Objectives Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker... Show moreObjectives Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker). In the current study, we examined whether the chronotype, which is influenced by the circadian rhythm, is also earlier. In addition, we explored whether chronotype is related to disease activity and patient-reported outcomes.Methods The chronotype (Munich Chronotype Questionnaire) of patients with RA (n = 121; mean age 60 years, 73% female) was compared with that of subjects from the general population (norm group; n = 1695) with a one-sample t test. In addition, we investigated chronotype in relation to disease activity (Disease Activity Score; DAS), reported morning stiffness, fatigue (Checklist Individual Strength), and health-related quality of life (RAND-36).Results The chronotype of patients with RA was, on average, 23 min (95% CI, 15 to 31 min) earlier than that of the norm group (t(115) = - 5.901, p < 0.001, d = 0.55). Chronotype was not related to disease activity or patient-reported outcomes (p > 0.05).Conclusion As expected, chronotype was earlier in RA patients. However, in this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm has a positive influence on these outcomes. This insight could improve our understanding of the pathophysiology of RA and contribute to exploring new treatment possibilities.Key Points This is the first study examining chronotype in patients with rheumatoid arthritis, and how chronotype relates to disease activity and patient-reported outcomes.We found an earlier chronotype in patients with rheumatoid arthritis than in subjects from the general population.In this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm positively influences these outcomes. Show less
Habers, G.E.A.; Van der Helm, A.H.M.; Veldhuijzen, D.S.; Allaart, C.F.; Vreugdenhil, E.; Starreveld D.E.J.; ... ; Evers, A.W.M. 2021
Objectives SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk... Show moreObjectives SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk of developing complications during pregnancy. Therefore, clinical practice guidelines recommend that patients with SLE/APS should receive multidisciplinary counselling before getting pregnant. We investigated the clinical effectiveness of implementing a multidisciplinary clinical pathway including prepregnancy counselling of patients with SLE/APS. Methods A clinical pathway with specific evaluation and prepregnancy counselling for patients with SLE/APS was developed and implemented in a tertiary, academic hospital setting. Patients were prospectively managed within the clinical pathway from 2014 onwards and compared with a retrospective cohort of patients that was not managed in a clinical pathway. Primary outcome was a combined outcome of disease flares for SLE and thromboembolic events for APS. Secondary outcomes were maternal and fetal pregnancy complications. Results Seventy-eight patients with 112 pregnancies were included in this study. The primary combined outcome was significantly lower in the pathway cohort (adjusted OR (aOR) 0.20 (95% CI 0.06 to 0.75)) which was predominantly determined by a fivefold risk reduction of SLE flares (aOR 0.22 (95% CI 0.04 to 1.09)). Maternal and fetal pregnancy complications were not different between the cohorts (respectively, aOR 0.91 (95% CI 0.38 to 2.17) and aOR 1.26 (95% CI 0.55 to 2.88)). Conclusions The outcomes of this study suggest that patients with SLE/APS with a pregnancy wish benefit from a multidisciplinary clinical pathway including prepregnancy counselling. Show less
Niemantsverdriet, E.; Dakkak, Y.J.; Burgers, L.E.; Bonte-Mineur, F.; Steup-Beekman, G.M.; Kooij, S.M. van der; ... ; Helm-van Mil, A.H.M. van der 2020
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... Show moreBackground: 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 (< 1 year) that is suspect to progress to RA according to the expertise of the treating rheumatologist. Second, patients need to have subclinical inflammation of the hand or foot joints at 1.5 T MRI. The trial aims to recruit 230 participants from secondary care hospital settings across the south-west region of The Netherlands. Intervention will be randomly assigned and includes a single-dose of intramuscular 120 mg methylprednisolon followed by methotrexate (increasing dose to 25 mg/week orally) or placebo (both; injection and tablets) over the course of 1 year. Thereafter, participants are followed for another year. The primary endpoint is the development of clinically detectable arthritis, either fulfilling the 2010 criteria for RA or unclassified clinical arthritis of >= 2 joints, which persists for at least 2 weeks. DMARD-free status is a co-primary endpoint. The patient-reported outcomes functioning, along with workability and symptoms, are key secondary endpoints. Participants, caregivers (including those assessing the endpoints), and scientific staff are all blinded to the group assignment.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. Show less
Vanier, A.; Smolen, J.S.; Allaart, C.F.; Vollenhoven, R. van; Verschueren, P.; Vastesaeger, N.; ... ; Fautrel, B. 2020
Objective. In early RA, some patients exhibit rapid radiographic progression (RRP) after one year, associated with poor functional prognosis. Matrices predicting this risk have been proposed,... Show moreObjective. In early RA, some patients exhibit rapid radiographic progression (RRP) after one year, associated with poor functional prognosis. Matrices predicting this risk have been proposed, lacking precision or inadequately calibrated. We developed a matrix to predict RRP with high precision and adequate calibration.Methods. Post-hoc analysis by pooling individual data from cohorts (ESPOIR and Leuven cohorts) and clinical trials (ASPIRE, BeSt and SWEFOT trials). Adult DMARD-naive patients with active early RA for which the first therapeutic strategy after inclusion was to prescribe methotrexate or leflunomide were included. A logistic regression model to predict RRP was built. The best model was selected by 10-fold stratified cross-validation by maximizing the Area Under the Curve. Calibration and discriminatory power of the model were checked. The probabilities of RRP for each combination of levels of baseline characteristics were estimated.Results. 1306 patients were pooled. 20.6% exhibited RRP. Four predictors were retained: rheumatoid factor positivity, presence of at least one RA erosion on X-rays, CRP>30mg/l, number of swollen joints. The matrix estimates RRP probability for 36 combinations of level of baseline characteristics with a greatly enhanced precision compared with previously published matrices (95% CI: from +/- 0.02 minimum to +/- 0.08 maximum) and model calibration is excellent (P = 0.79).Conclusion. A matrix proposing RRP probability with high precision and excellent calibration in early RA was built. Although the matrix has moderate sensitivity and specificity, it is easily usable and may help physicians and patients to make treatment decisions in daily clinical practice. Show less
Objectives To study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in... Show moreObjectives To study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in a real-life longitudinal international registry.Methods Data from 5230 patients with RA starting treatment with any TNFi were selected from the METEOR registry. Patients were divided into six BMI categories: 3.7% underweight, BMI<18.5 kg/m(2); 46% normal weight, BMI 18.5-25 kg/m(2); 32% pre-obesity, BMI 25-30 kg/m(2); 13% obesity class I, BMI 30-35 kg/m(2); 3.4% obesity class II, BMI 35-40 kg/m(2); and 1.6% obesity class III, BMI >40 kg/m(2). Time on treatment in the different BMI categories was compared for all TNFi combined and for the infliximab, adalimumab and etanercept separately, using Kaplan-Meier curves and Cox regression analyses. Cox regression analyses were adjusted for potential confounders, with follow-up censored at 5000 days.Results Patients in obesity class II (HR 1.28, 95% CI 1.06 to 1.54) and III (HR 1.67, 95% CI 1.29 to 2.18) and underweight patients (HR 1.30, 95% CI 1.07 to 1.58) showed statistically significantly shorter TNFi survival than normal weight patients. The effect in underweight patients was strongest for infliximab (HR 1.82, 95% CI 1.20 to 2.76), the effect in overweight patients was strongest for infliximab (category II (HR 1.49, 95% CI 0.98 to 2.26); category III (HR 1.46, 95% CI 0.79 to 2.71)) and etanercept (category II (HR 1.27 95% CI 0.98 to 1.65); category III (HR 1.79, 95% CI 1.25 to 2.55)). No significant effect modification from reported pain was found.Conclusion Both underweight and overweight patients discontinued TNFi treatment earlier than normal weight patients, without evidence of reported pain as the main determinant. It remains uncertain what determines TNFi survival in individual patients. Show less
Ramiro, S.; Landewe, R.B.M.; Heijde, D. van der; Sepriano, A.; FitzGerald, O.; Ostergaard, M.; ... ; Maksymowych, W.P. 2020
ObjectivesTo investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target.MethodsRA... Show moreObjectivesTo investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target.MethodsRA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in >= 2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models.ResultsIn total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52).ConclusionIn daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission. Show less
Multiple pharmacogenetic studies investigated the effectiveness of methotrexate. However, due to the use of nonvalidated outcomes, lack of validation or conflicting results it remains unclear if... Show moreMultiple pharmacogenetic studies investigated the effectiveness of methotrexate. However, due to the use of nonvalidated outcomes, lack of validation or conflicting results it remains unclear if genetic markers can help to predict response to MTX treatment. Therefore, a systematic review was performed. PubMed was searched for articles reporting potential pharmacogenetic biomarkers associated (p < 0.05) with MTX efficacy using the validated endpoints DAS(28), EULAR, or ACR response criteria. The PICO method was used for study selection, and PRISMA guidelines to prepare the report. Thirty-five studies met the inclusion criteria, providing 39 potential genetic biomarkers in 19 genes. After Bonferroni correction, six genetic biomarkers were associated with the efficacy of MTX: ATIC rs7563206; SLC19A1 rs1051266; DHFR rs836788; TYMS rs2244500, rs2847153, and rs3786362 in at least one study. Only SLC19A1 rs1051266 was replicated in an independent cohort and promising for predicting methotrexate efficacy. Show less
Objectives The window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic (... Show moreObjectives The window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic ('curved') decline in the chance to achieve the outcome sustained drug-free remission (sDFR) over time, after which achieving sDFR is not possible anymore, or by a more gradual linear decline approaching zero chance to achieve sDFR.Methods Patients with RA (symptom duration <2 years) were included from two randomised trials: BehandelStrategieen (BeSt), n=508 and Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED), n=479. Cox-regression was performed to assess the shape of the association between symptom duration and sDFR (Disease Activity Score<1.6, no disease-modifying anti-rheumatic drugs for >= 1 year) for patients starting slow-acting monotherapy (IMPROVED, BeSt) or fast-acting combination therapy (BeSt). Likelihood ratio tests were used to compare the fit of linear and non-linear models in both databases separately. Predictions from the best fitting models were used to assess whether the absolute risk to achieve sDFR approaches zero with increasing symptom duration.Results In BeSt and IMPROVED, 54/226 and 110/421 patients achieved sDFR with fast-acting treatment, and 53/243 (BeSt) with slow-acting treatment. Non-linear models did not fit better than linear models (fast-acting treatment BeSt p=0.743, IMPROVED p=0.337; slow-acting treatment BeSt p=0.609). After slow-acting monotherapy, linear models declined steeper. None of the models approached zero chance to achieve sDFR over time.Conclusions The chance to achieve sDFR decreased gradually over time, and decreased fastest in patients starting slow-acting monotherapy. In both treatment groups, we found no evidence for a WOO within 2 years symptom duration. Show less
Objective: To investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA)... Show moreObjective: To investigate whether calprotectin (S100A8/A9 or MRP8/14), an inflammatory complex released by monocytes, could indicate residual subclinical inflammation in rheumatoid arthritis (RA) patients who are in stable remission on disease-modifying anti-rheumatic drugs (DMARDs) and serve as a marker for disease flare after DMARD tapering.Methods: We used data from two trials. Patients from the IMPROVED study had early (< 2 years) RA, and when they achieved disease activity score remission (DAS44 < 1.6), they stopped methotrexate to attempt drug-free remission. Patients from the RETRO study had established RA in stable remission (DAS28 < 2.6) and either tapered by 50% or stopped (biological or conventional) DMARDs. Circulating calprotectin at the tapering time point was determined by ELISA, and its predictive value for flare (loss of remission) within 12 months of DMARD tapering/stopping was determined.Results: In both IMPROVED (n = 104) and RETRO (n = 57), patients that flared within 12 months had higher calprotectin at the moment of DMARD tapering/stopping. Twofold higher calprotectin at the moment of DMARD tapering/stopping was associated with an increased risk (odds ratio) of flare of 1.07 (95% CI 0.98-1.18, p = 0.14) in the IMPROVED and 3.62 (95% CI 1.76-7.46, p < 0.001) in the RETRO. Correcting for clinical predictors of flare (DAS at study inclusion, anti-CCP2 positivity, gender) did not change these estimates. The area under the receiver operating curve of calprotectin levels for predicting flare within 12 months was 0.63 (95% CIs 0.51-0.76) in the IMPROVED study and 0.80 (95% CIs 0.69 to 0.92) in the RETRO study.Conclusion: Circulating calprotectin levels in RA patients in remission on DMARDs are higher in patients that will flare upon DMARD tapering/stopping. Since the differences between the cohorts precluded definitive conclusions, more research is needed to determine whether calprotectin has prognostic value in predicting flare after attempting drug tapering in RA. Show less
Kroon, F.P.B.; Kortekaas, M.C.; Boonen, A.; Bohringer, S.; Reijnierse, M.; Rosendaal, F.R.; ... ; Kloppenburg, M. 2019
Background Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised... Show moreBackground Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised as contributing to osteoarthritic complaints, the Hand Osteoarthritis Prednisolone Efficacy (HOPE) study aimed to investigate the efficacy and safety of short-term prednisolone in patients with painful hand osteoarthritis and synovial inflammation.Methods The HOPE study is a double-blind, randomised, placebo-controlled trial. We recruited eligible adults from rheumatology outpatient clinics at two sites in the Netherlands. Patients were considered eligible if they had symptomatic hand osteoarthritis and signs of inflammation in their distal and proximal interphalangeal (DIP/PIP) joints. For inclusion, patients were required to have four or more DIP/PIP joints with osteoarthritic nodes; at least one DIP/PIP joint with soft swelling or erythema; at least one DIP/PIP joint with a positive power Doppler signal or synovial thickening of at least grade 2 on ultrasound; and finger pain of at least 30 mm on a 100-mm visual analogue scale (VAS) that flared up during a 48-h non-steroidal anti-inflammatory drug (NSAID) washout (defined as worsening of finger pain by at least 20 mm on the VAS). Eligible patients were randomly assigned (1:1) to receive 10 mg prednisolone or placebo orally once daily for 6 weeks, followed by a 2-week tapering scheme, and a 6-week follow-up without study medication. The patients and study team were masked to treatment assignment. The primary endpoint was finger pain, assessed on a VAS, at 6 weeks in participants who had been randomly assigned to groups and attended the baseline visit. This study is registered with the Netherlands Trial Registry, number NTR5263.Findings We screened patients for enrolment between Dec 3, 2015, and May 31, 2018. Patients completed baseline visits and started treatment between Dec 14, 2015, and July 2, 2018, and the last study visit of the last patient was Oct 4, 2018. Of 149 patients assessed for eligibility, 57 (38%) patients were excluded (predominantly because they did not meet one or several inclusion criteria, most often because of an absence of synovial inflammation or of flare-ups after NSAID washout) and 92 (62%) patients were eligible for inclusion. We randomly assigned 46 (50%) patients to receive prednisolone and 46 (50%) patients to receive placebo, all of whom were included in the modified intention-to-treat analysis of the primary endpoint. 42 (91%) patients in the prednisolone group and 42 (91%) in the placebo group completed the 14-week study. The mean change between baseline and week 6 on VAS-reported finger pain was -21.5 (SD 21.7) in the prednisolone group and -5.2 (24.3) in the placebo group, with a mean between-group difference (of prednisolone vs placebo) of -16.5 (95% CI -26.1 to -6.9; p=0.0007). The number of non-serious adverse events was similar between the groups. Five serious adverse events were reported during our study: one serious adverse event in the prednisolone group (a myocardial infarction) and four serious adverse events in the placebo group (an infected traumatic leg haematoma that required surgery, bowel surgery, atrial fibrillation that required a pacemaker implantation, and symptomatic uterine myomas that required a hysterectomy). Four (4%) patients discontinued the study because of an adverse event: one (2%) patient receiving prednisolone (for a myocardial infarction) and three (7%) patients receiving placebo (for surgery of the bowel and for an infected leg haematoma and for Lyme disease arthritis of the knee).Interpretation Treatment with 10 mg prednisolone for 6 weeks is efficacious and safe for the treatment of patients with painful hand osteoarthritis and signs of inflammation. The results of our study provide clinicians with a new short-term treatment option for patients with hand osteoarthritis who report a flare-up of their disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Show less
