can be used to help determine which patients could benefit from a multidisciplinary intervention to improve sexual health.

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 Morning stiffness (MS) is characteristic of RA and associates with markers of systemic and local inflammation in RA patients. In patients with arthralgia, MS is a cardinal symptom to recognize arthralgia at-risk for RA development [i.e. clinically suspect arthralgia (CSA)]. In CSA, MS is also assumed to reflect inflammation, but this has never been studied. Therefore we aimed to study whether MS in CSA patients is associated with systemic and subclinical joint inflammation. Methods A total of 575 patients presenting with CSA underwent laboratory investigations and contrast-enhanced 1.5 T MRI of the hand and forefoot (scored according to the Rheumatoid Arthritis MRI Score method). Associations of MS (duration ≥60 min) with the presence of subclinical joint inflammation (synovitis, tenosynovitis and osteitis) and increased CRP (≥5 mg/l) were determined with logistic regression. Additionally, the effect of MS duration (≥30, ≥60 and ≥120 min) was studied. Results A total of 195 (34%) CSA patients experienced MS. These patients more often had subclinical synovitis [34% vs 21%; odds ratio (OR) 1.95 (95% CI 1.32, 2.87)], subclinical tenosynovitis [36% vs 26%; OR 1.59 (95% CI 1.10, 2.31)] and increased CRP [31% vs 19%; OR 1.93 (95% CI 1.30, 2.88)] than patients without MS. In multivariable analyses, subclinical synovitis [OR 1.77 (95% CI 1.16, 2.69)] and CRP [OR 1.78 (95% CI 1.17–2.69)] remained independently associated with MS. In CSA patients who later developed RA, and thus in retrospect were ‘pre-RA’ at the time of CSA, MS was more strongly associated with subclinical synovitis [OR 2.56 (95% CI 1.04, 6.52)] and CRP [OR 3.86 (95% CI 1.45, 10.24)]. Furthermore, associations increased with longer MS durations. Conclusion Inflammation associates with MS in the CSA phase that preceded clinical arthritis. These results increase our understanding of MS when assessing arthralgia in clinical practice.

BackgroundClinically suspect arthralgia (CSA) is characterised by arthralgia of small joints and considered a risk stage for development of rheumatoid arthritis (RA). However, it remains unknown if the function of the hands is already affected and what mechanisms underlie impaired hand-function in CSA.MethodsWe studied various measures of hand function in two CSA populations. CSA patients in the TREAT EARLIER-trial (n=236) were evaluated at baseline for: grip strength on a dynamometer (GS), patient-reported difficulties in the grip domain of the Health Assessment Questionnaire (HAQ) questionnaire and incomplete fist closure at physical examination. Findings were validated in an independent CSA cohort (n=600) where hand function was measured as: GS evaluated by squeezing the examiner’s fingers, grip domain of the HAQ questionnaire and fist closure. Contrast-enhanced MRI of the hands measured synovitis, tenosynovitis and bone marrow oedema (summed as subclinical inflammation) in both cohorts.ResultsGS (on a dynamometer) was reduced in 75% compared with reference values in healthy controls, 60% reported grip difficulties and 13% had incomplete fist closure. Reduced GS was associated with subclinical inflammation (−0.38 kg/point inflammation, 95% CI −0.68 to −0.08). Studying separate MRI features, GS reduction was independently associated with tenosynovitis, decreasing with −2.63 kg (95% CI −2.26 to −0.33)/point tenosynovitis (range observed tenosynovitis scores: 0–20). Similar relations with tenosynovitis were seen for patient-reported grip difficulties (OR 1.12/point, 95% CI 1.07 to 1.42) and incomplete fist closure (OR 1.36/point, 95% CI 1.03 to 1.79). In the validation cohort, 36% had decreased examiner-assessed GS, 51% reported grip difficulties and 14% incomplete fist closure: all were associated with tenosynovitis. Decreased dynamometer-measured GS was most sensitive for detecting tenosynovitis (75%), while incomplete fist closure was most specific (88%–90%).ConclusionHand function is already often affected before RA development. These limitations are related to subclinical inflammation and tenosynovitis in particular.

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 (

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.

Objective: Fatigue is a prominent and disabling symptom in patients with rheumatoid arthritis (RA), that is only partially explained by inflammation and responds poorly to DMARD-therapy. We hypothesized that inflammation explains fatigue to a larger extent in the phase of clinically suspect arthralgia (CSA), when persistent clinical arthritis is still absent and fatigue has not yet become chronic. We therefore studied the course of fatigue in CSA during progression to RA and the association with inflammation at CSA-onset and at RA-diagnosis. Methods: 600 consecutive CSA-patients were followed for RA-development. Additionally, 710 early RA-patients were studied at diagnosis. Fatigue was assessed every study visit and expressed on a 0-100 scale. Inflammation was measured with the DAS44-CRP, with and without including subclinical inflammation. The course of fatigue over time was studied with linear mixed models. Associations between fatigue and inflammation were studied with linear regression. Analyses were stratified by ACPA-status. Results: In 88 CSA-patients who developed RA, pre-arthritis fatigue-levels increased gradually with 7 points/year, towards 48 (95%CI=41-55) at RA-development (P=ns). Fatigue decreased in CSA-patients who did not develop RA (4 points/year, P

Objectives Identifying patients that will develop RA among those presenting with undifferentiated arthritis (UA) remains a clinical dilemma. Although MRI is helpful according to EULAR recommendations, this has only been determined in UA patients not fulfilling 1987 RA criteria, while some of these patients are currently considered as RA because they fulfil the 2010 criteria. Therefore, we studied the predictive value of MRI for progression to RA in the current UA population, i.e. not fulfilling RA classification criteria (either 1987 or 2010 criteria) and not having an alternate diagnosis. Additionally, the value of MRI was studied in patients with a clinical diagnosis of UA, regardless of the classification criteria. Methods Two UA populations were studied: criteria-based UA as described above (n = 405) and expert-opinion-based UA (n = 564), i.e. UA indicated by treating rheumatologists. These patients were retrieved from a large cohort of consecutively included early arthritis patients that underwent contrast-enhanced MRI scans of hand and foot at baseline. MRIs were scored for osteitis, synovitis and tenosynovitis. Patients were followed for RA development during the course of 1 year. Test characteristics of MRI were determined separately for subgroups based on joint involvement and autoantibody status. Results Among criteria-based UA patients (n = 405), 21% developed RA. MRI-detected synovitis and MRI-detected tenosynovitis were predictive for progression to RA. MRI-detected tenosynovitis was independently associated with RA progression (odds ratio (OR) 2.79; 95% CI 1.40, 5.58), especially within ACPA-negative UA patients (OR 2.91; 95% CI 1.42, 5.96). Prior risks of RA development for UA patients with mono-, oligo- and polyarthritis were 3%, 19% and 46%, respectively. MRI results changed this risk most within the oligoarthritis subgroup: positive predictive value was 27% and negative predictive value 93%. Similar results were found in expert-opinion-based UA (n = 564). Conclusion This large cohort study showed that MRI is most valuable in ACPA-negative UA patients with oligoarthritis; a negative MRI could aid in preventing overtreatment.

To compare (sustained) DMARD-free remission rates((S)DFR), defined as respectively ≥6 months and1 year, after 2 and 5 years between three clinical arthritis phenotypes; undifferentiated arthritis(UA), autoantibody-negative(RA-) and positive rheumatoid arthritis(RA+).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 used. (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), respectively defined as 12 and12 months after reaching DFR, were also compared. Cox proportional hazard models were used to evaluate potential predictors for (S)DFR.Within 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 within 2 and 5 years (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, BMI and smoking were negatively associated with (S)DFR, while clinical phenotype(reference RA+), short symptom duration(6 months) and remission within 6 months were positively associated.(Long-term) clinical outcomes differ between undifferentiated arthritis, autoantibody-negative and positive rheumatoid arthritis(RA). These data reconfirm that RA can be subdivided into aforementioned clinical phenotypes and that treatment might be stratified upon these phenotypes, although validation is needed.ISRCTN, https://www.isrctn.com/, ISRCTN26791028.

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, …

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.

In vascular tissue engineering strategies, the addition of vascular-specific extracellular matrix (ECM) components may better mimic the in vivo microenvironment and potentially enhance cell&ndash, matrix interactions and subsequent tissue growth. For this purpose, the exact composition of the human vascular ECM first needs to be fully characterized. Most research has focused on characterizing ECM components in mature vascular tissue, however, the developing fetal ECM matches the active environment required in vascular tissue engineering more closely. Consequently, we characterized the ECM protein composition of active (fetal) and quiescent (mature) renal arteries using a proteome analysis of decellularized tissue. The obtained human fetal renal artery ECM proteome dataset contains higher levels of 15 ECM proteins versus the mature renal artery ECM proteome, whereas 16 ECM proteins showed higher levels in the mature tissue compared to fetal. Elastic ECM proteins EMILIN1 and FBN1 are significantly enriched in fetal renal arteries and are mainly produced by cells of mesenchymal origin. We functionally tested the role of EMILIN1 and FBN1 by anchoring the ECM secreted by vascular smooth muscle cells (SMCs) to glass coverslips. This ECM layer was depleted from either EMILIN1 or FBN1 by using siRNA targeting of the SMCs. Cultured endothelial cells (ECs) on this modified ECM layer showed alterations on the transcriptome level of multiple pathways, especially the Rho GTPase controlled pathways. However, no significant alterations in adhesion, migration or proliferation were observed when ECs were cultured on EMILIN1- or FNB1-deficient ECM. To conclude, the proteome analysis identified unique ECM proteins involved in the embryonic development of renal arteries. Alterations in transcriptome levels of ECs cultured on EMILIN1- or FBN1-deficient ECM showed that these candidate proteins could affect the endothelial (regenerative) response.

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

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) …

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 …

Pericytes are perivascular cells that can be distinguished from vascular smooth muscle cells by their specific morphology and expression of distinct molecular markers. Found in the microvascular beds distributed throughout the body, they are well known for their regulation of a healthy vasculature. In this review, we examine the mechanism of pericyte support to vasomotion, and the known pathways that regulate pericyte response in angiogenesis and neovascular stabilization. We will also discuss the role of pericytes in vascular basement membrane and endothelial barrier function regulation. In contrast, recent findings have indicated that pericyte dysfunction, characterized by changes in pericyte contractility or pericyte loss of microvascular coverage, plays an important role in onset and progression of vascular-related and fibrogenic diseases. From a therapeutic point of view, pericytes have recently been identified as a putative pool of endogenous mesenchymal stem cells that could be activated in response to tissue injury to contribute to the regenerative process on multiple levels. We will discuss the mechanisms via which pericytes are involved in disease onset and development in a number of pathophysiological conditions, as well as present the evidence that supports a role for multipotent pericytes in tissue regeneration. The emerging field of pericyte research will not only contribute to the identification of new drug targets in pericyte dysfunction associated diseases, but may also boost the use of this cell type in future cell-based regenerative strategies. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Objectives Intermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB. Methods A total of 577 consecutive CSA patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation (synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months follow-up. ACPA stratification was performed. Results At presentation with CSA, 23% had IMB. IMB was more frequent in ACPA-positive than ACPA-negative CSA (47% vs 19%, P Conclusion Approximately a quarter of CSA patients have IMB, which is frequently accompanied by subclinical synovitis and tenosynovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA development.