Objectives: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may... Show moreObjectives: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may affect this. Methods: Data from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (>= 3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome. Results: The probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended. Conclusions Based on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low. Show less
In each era we need to balance between being able to provide care with our "technical skill, scientific knowledge, and human understanding" (Harrison's Principles of Internal Medicine, 1950) to the... Show moreIn each era we need to balance between being able to provide care with our "technical skill, scientific knowledge, and human understanding" (Harrison's Principles of Internal Medicine, 1950) to the individual patient and simultaneously ensure that our healthcare serves all. With the increasing demand of healthcare by an aging population and the lack of specialists, accessible healthcare within a reasonable time frame is not always guaranteed. E-health provides solutions for current situations where we do not meet our own aims of good healthcare, such as restrictions in access to care and a reduction in care availability by a reducing workforce. In addition, telemedicine offers opportunities to improve our healthcare beyond what is possible by in person visits. However, e-health is often viewed as an deficient version of healthcare of low quality. We disagree with this view. In this article we will discuss how to position e-health in the current situation of healthcare, given the continuing rapid development of digital technologies and the changing needs of healthcare professionals and patients. We will address the evolution of e-health towards connected and intelligent systems and the stakeholders perspective, aiming to open up the discussion on e-Health. Show less
Baraliakos, X.; Gossec, L.; McInnes, I.; Kerschbaumer, A.; Wit, M. de; Dougados, M.; ... ; Smolen, J.S. 2022
Objectives To compare the benefits of a tight-control/treat-to-target strategy (TC/T2T) in axial spondyloarthritis (axSpA) with those of usual care (UC).Methods Pragmatic, prospective, cluster... Show moreObjectives To compare the benefits of a tight-control/treat-to-target strategy (TC/T2T) in axial spondyloarthritis (axSpA) with those of usual care (UC).Methods Pragmatic, prospective, cluster-randomised, controlled, open, 1-year trial (NCT03043846). 18 centres were randomised (1:1). Patients met Axial Spondylo Arthritis International Society (ASAS) criteria for axSpA, had an Ankylosing Spondylitis Disease Activity Score (ASDAS) >= 2.1, received non-optimal treatment by non-steroidal anti-inflammatory drugs and were biologic-naive.Interventions (1) TC/T2T: visits every 4 weeks and prespecified strategy based on treatment intensification until achieving target (ie, ASDAS <2.1); (2) UC: visits every 12 weeks and treatment at the rheumatologist's discretion.Main outcome Percentage of patients with a >= 30% improvement on the ASAS-Health Index (ASAS-HI). Other efficacy outcomes and adverse events were recorded. A health economic evaluation was performed.Statistical analysis Two-level mixed models were used to estimate efficacy outcomes. Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained for TC/T2T versus UC.Results 160 patients were included (80/group). Mean (SD) age was 37.9 (11.0) years and disease duration was 3.7 (6.2) years; 51.2% were men. ASDAS at inclusion was 3.0 (0.7), and ASAS-HI was 8.6 (3.7). ASAS-HI improved by >= 30% in 47.3% of the TC/T2T arm and in 36.1% of those receiving UC (non-significant). All secondary efficacy outcomes were more frequent in the TC/T2T arm, although not all statistically significant. Safety was similar in both arms. From a societal perspective, TC/T2T resulted in an additional 0.04 QALY, and saved euro472 compared with UC.Conclusion TC/T2T was not significantly superior to UC for the primary outcome, while many secondary efficacy outcomes favoured it, had a similar safety profile and was favourable from a societal health economic perspective. Show less
Deodhar, A.; Sliwinska-Stanczyk, P.; Xu, H.J.; Baraliakos, X.; Gensler, L.S.; Fleishaker, D.; ... ; Heijde, D. van der 2021
Objective To assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS).Methods This phase III, randomised, double-blind, placebo-controlled study enrolled... Show moreObjective To assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS).Methods This phase III, randomised, double-blind, placebo-controlled study enrolled patients aged >= 18 years diagnosed with active AS, meeting the modified New York criteria, with centrally read radiographs, and an inadequate response or intolerance to >= 2 non-steroidal anti-inflammatory drugs. Patients were randomised 1:1 to receive tofacitinib 5 mg two times per day or placebo for 16 weeks. After week 16, all patients received open-label tofacitinib until week 48. The primary and key secondary endpoints were Assessment of SpondyloArthritis international Society >= 20% improvement (ASAS20) and >= 40% improvement (ASAS40) responses, respectively, at week 16. Safety was assessed throughout.Results 269 patients were randomised and treated: tofacitinib, n=133; placebo, n=136. At week 16, the ASAS20 response rate was significantly (p<0.0001) greater with tofacitinib (56.4%, 75 of 133) versus placebo (29.4%, 40 of 136), and the ASAS40 response rate was significantly (p<0.0001) greater with tofacitinib (40.6%, 54 of 133) versus placebo (12.5%, 17 of 136). Up to week 16, with tofacitinib and placebo, respectively, 73 of 133 (54.9%) and 70 of 136 (51.5%) patients had adverse events; 2 of 133 (1.5%) and 1 of 136 (0.7%) had serious adverse events. Up to week 48, with tofacitinib, 3 of 133 (2.3%) patients had adjudicated hepatic events, 3 of 133 (2.3%) had non-serious herpes zoster, and 1 of 133 (0.8%) had a serious infection; with placebo -> tofacitinib, 2 (1.5%) patients had non-serious herpes zoster. There were no deaths, malignancies, major adverse cardiovascular events, thromboembolic events or opportunistic infections.Conclusions In adults with active AS, tofacitinib demonstrated significantly greater efficacy versus placebo. No new potential safety risks were identified. Show less
Combe, B.; Kivitz, A.; Tanaka, Y.; Heijde, D. van der; Simon, J.A.; Baraf, H.S.B.; ... ; Nash, P. 2021
Objective To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-alpha inhibitor therapy in patients with active... Show moreObjective To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-alpha inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).Methods This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.Results The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein <= 3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.Conclusions Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab. Show less
Molto, A.; Heijde, D. van der; Bosch, F.E. van den; Dougados, M. 2021
Objectives To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure... Show moreObjectives To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure.MethodsThis 52-week, phase 3, multicentre, double-blind clinical trial (NCT02886728) evaluated once-daily oral filgotinib in 1252 patients with RA randomised 2:1:1:2 to filgotinib 200 mg with MTX (FIL200 +MTX), filgotinib 100 mg with MTX (FIL100 +MTX), filgotinib 200 mg monotherapy (FIL200), or MTX. The primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 24.ResultsThe primary endpoint was achieved by 81% of patients receiving FIL200+ MTX versus 71% receiving MTX (p<0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24. Significant improvement in Health Assessment Questionnaire-Disability Index was seen at week 24; least-squares mean change from baseline was -1.0 and -0.94 with FIL200+MTX and FIL100+MTX, respectively, versus -0.81 with MTX (p<0.001, p=0.008, respectively). Significantly higher proportions receiving FIL200+MTX (54%) and FIL100+MTX (43%) achieved DAS28(CRP) <2.6 versus MTX (29%) (p<0.001 for both) at week 24. Hierarchical testing stopped for comparison of ACR20 for FIL200 monotherapy (78%) versus MTX (71%) at week 24 (p=0.058). Adverse event rates through week 52 were comparable between all treatments.ConclusionsFIL200+MTX and FIL100+MTX both significantly improved signs and symptoms and physical function in patients with active RA and limited or no prior MTX exposure; FIL200 monotherapy did not have a superior ACR20 response rate versus MTX. Filgotinib was well tolerated, with acceptable safety compared with MTX. Show less
Background Phosphorylcholine (PC) is an important pro-inflammatory damage-associated molecular pattern. Previous data have shown that natural IgM anti-PC protects against cardiovascular disease. We... Show moreBackground Phosphorylcholine (PC) is an important pro-inflammatory damage-associated molecular pattern. Previous data have shown that natural IgM anti-PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti-inflammatory and anti-atherosclerotic properties.Methods Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys.Results A chimeric anti-PC (PC-mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC-mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti-PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti-PC (PC-mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC-mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC-mAb antibodies resulted in selection of PC-mAb X19-A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys.Conclusions Chimeric anti-PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC-mAb represents a novel strategy for cardiovascular disease prevention. Show less
Roodenrijs, N.M.T.; Hamar, A.; Kedves, M.; Nagy, G.; Laar, J.M. van; Heijde, D. van der; Welsing, P.M.J. 2021
Objectives To summarise, by a systematic literature review (SLR), the evidence regarding pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis ... Show moreObjectives To summarise, by a systematic literature review (SLR), the evidence regarding pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis (D2T RA), informing the EULAR recommendations for the management of D2T RA.Methods PubMed, Embase and Cochrane databases were searched up to December 2019. Relevant papers were selected and appraised.Results Two hundred seven (207) papers studied therapeutic strategies. Limited evidence was found on effective and safe disease-modifying antirheumatic drugs (DMARDs) in patients with comorbidities and other contraindications that limit DMARD options (patients with obesity, hepatitis B and C, risk of venous thromboembolisms, pregnancy and lactation). In patients who previously failed biological (b-)DMARDs, all currently used b/targeted synthetic (ts-)DMARDs were found to be more effective than placebo. In patients who previously failed a tumour necrosis factor inhibitor (TNFi), there was a tendency of non-TNFi bDMARDs to be more effective than TNFis. Generally, effectiveness decreased in patients who previously failed a higher number of bDMARDs. Additionally, exercise, psychological, educational and self-management interventions were found to improve non-inflammatory complaints (mainly functional disability, pain, fatigue), education to improve goal setting, and self-management programmes, educational and psychological interventions to improve self-management.The identified evidence had several limitations: (1) no studies were found in patients with D2T RA specifically, (2) heterogeneous outcome criteria were used and (3) most studies had a moderate or high risk of bias.Conclusions This SLR underscores the scarcity of high-quality evidence on the pharmacological and non-pharmacological treatment of patients with D2T RA. Effectiveness of b/tsDMARDs decreased in RA patients who had failed a higher number of bDMARDs and a subsequent b/tsDMARD of a previously not targeted mechanism of action was somewhat more effective. Additionally, a beneficial effect of non-pharmacological interventions was found for improvement of non-inflammatory complaints, goal setting and self-management. Show less
Bouwman, L.F.; Maarel, S.M. van der; Greef, J.C. de 2020
Purpose of review Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder, which is caused by incomplete repression of the transcription factor double homeobox 4 (DUX4) in... Show morePurpose of review Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder, which is caused by incomplete repression of the transcription factor double homeobox 4 (DUX4) in skeletal muscle. To date, there is no DUX4-targeting treatment to prevent or delay disease progression. In the present review, we summarize developments in therapeutic strategies with the focus on inhibiting DUX4 and DUX4 target gene expression. Recent findings Different studies show that DUX4 and its target genes can be repressed with genetic therapies using diverse strategies. Additionally, different small compounds can reduce DUX4 and its target genes in vitro and in vivo. Most studies that show DUX4 repression by genetic therapies have only been tested in vitro. More efforts should be made to test them in vivo for clinical translation. Several compounds have been shown to prevent DUX4 and target gene expression in vitro and in vivo. However, their efficiency and specificity has not yet been shown. With emerging clinical trials, the clinical benefit from DUX4 repression in FSHD will likely soon become apparent. Show less
Purpose of review To provide a comprehensive overview of the current insight into the role of complement activation in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). In addition,... Show morePurpose of review To provide a comprehensive overview of the current insight into the role of complement activation in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). In addition, the therapeutic options targeting the complement system in AAV are discussed. Recent findings It has become increasingly clear that complement, and more specifically signalling through the C5a receptor, contributes to the immunopathology of AAV. This has led to the design of clinical trials with a C5a receptor blocker. The first results show a reduction in tissue damage and a favourable safety profile, as other parts of the complement defence system are left intact. Summary Although AAV was initially regarded as a pauci-immune disease, it is now well established that, in addition to autoantibodies, complement plays an essential role in the disease process. Animal models delivered the first insight, but the effective therapeutic interventions using complement inhibitors provided the proof that indeed complement activation contributes to disease activity and tissue damage in human AAV. Show less
Jong, A. de; Dirven, R.J.; Oud, J.A.; Tio, D.; Vlijmen, B.J.M. van; Eikenboom, J. 2018