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Bartelds G.M.,Jan Van Breemen Research Institute | Krieckaert C.L.M.,Jan Van Breemen Research Institute | Nurmohamed M.T.,Jan Van Breemen Research Institute | Nurmohamed M.T.,Medical Center | And 7 more authors.
JAMA - Journal of the American Medical Association | Year: 2011

Context Short-term data on the immunogenicity of monoclonal antibodies showed associations between the development of antidrug antibodies and diminished serum drug levels, and a diminished treatment response. Little is known about the clinical relevance of antidrug antibodies against these drugs during long-term follow-up. Objective To examine the course of antidrug antibody formation against fully human monoclonal antibody adalimumab and its clinical relevance during long-term (3- year) follow-up of patients with rheumatoid arthritis (RA). Design, Setting, and Patients Prospective cohort study February 2004- September 2008; end of follow-up was September 2010. All 272 patients were diagnosed with RA and started treatment with adalimumab in an outpatient clinic. Main Outcome Measures Disease activity was monitored and trough serum samples were obtained at baseline and 8 time points to 156 weeks. Serum adalimumab concentrations and antiadalimumab antibody titers were determined after follow-up. Treatment discontinuation, minimal disease activity, and clinical remission were compared for patients with and without antiadalimumab antibodies. Results After 3 years, 76 of 272 patients (28%) developed antiadalimumab antibodies- 51 of these (67%) during the first 28 weeks of treatment. Patients without antiadalimumab antibodies had much higher adalimumab concentrations (median, 12 mg/L; IQR, 9-16 mg/L) compared with patients with antibody titers from 13 to 100 AU/mL (median, 5 mg/L; IQR, 3-9 mg/L; regression coefficient, -4.5; 95% CI, -6.0 to -2.9; P<.001) and also those greater than 100 AU/mL (median, 0 mg/L; IQR, 0-3 mg/L; regression coefficient, -7.1; 95% CI, -8.4 to -5.8; P<.001). Patients with antiadalimumab antibodies more often discontinued participation due to treatment failure (n=29 [38%]; hazard ratio [HR], 3.0; 95% CI, 1.6-5.5; P<.001) compared with antiadalimumab antibody-negative ones (n=28 [14%]). Ninety-five of 196 patients (48%)without antiadalimumab antibodies had minimal disease activity vs 10 of 76 patients (13%) with antiadalimumab antibodies; patients with antiadalimumab antibodies less often had sustained minimal disease activity score in 28 joints (DAS28) (<3.2; HR, 3.6; 95% CI, 1.8-7.2; P<.001) compared with antiadalimumab antibody-negative ones. Three of 76 patients (4%) with antiadalimumab antibodies achieved sustained remission compared with 67 of 196 (34%) antiadalimumab antibody-negative ones; patients with antiadalimumab antibodies less often achieved remission (DAS28 <2.6; HR, 7.1; 95% CI, 2.1- 23.4; P<.001) compared with antiadalimumab antibody-negative ones. Conclusion Among outpatients with RA inwhomadalimumab was started over 3 years, the development of antidrug antibodies was associated with lower adalimumab concentration and lower likelihood of minimal disease activity or clinical remission. © 2011 American Medical Association. All rights reserved.


Klarenbeek N.B.,Leiden University | Koevoets R.,Leiden University | Van Der Heijde D.M.F.M.,Leiden University | Gerards A.H.,Vlietland Ziekenhuis | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objective: To compare nine disease activity indices and the new American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) remission criteria in rheumatoid arthritis (RA) and to relate these to physical function and joint damage progression. Methods: Five-year data from the BeSt study were used, a randomised clinical trial comparing four treatment strategies in 508 patients with recent-onset RA. Every three months disease activity was assessed with nine indices (Disease Activity Score (DAS), DAS-C reactive proteine (DAS-CRP), Disease Activity Score in 28 joints (DAS-28), DAS28-CRP, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and three DAS versions with adjusted tender joint scores) and categorized into remission, low, moderate and high disease activity (LDA, MDA, HDA). In addition, the recent ACR/EULAR clinical trial and practice remission was assessed 3-monthly with 28 and 68/66 joint counts. For each index, Generalized Estimating Equations analyses were performed to relate disease activity levels and the absence/ presence of remission to 3-monthly assessments of physical functioning and annual radiological progression. Results: From the composite indices, CDAI and SDAI were the most stringent definitions of remission and classified more patients as LDA. DAS28 and DAS28- CRP had the highest proportions of remission and MDA and a smaller proportion of LDA. ACR/EULAR remission percentages were comparable to CDAI/SDAI: remission percentages. The variant including CRP and 68/66 joint counts was the most stringent. For all indices, higher levels of disease activity were associated with decreased physical functioning and more radiological damage progression. Despite differences in classification between the indices, no major differences in relation to the two outcomes were observed. Conclusion: The associations of nine composite indices and ACR/EULAR remission criteria with functional status and joint damage progression showed high accordance, whereas the proportions of patients classified in the disease activity levels differed.


Shi J.,Leiden University | Van De Stadt L.A.,Jan van Breemen Research Institute | Van De Stadt L.A.,University of Amsterdam | Levarht E.W.N.,Leiden University | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective: The presence of anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (IgM-RF) years before the clinical diagnosis of rheumatoid arthritis (RA) suggests they are possibly involved in the pathogenic process underlying RA. In this study, we analysed whether anti-carbamylated protein (anti-CarP) antibodies, a novel autoantibody system against carbamylated proteins, can also be detected in healthy individuals before they developed RA. Methods: Multiple sera from asymptomatic blood donors prior to the onset of their RA symptoms and sera from age-matched and sex-matched controls were tested for the presence of antibodies directed against carbamylated-fetal calf serum (Ca-FCS), carbamylatedfibrinogen (Ca-Fib), cyclic citrullinated-peptide 2 and IgM-RF. Results: Anti-Ca-FCS and anti-Ca-Fib antibodies were each present in 27% and 38% of the last serum samples of blood donors prior to the diagnosis of RA. Both anti-Ca-FCS and anti-Ca-Fib antibodies could be detected many years before the onset of RA. Anti-CarP antibodies as well as ACPA are, on average, detected earlier than IgM-RF. Conclusions: In addition to ACPA and IgM-RF, also the newly identified anti-CarP antibodies appear many years before the diagnosis of RA.


Van Schouwenburg P.A.,Sanquin Research | Rispens T.,Sanquin Research | Wolbink G.J.,Jan Van Breemen Research Institute
Nature Reviews Rheumatology | Year: 2013

Currently, five anti-TNF biologic agents are approved for the treatment of rheumatoid arthritis (RA): adalimumab, infliximab, etanercept, golimumab and certolizumab pegol. Formation of anti-drug antibodies (ADA) has been associated with all five agents. In the case of adalimumab and infliximab, immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response, but for the other three agents, data on immunogenicity are scarce, suggesting that further research would be valuable. Low ADA levels might not influence the efficacy of anti-TNF therapy, whereas high ADA levels impair treatment efficacy by considerably reducing unbound drug levels. Immunogenicity is not only an issue in patients treated with anti-TNF biologic agents; the immunogenicity of other therapeutic proteins, such as factor VIII and interferons, is well known and has been investigated for many years. The results of such studies suggest that investigations to determine the optimal treatment regimen (drug dosing, treatment schedule and co-medication) required to minimize the likelihood of ADA formation might be an effective and practical way to deal with the immunogenicity of anti-TNF biologic agents for RA. © 2013 Macmillan Publishers Limited. All rights reserved.


Van Tuyl L.H.D.,VU University Amsterdam | Britsemmer K.,Jan Van Breemen Research Institute | Wells G.A.,University of Ottawa | Smolen J.S.,Medical University of Vienna | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Introduction: The new American College for Rheumatology (ACR)/European League Against Rheumatism (EULAR) remission criteria are based on the assessment of 28 joints. A study was undertaken to study the consequences of remission misclassification due to residual disease activity in the feet on physical function and joint damage in the subsequent year in an observational early disease cohort. Methods: All patients with rheumatoid arthritis at inclusion or at 1-year follow-up in the early arthritis cohort of the Jan van Breemen Institute, The Netherlands were included. ACR/EULAR remission definitions for trials and clinical practice were calculated twice, once using a 28-joint count and once using a 38-joint count that included the 10 metatarsophalangeal joints. Disease stability was defined as stable x-ray scores over 1 year (change ≤0 in Sharp/van der Heijde scores) and stable and low scores on the Health Assessment Questionnaire (HAQ change ≤0 and HAQ score consistently ≤0.5), all during the second year after inclusion. Analyses comprised residual disease activity (swollen or tender joints >0) in the feet of patients who fulfilled the candidate remission criteria using a 28-joint count and likelihood ratios of remission definitions to predict disease stability. Results: Of 421 patients, 9-15% reached remission at 1 year using a 28-joint count. Of these, 26-40% showed activity in the feet. Misclassification due to reduced joint counts was observed in 2-3%. A state of remission increased the likelihood of stability of both x-ray and HAQ, with similar likelihood ratios for definitions using 38-joint counts and those using 28-joint counts. Conclusion: The ability of remission definitions with 28-joint counts versus 38-joint counts to predict long-term good radiological and functional outcome is similar. This confirms that inclusion of ankles and forefeet in the assessment of remission is not required, although inclusion of these joints in the examination is recommended.


van der Horst-Bruinsma I.E.,VU University Amsterdam | van der Horst-Bruinsma I.E.,Jan van Breemen Research Institute | Nurmohamed M.T.,VU University Amsterdam | Nurmohamed M.T.,Jan van Breemen Research Institute | Landewe R.B.M.,University of Amsterdam
Rheumatic Disease Clinics of North America | Year: 2012

Chronic inflammatory spondyloarthritis involves axial symptoms of the spine and sacroiliac joints, or peripheral arthritis. Many patients suffer from extra-articular manifestations. With acute anterior uveitis, rapid treatment prevents synechiae. Other organs can be involved. Treatment includes exercise, nonsteroidal antiinflammatory drugs (if insufficient response, tumor necrosis factor blockers), and (with peripheral arthritis) sulfasalazine. Patients with ankylosing spondylitis have comorbidities and increased cardiovascular risk. For uveitis or inflammatory bowel disease, patients should be referred to an ophthalmologist or gastroenterologist. Cardiovascular risk may originate from atherosclerotic disease and cardiac manifestations. Epidemiological studies should be conducted before echocardiogram screening and cardiovascular risk management. © 2012 Elsevier Inc.


Rombouts Y.,Leiden University | Ewing E.,Leiden University | Van De Stadt L.A.,Jan van Breemen Research Institute | Selman M.H.J.,Leiden University | And 8 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Methods: Serum samples of patients with ACPA-positive arthralgia (n=183) were collected at baseline and at various time points of follow-up. 105 patients developed arthritis after a median of 12 months (IQR 6-24) and were classified as having either rheumatoid arthritis (RA, n=48) or undifferentiated arthritis (UA, n=57) based on the 1987 American College of Rheumatology (ACR) criteria. ACPA and total serum IgG were isolated by affinity purification and cleaved by trypsin. ACPA-IgG1 Fc-glycopeptides were subsequently analysed by nano-liquid chromatography mass spectrometry and compared to those of total IgG1.Objective: To determine whether anticitrullinated protein antibodies (ACPA) exhibit specific changes in Fc glycosylation prior to the onset of arthritis.Results: At baseline, ACPA-IgG1 and total IgG1 from arthralgia patients displayed similar Fc glycosylation patterns. By contrast, at the onset of arthritis, ACPA exhibited a decrease in galactose residues in RA patients, but not in UA patients. This decrease occurred around 3 months prior to diagnosis and was paralleled by an increase in systemic inflammation (erythrocyte sedimentation rate). Galactosylation of total IgG1 was also decreased in RA, but this did not precede the onset of arthritis. Interestingly, we additionally noted a higher degree of ACPA-IgG1 Fc core fucosylation at baseline as compared with total IgG1, which further increased prior to diagnosis.Conclusions: ACPA display significant changes in Fc galactosylation and fucosylation prior to the onset of RA. These changes towards a more pro-inflammatory phenotype could be involved in driving the disease process.


Karlson E.W.,Brigham and Women's Hospital | Van Schaardenburg D.,Jan van Breemen Research Institute | Van der Helm-van Mil A.H.,Leiden University
Rheumatology (United Kingdom) | Year: 2016

The development of RA is conceived as a multiple hit process and the more hits that are acquired, the greater the risk of developing clinically apparent RA. Several at-risk phases have been described, including the presence of genetic and environmental factors, RA-related autoantibodies and biomarkers and symptoms. Intervention in these preclinical phases may be more effective compared with intervention in the clinical phase. One prerequisite for preventive strategies is the ability to estimate an individual's risk adequately. This review evaluates the ability to predict the risk of RA in the various preclinical stages. Present data suggest that a combination of genetic and environmental factors is helpful to identify persons at high risk of RA among first-degree relatives. Furthermore, a combination of symptoms, antibody characteristics and environmental factors has been shown to be relevant for risk prediction in seropositive arthralgia patients. Large prospective studies are needed to validate and improve risk prediction in preclinical disease stages. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.


Suwannalai P.,Leiden University | Suwannalai P.,Mahidol University | Britsemmer K.,Jan Van Breemen Research Institute | Knevel R.,Leiden University | And 7 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibodyavidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. Methods We determined the avidity of ACPA and related this with severity of joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high-avidity ACPA were studied. Results Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of joint destruction. This finding was replicated in an independent cohort. Analysis of the properties of lowversus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind 'new' citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-γ receptors, low-avidity ACPA were more potent in activating the complement system. Conclusions Patients with low-avidity ACPA display a higher rate of joint destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome.


Jamnitski A.,Jan Van Breemen Research Institute | Levels J.H.,Academic Medical Center Amsterdam | Van Den Oever I.A.,Jan Van Breemen Research Institute | Nurmohamed M.T.,Jan Van Breemen Research Institute | Nurmohamed M.T.,VU University Amsterdam
Journal of Rheumatology | Year: 2013

Objective. We investigated changes in high-density lipoprotein (HDL) profiling in patients with rheumatoid arthritis who started treatment by taking tumor necrosis factor (TNF) inhibitors. The patients were stratified for European League Against Rheumatism (EULAR) response. Methods. A group of 100 patients naive for TNF inhibitors at baseline were randomly selected from 204 adalimumab-treated and 203 etanercept-treated patients on the basis of their EULAR response. HDL profiling was measured using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Results. In EULAR good responders, mass charged markers representing serum amyloid A (SAA-1 and -2) decreased significantly after 4 months' therapy. There were no significant differences in HDL profiling in EULAR nonresponders. Conclusion. Effective suppression of inflammation with TNF inhibitors results in favorable changes in HDL composition. Copyright © 2013. All rights reserved.

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