Linda Dirven

Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study

Objective To describe the disease course after the cessation of infliximab in early rheumatoid arthritis patients with disease activity score (DAS)-steered treatment and to identify predictors of persistent low disease activity. Methods In a post-hoc analysis of the BeSt study, disease activity and joint damage progression were observed in patients treated with methotrexate plus infliximab, who discontinued infliximab after achieving low disease activity (DAS ≤2.4) for 6 months. Predictors were identified using Cox regression analysis. Results 104 patients discontinued infliximab, of whom 77 had received infliximab plus methotrexate as initial treatment. Mean DAS at the time of infliximab cessation was 1.3, median symptom duration was 23 months and median Sharp/van derHeijde score was 5.5. The median follow-up was 7.2 years. Infliximab was re-introduced after loss of low disease activity in 48%, after a median of 17 months. The joint damage progression rate did not increase in the year after cessation, regardless of flare. After re-introduction of infliximab, 84% of these patients again achieved a DAS ≤2.4. In the multivariable model, smoking, infliximab treatment duration ≥18 months and shared epitope (SE) were independently associated with the re-introduction of infliximab: 6% of the non-smoking, SE-negative patients treated <18 months needed infliximab re-introduction. Conclusion Cessation of infliximab was successful in 52%, with numerically higher success rates in patients initially treated with infliximab. Of the 48% who flared, 84% regained low disease activity. The joint damage progression rate did not increase in the year after cessation. Smoking, long infliximab treatment duration and SE were independently associated with re-introduction of infliximab.

The association of treatment response and joint damage with ACPA-status in recent-onset RA: a subanalysis of the 8-year follow-up of the BeSt study

Objective Anticitrullinated protein antibodies (ACPAs) are suggested to identify different subsets of patients with rheumatoid arthritis (RA). The authors compared the clinical and radiological responses to Disease Activity Score (DAS)-steered treatment in patients with RA positive or RA negative for ACPA. Methods In the BehandelStrategieën (BeSt) study, 508 patients with recent-onset RA were randomised to four treatment strategies aimed at a DAS ≤2.4. Risks of damage progression and (drug-free) remission in 8 years were compared for ACPA-positive and ACPA-negative patients using logistic regression analysis. Functional ability and DAS components over time were compared using linear mixed models. Results DAS reduction was achieved similarly in ACPA-positive and ACPA-negative patients in all treatment strategy groups, with a similar need to adjust treatment because of inadequate response. Functional ability and remission rates were not different for ACPA-positive and ACPA-negative patients. ACPA-positive patients had more radiological damage progression, especially after initial monotherapy. They had a lower chance of achieving (persistent) drug-free remission. Conclusion Clinical response to treatment was similar in ACPA-positive and ACPA-negative patients. However, more ACPA-positive patients, especially those treated with initial monotherapy, had significant radiological damage progression, indicating that methotrexate monotherapy and DAS- (≤2.4) steered treatment might be insufficient to adequately suppress joint damage progression in these patients.

Disease flares in rheumatoid arthritis are associated with joint damage progression and disability: 10-year results from the BeSt study

IntroductionFlares in patients with rheumatoid arthritis are suggested to sometimes spontaneously resolve. Targeted therapy could then entail possible overtreatment. We aimed to determine the flare prevalence in patients who are treated-to-target and to evaluate associations between flares and patient-reported outcomes and radiographic progression.MethodsIn the BeSt study, 508 patients were treated-to-target for 10 years. After initial treatment adjustments to achieve disease activity score ≤2.4, a flare was defined from the second year of follow-up onwards, according to three definitions. The first definition is a disease activity score >2.4 with an increase of ≥0.6 regardless of the previous disease activity score. The other definitions will be described in the manuscript.ResultsThe flare prevalence was 4–11 % per visit; 67 % of the patients experienced ≥1 flare during 9 years of treatment (median 0 per patient per year). During a flare, functional ability decreased with a mean difference of 0.25 in health assessment questionnaire (p < 0.001), and the odds ratios (95 % confidence intervals) for an increase in patients’ assessment of disease activity, pain and morning stiffness of ≥20 mm on a visual analogue scale were 8.5 (7.3–9.8), 8.4 (7.2–9.7) and 5.6 (4.8–6.6), respectively, compared to the absence of a flare. The odds ratio for radiographic progression was 1.7 (1.1–2.8) in a year with a flare compared to a year without a flare. The more flares a patient experienced, the higher the health assessment questionnaire at year 10 (p < 0.001) and the more radiographic progression from baseline to year 10 (p = 0.005).ConclusionFlares were associated with concurrent increase in patient’s assessment of disease activity, pain and morning stiffness, functional deterioration and development of radiographic progression with a dose–response-effect, both during the flare and long term. This suggests that intensifying treatment during a flare outweighs the risk of possible overtreatment.Trial registrationDutch trial registry NTR262 (7 September 2005) and NTR265 (8 September 2005).

Prevalence of vertebral fractures in a disease activity steered cohort of patients with early active rheumatoid arthritis

ObjectiveTo determine the prevalence of vertebral fractures (VFs) after 5u2009years of disease activity score (DAS)-steered treatment in patients with early rheumatoid arthritis (RA) and to investigate the association of VFs with disease activity, functional ability and bone mineral density (BMD) over time.MethodsFive-year radiographs of the spine of 275 patients in the BeSt study, a randomized trial comparing four treatment strategies, were used. Treatment was DAS-steered (DASu2009≤u20092.4). A height reduction >20% in one vertebra was defined a vertebral fracture. With linear mixed models, DAS and Health Assessment Questionnaire (HAQ) scores over 5u2009years were compared for patients with and without VFs. With generalized estimating equations the association between BMD and VFs was determined.ResultsVFs were observed in 41/275 patients (15%). No difference in prevalence was found when stratified for gender, prednisone use and menopausal status. Disease activity over time was higher in patients with VFs, mean difference 0.20 (95% CI: 0.05-0.36), and also HAQ scores were higher, independent of disease activity, with a mean difference of 0.12 (95% CI: 0.02-0.2). Age was associated with VFs (OR 1.06, 95% CI: 1.02-1.09), mean BMD in spine and hip over time were not (OR 95% CI, 0.99: 0.78-1.25 and 0.94: 0.65-1.36, respectively).ConclusionAfter 5u2009years of DAS-steered treatment, 15% of these RA patients had VFs. Higher age was associated with the presence of VFs, mean BMD in hip and spine were not. Patients with VFs have greater functional disability over time and a higher disease activity, suggesting that VFs may be prevented by optimal disease activity suppression.

Rapid radiological progression in the first year of early rheumatoid arthritis is predictive of disability and joint damage progression during 8 years of follow-up

Objective Several prediction models for rapid radiological progression (RRP) in the first year of rheumatoid arthritis have been designed to aid rheumatologists in their choice of initial treatment. The association was assessed between RRP and disability and joint damage progression in 8 years. Methods Patients from the BeSt cohort were used. RRP was defined as an increase of ≥5 points in the Sharp/van der Heijde score (SHS) in year 1. Functional ability over 8 years, measured with the health assessment questionnaire (HAQ), was compared for patients with and without RRP using linear mixed models. Joint damage progression from years 1 to 8 was compared using logistic regression analyses. Results RRP was observed in 102/465 patients. Over 8 years, patients with RRP had worse functional ability: difference in HAQ score 0.21 (0.14 after adjustment for disease activity score (over time)). RRP was associated with joint damage progression ≥25 points in SHS in years 1–8: OR 4.6. Conclusion RRP in year 1 is a predictor of worse functional ability over 8 years, independent of baseline joint damage and disease activity. Patients with RRP have more joint damage progression in subsequent years. RRP is thus a relevant outcome on which to base the initial treatment decision.

A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study.

Objective. To determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis. Methods. There were 180 serum samples available in the BeSt study (trial numbers NTR262, NTR 265): 91 at baseline (84 with radiographs available) and 89 at 1-year followup (81 with radiographs available). Radiographs were assessed using the Sharp/van der Heijde Score (SvdH). Twelve serum biomarkers were measured to determine MBDA scores using a validated algorithm. Receiver-operating curves and Poisson regression analyses were performed, with Disease Activity Score (DAS) and MBDA score as independent variables, and radiographic progression as dependent variable. Results. At baseline, MBDA scores discriminated more between patients who developed radiographic progression (increase in SvdH ≥ 5 points) and patients who did not [area under the curve (AUC) 0.767, 95% CI 0.639–0.896] than did DAS (AUC 0.521, 95% CI 0.358–0.684). At 1 year, MBDA score had an AUC of 0.691 (95% CI 0.453–0.929) and DAS had an AUC of 0.649 (95% CI 0.417–0.880). Adjusted for anticitrullinated protein antibody status and DAS, higher MBDA scores were associated with an increased risk for SvdH progression [relative risk (RR) 1.039, 95% CI 1.018–1.059 for baseline MBDA score; 1.037, 95% CI 1.009–1.065 for Year 1 MBDA score]. Categorized high MBDA scores were also correlated with SvdH progression (RR for high MBDA score at baseline 3.7; low or moderate MBDA score as reference). At 1 year, high MBDA score gave a RR of 4.6 compared to low MBDA score. Conclusion. MBDA scores predict radiographic damage progression at baseline and during disease course.

European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma

Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning.

Changes in hand bone mineral density and the association with the level of disease activity in patients with rheumatoid arthritis: Bone mineral density measurements in a multicenter randomized clinical trial†

To determine if metacarpal bone mineral density (mBMD) gain occurs in patients with rheumatoid arthritis (RA). If mBMD loss is driven by inflammation, we expect to find mBMD gain in patients who are in remission.

Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide

We aimed to analyze the value of seizure reduction and radiological response as prognostic markers of survival in patients with low-grade glioma (LGG) treated with temozolomide (TMZ) chemotherapy. We retrospectively reviewed adult patients with a progressive LGG and uncontrolled epilepsy in two hospitals (VUmc Amsterdam; MCH The Hague), who received chemotherapy with TMZ between 2002 and 2014. End points were axa0≥50xa0% seizure reduction and MRI response 6, 12 and 18xa0months (mo) after the start of TMZ, and their relation with progression-free survival (PFS) and overall survival (OS). We identified 53 patients who met the inclusion criteria. Seizure reduction was an independent prognostic factor for both PFS (HR 0.38; 95xa0% CI 0.19–0.73; pxa0=xa00.004) and OS (HR 0.39; 95xa0% CI 0.18–0.85; pxa0=xa00.018) after 6mo, adjusting for age and histopathological diagnosis, as well as after 12 and 18mo. Patients with an objective radiological response showed a better OS (median 87.5mo; 95xa0% CI 62.0–112.9) than patients without a response (median 34.4mo; 95xa0% CI 26.1–42.6; pxa0=xa00.046) after 12mo. However, after 6 and 18mo OS was similar in patients with and without a response on MRI. Seizure reduction is an early and consistent prognostic marker for survival after treatment with TMZ, that seems to precede the radiological response. Therefore, seizure reduction may serve as a surrogate marker for tumor response.

Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy.

ObjectiveTo determine incidence of increased levels of alanine transferase (ALT) >2× upper limit of normal (ULN) in patients receiving methotrexate (MTX), treated according to a dynamic strategy, and to identify predictors of ALT of >2× ULN.MethodsData of 508 recent-onset rheumatoid arthritis (RA) patients from the BeSt study, randomized to initial monotherapy or combination therapy, were used. Treatment was dynamic, aiming at a disease activity scoreu2009=u2009≤u20092.4. ALT was measured every three months. With logistic regression analyses, baseline variables predictive of first ALT of >2× ULN were identified and the association between use of concomitant antirheumatic drugs, the actual and cumulative dose of MTX and ALT of >2× ULN was determined.ResultsIn total, 498 patients ever initiated MTX, with a total duration on MTX of 1,416 patient-years. In 89 patients, a first incidence of ALT of >2× ULN occurred. Incidence rate was 6.3 per 100 patient-years and cumulative incidence 18xa0%. ACPA positivity and baseline ALT of >1× ULN were independent predictors of later ALT of >2× ULN (OR 1.8 (95xa0% CI, 1.1–3.1) and OR 3.1 (95xa0% CI, 1.6–6.2), respectively). Smoking showed a trend (OR 1.6 (95xa0% CI, 0.98–2.7)). Mean MTX dosage over time was higher in patients with an ALT of >2× ULN. Patients who did not have an ALT of >2× ULN used more concomitant disease-modifying antirheumatic drugs and longer.ConclusionsIn RA patients treated with MTX according to a dynamic strategy resembling daily clinical practice, incidence of increased ALT of >2× ULN was lower than previously reported, and also without treatment adjustments, persistence was rare. The recommendations for ALT monitoring may be reevaluated.