Objectives: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. Methods: Eight-year follow-up... Show moreObjectives: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. Methods: Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)<= 2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative Delta SHS in an individual joint, seen by >= 3 out of 4 readers and persisting >= 2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS. Results: Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses. Conclusion: After 8 years of treatment to target DAS <= 2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair. Show less
Pol, J.A. van der; Akdemir, G.; Broek, M. van den; Dirven, L.; Kerstens, P.J.S.M.; Lems, W.F.; ... ; Allaart, C.F. 2023
Objectives To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this.Methods Eight-year follow-up... Show moreObjectives To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this.Methods Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)≤2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative ΔSHS in an individual joint, seen by ≥3 out of 4 readers and persisting ≥2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS.Results Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses.Conclusion After 8 years of treatment to target DAS≤2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair. Show less
Boas, S.E.M.; Carvalhol, J.; Broek, M. van den; Weijers, E.M.; Goumans, M.J.; Koolwijk, P.; Merks, R.M.H. 2018
In experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting.... Show moreIn experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting. More sprouts form on high molecular weight (HMW) than on low molecular weight (LMW) fibrin. It is unclear what mechanisms regulate the number and the positions of the vascular-like structures in cell cultures. To address this question, we propose a mechanistic simulation model of endothelial cell migration and fibrin proteolysis by the plasmin system. The model is a hybrid, cell-based and continuum, computational model based on the cellular Potts model and sets of partial-differential equations. Based on the model results, we propose that a positive feedback mechanism between uPAR, plasmin and transforming growth factor β1 (TGFβ1) selects cells in the monolayer for matrix invasion. Invading cells releases TGFβ1 from the extracellular matrix through plasmin-mediated fibrin degradation. The activated TGFβ1 further stimulates fibrin degradation and keeps proteolysis active as the sprout invades the fibrin matrix. The binding capacity for TGFβ1 of LMW is reduced relative to that of HMW. This leads to reduced activation of proteolysis and, consequently, reduced cell ingrowth in LMW fibrin compared to HMW fibrin. Thus our model predicts that endothelial cells in LMW fibrin matrices compared to HMW matrices show reduced sprouting due to a lower bio-availability of TGFβ1. Show less
Boas, S.E.M.; Carvalho, J.; Broek, M. van den; Weijers, E.M.; Goumans, M.J.; Koolwijk, P.; Merks, R.M.H. 2018
In experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting.... Show moreIn experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting. More sprouts form on high molecular weight (HMW) than on low molecular weight (LMW) fibrin. It is unclear what mechanisms regulate the number and the positions of the vascular-like structures in cell cultures. To address this question, we propose a mechanistic simulation model of endothelial cell migration and fibrin proteolysis by the plasmin system. The model is a hybrid, cell-based and continuum, computational model based on the cellular Potts model and sets of partial-differential equations. Based on the model results, we propose that a positive feedback mechanism between uPAR, plasmin and transforming growth factor beta 1 (TGF beta 1) selects cells in the monolayer for matrix invasion. Invading cells releases TGF beta 1 from the extracellular matrix through plasmin-mediated fibrin degradation. The activated TGF beta 1 further stimulates fibrin degradation and keeps proteolysis active as the sprout invades the fibrin matrix. The binding capacity for TGF beta 1 of LMW is reduced relative to that of HMW. This leads to reduced activation of proteolysis and, consequently, reduced cell ingrowth in LMW fibrin compared to HMW fibrin. Thus our model predicts that endothelial cells in LMW fibrin matrices compared to HMW matrices show reduced sprouting due to a lower bio-availability of TGF beta 1. Show less
Pol, J.A. van der; Akdemir, G.; Broek, M. van den; Dirven, L.; Kerstens, P.J.S.M.; Lems, W.F.; ... ; Huizinga, T.W.J. 2017
OBJECTIVE\nTo determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis.\nMETHODS... Show moreOBJECTIVE\nTo determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis.\nMETHODS\nThere 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.\nRESULTS\nAt 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.\nCONCLUSION\nMBDA scores predict radiographic damage progression at baseline and during disease course. Show less
Akdemir, G.; Markusse, I.; Dirven, L.; Broek, M. van den; Molenaar, E.; Schouffoer, A.; ... ; Allaart, C. 2014
This thesis describes the outcomes an possibilities of drug-tapering in rheumatoid arthritis (RA) patients treated to target. Data from the BeSt cohort were used, in which early RA patients were... Show moreThis thesis describes the outcomes an possibilities of drug-tapering in rheumatoid arthritis (RA) patients treated to target. Data from the BeSt cohort were used, in which early RA patients were randomized to 4 treatment arms: initial monotherapy, sequential or step-up, or initial combination therapy, with prednisone or TNF-blocker infliximab. The disease activity score (DAS) was measured every three months and treatment was changed or added to in case of insufficient response (DAS >2.4). This thesis shows that continued low disease activity steered treatment is possible and leads to maintenance of good functional ability in the majority of patients during 8 years of follow-up. Initial combination therapy is beneficial in the first months of treatment but is not associated with better longer-term results, except in anti-citrullinated protein antibodies positive patients. Initial combination therapy with TNF-blo cker infliximab can be successfully discontinued in over 50% of early RA patients, and in around 20% of all patients, all medication can be stopped when prolonged remission is achieved. Show less
Heimans, L.; Broek, M. van den; Cessie, S. le; Siegerink, B.; Riyazi, N.; Han, K.H.; ... ; Allaart, C.F. 2013
