Janneke Tekstra

Background: Biological disease-modifying anti-rheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis (RA) but are expensive and increase the risk of infection. Therefore, in patients with a stable low level of disease activity or remission, tapering bDMARDs should be considered. Although tapering does not seem to affect long-term disease control, (short-lived) flares are frequent during the tapering process. We have previously developed and externally validated a dynamic flare prediction model for use as a decision aid during stepwise tapering of bDMARDs to reduce the risk of a flare during this process. Methods: In this investigator-initiated, multicenter, open-label, randomized (1:1) controlled trial, we will assess the effect of incorporating flare risk predictions into a bDMARD tapering strategy. One hundred sixty RA patients treated with a bDMARD with stable low disease activity will be recruited. In the control group, the bDMARD will be tapered according to “disease activity guided dose optimization” (DGDO). In the intervention group, the bDMARD will be tapered according to a strategy that combines DGDO with the dynamic flare prediction model, where the next bDMARD tapering step is not taken in case of a high risk of flare. Patients will be randomized 1:1 to the control or intervention group. The primary outcome is the number of flares per patient (DAS28-CRP increase > 1.2, or DAS28-CRP increase > 0.6 with a current DAS28-CRP ≥ 2.9) during the 18-month follow-up period. Secondary outcomes include the number of patients with a major flare (flare duration ≥ 12 weeks), bDMARD dose reduction, adverse events, disease activity (DAS28-CRP) and patient-reported outcomes such as quality of life and functional disability. Health Care Utilization and Work Productivity will also be assessed. Discussion: This will be the first clinical trial to evaluate the benefit of applying a dynamic flare prediction model as a decision aid during bDMARD tapering. Reducing the risk of flaring during tapering may enhance the safety and (cost)effectiveness of bDMARD treatment. Furthermore, this study pioneers the field of implementing predictive algorithms in clinical practice. Trial registration: Dutch Trial Register number NL9798, registered 18 October 2021, https://www.trialregister.nl/trial/9798. The study has received ethical review board approval (number NL74537.041.20).

Background: COVID-19 (severe acute respiratory syndrome coronavirus 2) infected patients have increased risk for thrombotic events, which initially may have been under recognized. The existence of cardiovascular emboli can be directly life threatening when obstructing the blood flow to vital organs such as the brain or other parts of the body. The exact mechanism for this hypercoagulable state in COVID-19 patients yet remains to be elucidated. Case summary: A 72-year-old man critically ill with COVID-19 was diagnosed with a free-floating and mural thrombus in the thoracic aorta. Subsequent distal embolization to the limbs led to ischaemia and necrosis of the right foot. Treatment with heparin and anticoagulants reduced thrombus load in the ascending and thoracic aorta. Discussion: One-third of COVID-19 patients show major thrombotic events, mostly pulmonary emboli. The endothelial expression of angiotensin-converting enzyme-2 receptors makes it feasible that in patients with viraemia direct viral-toxicity to the endothelium of also the large arteries results in local thrombus formation. Up to date, prophylactic anticoagulants are recommended in all patients that are hospitalized with COVID-19 infections to prevent venous and arterial thrombotic complications.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. Methods: In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. Discussion: This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. Trial registration: This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set.

The aim of this study was to identify predictors of prolonged disease control after discontinuation of tumor necrosis factor inhibitor (TNFi) treatment in patients with rheumatoid arthritis (RA). Post-hoc analysis of 439 RA patients (67.3% rheumatoid factor positive) with longstanding RA in remission or with stable low disease activity, randomized to stopping TNFi treatment in the multicenter POET trial. Prolonged acceptable disease control was defined as not restarting TNFi treatment within 12 months after stopping. Baseline demographic and disease-related variables were included in univariate and multivariate logistic regression analysis for identifying predictors of relapse. One year after baseline, 220 patients (50.1%) had not restarted TNFi treatment. Use of an anti-TNF monoclonal antibody (versus a receptor antagonist, OR = 2.41; 95% CI: 1.58–3.67), ≤10 yrs. disease duration (OR = 2.15; 95% CI: 1.42–3.26) and low or moderate multi-biomarker disease activity (MBDA) scores (OR = 2.00; 95% CI: 1.10–3.64) at baseline were independently predictive of successful TNFi discontinuation (area under the receiver operating characteristic curve = 0.66; 95% CI: 0.61–0.71). Results were similar when using no physician-reported flare as the criterion. TNFi-free survival was significantly different for patient groups based on the number of predictors present, ranging from 21.4% of patients with no predictor present to 66.7% of patients with all three predictors present. Patients using an anti-TNF monoclonal antibody, with shorter disease duration and low or moderate baseline MBDA score are most likely to achieve prolonged disease control after TNFi discontinuation. Netherlands Trial Register NTR3112 , 21 October 2011.

Assessment of disease activity is a critical component of tight-control, treat-to-target treatment strategies of rheumatoid arthritis (RA). Recently, the HandScan has been validated as a novel method for objectively assessing RA disease activity in only 1.5 min, using optical spectral transmission (OST) in hands and wrists. We describe the protocol of a randomized controlled clinical trial (RCT) to investigate whether HandScan-guided treatment aimed at ‘HandScan remission’ (HandScan arm) is at least as effective as and more cost-effective than clinically guided treatment aimed at ACR/EULAR 2011 Boolean remission (DAS arm). The study is a multi-center, double-blind, non-inferiority RCT of 18 months duration. Patients ≥ 18 years with newly diagnosed, disease-modifying antirheumatic drug (DMARD)-naïve RA according to the ACR 2010 classification criteria, will be randomized to the DAS arm or the HandScan arm. The efficacy of the arms will be compared by evaluating Health Assessment Questionnaire (HAQ) scores (primary outcome) after 18 months of DMARD therapy, aimed at remission. The equivalence margin in HAQ scores between study arms is 0.2. Secondary outcomes are differences in cost-effectiveness and radiographic joint damage between treatment arms. The non-inferiority sample size calculation to obtain a power of 80% at a one-sided p value of 0.05, with 10% dropouts, resulted in 61 patients per arm. In both arms, DMARD strategy will be intensified monthly according to predefined steps until remission is achieved; in both arms DMARDs and treatment steps are identical. If sustained remission, defined as remission that persists consistently over three consecutive months, is achieved, DMARD therapy will be tapered. The study protocol and the specifically designed decision-making software application allow for implementation of this RCT. To test a novel method of assessing disease activity and comparing (cost-)effectiveness with the contemporary method in treat-to-target DMARD strategies in early RA patients. Dutch Trial Register, NTR6388. Registered on 6 April 2017 ( NL50026.041.14 ). Protocol version 3.0, 19-01-2017.

A multi-biomarker disease activity (MBDA) score has been validated as an objective measure of disease activity in rheumatoid arthritis (RA) and shown to track response to treatment with several disease-modifying anti-rheumatic drugs (DMARDs). The objective of this study was to evaluate the ability of the MBDA score to track response to treatment with rituximab. Data were used from 57 RA patients from three cohorts treated with rituximab 1000 mg and methylprednisolone 100 mg at days 1 and 15. The MBDA score was assessed in serum samples obtained at baseline and 6 months. Spearman’s rank correlation coefficients were calculated for baseline values, 6-month values, and change from baseline to 6 months (∆), between MBDA score and the following measures: disease activity score assessing 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) or high-sensitivity C-reactive protein (hsCRP), ESR, (hs)CRP, swollen and tender joint counts assessing 28 joints (SJC28, TJC28), patient visual analogue scale for general health (VAS-GH), health assessment questionnaire (HAQ), and radiographic progression over 12 months using Sharp/van der Heijde score (SHS), as well as six bone turnover markers. Additionally, multivariable linear regression analyses were performed using these measures as dependent variable and the MBDA score as independent variable, with adjustment for relevant confounders. The association between ∆MBDA score and European League Against Rheumatism (EULAR) response at 6 months was assessed with adjustment for relevant confounders. At baseline, the median MBDA score and DAS28-ESR were 54.0 (IQR 44.3–70.0) and 6.3 (IQR 5.4–7.1), respectively. MBDA scores correlated significantly with DAS28-ESR, DAS28-hsCRP, ESR and (hs)CRP at baseline and 6 months. ∆MBDA score correlated significantly with changes in these measures. ∆MBDA score was associated with EULAR good or moderate response (adjusted OR = 0.89, 95% CI = 0.81–0.98, p = 0.02). Neither baseline MBDA score nor ΔMBDA score correlated statistically significantly with ∆SHS (n = 11) or change in bone turnover markers (n = 23), although ∆SHS ≥ 5 was observed in 5 (56%) of nine patients with high MBDA scores. We have shown, for the first time, that the MBDA score tracked disease activity in RA patients treated with rituximab and that change in MBDA score reflected the degree of treatment response.