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Gertjan Wolbink - One of the best experts on this subject based on the ideXlab platform.
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key findings towards optimising Adalimumab treatment the concentration effect curve
Annals of the Rheumatic Diseases, 2015Co-Authors: Mieke F Pouw, Desiree Van Der Kleij, Charlotte L. M. Krieckaert, Theo Rispens, Michael T. Nurmohamed, Lucien A Aarden, Gertjan WolbinkAbstract:Objective To determine a concentration–effect curve of Adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for Adalimumab concentrations. Methods In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg Adalimumab subcutaneously every other week. The relationship between Adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration–effect curve. A receiver–operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on Adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration–effect curve and a concentration table. Results Clinical efficacy improved with increasing Adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5–8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and Adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on Adalimumab monotherapy had a median Adalimumab level of 4.1 μg/mL (IQR 1.3–7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3–10.6, p Conclusions Adalimumab trough levels in a range of 5–8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.
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a novel method for the detection of antibodies to Adalimumab in the presence of drug reveals hidden immunogenicity in rheumatoid arthritis patients
Journal of Immunological Methods, 2010Co-Authors: Pauline A Van Schouwenburg, Gertjan Wolbink, Lucien A Aarden, G. M. Bartelds, Margreet Hart, Diana WoutersAbstract:Production of anti drug antibodies (ADA) in Adalimumab treated RA patients is associated with reduced serum Adalimumab levels and less clinical response. However, most current assays to measure ADA are unable to detect ADA in complex with Adalimumab. Thus, ADA is only measured if antibody production exceeds drug levels in the serum, meaning that ADA formation is underestimated. The aim of this study is to develop a method to detect ADA in the presence of drug. A pH-shift-anti-idiotype Antigen binding test (PIA) was used to enable ADA measurement in the presence of Adalimumab. ADA-Adalimumab complexes were dissociated by acid treatment and addition of excess rabbit anti-idiotype-F(ab) before neutralization. Rabbit anti-idiotype-F(ab) blocks reformation of ADA-drug complexes by competing with patient ADA for Adalimumab binding. Released ADA are measured by an antigen binding test (ABT). The PIA enabled detection of ADA in the presence of large excess of Adalimumab and was used to measure ADA in 30 Adalimumab treated rheumatoid arthritis (RA) patients during the first 28 weeks of treatment. It revealed ADA in 21 out of 30 tested patients, while the ABT detected ADA in only 5 patients. Indicating that an immunogenic reaction towards Adalimumab is present in the majority of Adalimumab treated patients.
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anti infliximab and anti Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti tumour necrosis factor naive patients a cohort study
Annals of the Rheumatic Diseases, 2010Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Ben A. C. Dijkmans, Paul P. Tak, W F Lems, Gertjan WolbinkAbstract:Objective To investigate how antibodies against anti-TNF agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). Methods: This cohort study consisted of 235 RA patients, all treated with Adalimumab. At baseline fifty-two patients (22%) were previously treated with infliximab ("switchers"), and 183(78%) were anti-TNF naive. Disease activity (using the DAS28score) and presence of antibodies against infliximab and Adalimumab was assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. Results After 28 weeks of Adalimumab therapy the decrease in DAS28 (ΔDAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). ΔDAS28 was 1.8±1.4 in patients without anti-Adalimumab and 0.6±1.3 in patients with anti-Adalimumab (P Conclusion Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF therapy should be offered to RA-patients who fail on initial treatment with anti-TNF, in the absence of anti-biological antibodies.
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extent and clinical consequences of antibody formation against Adalimumab in patients with plaque psoriasis
Archives of Dermatology, 2010Co-Authors: L L A Lecluse, R J B Driessen, Phyllis I Spuls, Elke M G J De Jong, S O Stapel, Martijn B A Van Doorn, Jan D Bos, Gertjan WolbinkAbstract:Objectives To investigate the extent antibodies to Adalimumab are formed in patients with plaque psoriasis and whether these antibodies have clinical consequences. Also, to examine the relationship between antibodies to Adalimumab and Adalimumab trough titers. Design Prospective observational cohort study. Setting Two Dutch dermatology departments in university hospitals. Patients All consecutive patients starting a regimen of Adalimumab for chronic plaque psoriasis. Patients were screened and fulfilled the Dutch reimbursement criteria for Adalimumab to treat psoriasis. Intervention Adalimumab treatment (per label). Main Outcome Measures The titer of antibodies to Adalimumab, the Adalimumab trough concentration, and the Psoriasis Area and Severity Index at weeks 12 and 24. Results Antibodies to Adalimumab were detected in 13 of 29 patients (45%) during 24 weeks of treatment. Differences in response rates among patients with low, high, and no titers of antibodies to Adalimumab were significant at weeks 12 and 24 ( P = .04 and P P P = .01). Conclusion Antibodies to Adalimumab are associated with lower serum Adalimumab trough concentrations and with nonresponse or loss of response to Adalimumab in patients with plaque psoriasis.
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Anti-infliximab and anti-Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study
Annals of the rheumatic diseases, 2009Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Willem F. Lems, Ben A. C. Dijkmans, Paul P. Tak, Gertjan WolbinkAbstract:To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). This cohort study consisted of 235 patients with RA, all treated with Adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab ('switchers'), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and Adalimumab were assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. After 28 weeks of Adalimumab treatment the decrease in DAS28 (Delta DAS28) for the 235 patients was 1.6+/-1.5 (mean+/-SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). Delta DAS28 was 1.8+/-1.4 in patients without anti-Adalimumab and 0.6+/-1.3 in patients with anti-Adalimumab (p<0.0001). Thirty-three of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-Adalimumab than anti-TNF naive patients (11 (33%) vs 32 (18%); p=0.039). Delta DAS28 was greater for anti-TNF naive patients (1.7+/-1.5) than for switchers without anti-infliximab antibodies (Delta DAS28=0.9+/-1.4) (p=0.009). Delta DAS28 for switchers with anti-infliximab was 1.2+/-1.3 and did not differ significantly from anti-TNF naive patients (p=0.262). Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF treatment should be offered to patients with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.
William J Sandborn - One of the best experts on this subject based on the ideXlab platform.
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effects of concomitant immunomodulators on the pharmacokinetics efficacy and safety of Adalimumab in patients with crohn s disease or ulcerative colitis who had failed conventional therapy
Alimentary Pharmacology & Therapeutics, 2017Co-Authors: J F Colombel, Brian G Feagan, William J Sandborn, Bindia Jharap, Laurent Peyrinbiroulet, Samantha Eichner, Anne M Robinson, Nael M Mostafa, Qian Zhou, Roopal ThakkarAbstract:SummaryBackground Adalimumab is approved for use in patients with moderate to severe Crohn's disease (CD) or ulcerative colitis (UC) who have not achieved disease control with conventional therapies including corticosteroids and/or immunomodulators (IMM). Aim To analyse six studies that examined efficacy, pharmacokinetics and safety of combination IMM/Adalimumab therapy, compared with Adalimumab monotherapy in patients with inadequate disease control on conventional therapy. Methods Patients with moderate to severe CD or UC from randomised, double-blind, placebo-controlled trials were analysed. Adalimumab was added to background therapy; patients were categorised as receiving Adalimumab monotherapy (CD induction, n = 245, maintenance, n = 185; UC induction, n = 213, maintenance, n = 157) or combination therapy (CD induction, n = 139, maintenance, n = 139; UC induction, n = 140, maintenance, n = 100) according to baseline immunomodulator use. Efficacy was reported for the intent-to-treat populations from each study, with remission defined as CD activity index 1 for UC. Safety was assessed via adverse events. Results The proportions of patients achieving remission were similar for Adalimumab monotherapy and immunomodulator combination therapy in all studies. Median Adalimumab concentrations at week 4 or 8 were numerically but not significantly higher with Adalimumab combination therapy vs. monotherapy in the CD and UC studies respectively. Incidence and rate of adverse events was similar for Adalimumab monotherapy and combination therapy. Conclusions Post hoc analysis of six randomised, controlled trials demonstrated no efficacy benefits with immunomodulator/Adalimumab combination therapy, compared with Adalimumab monotherapy in CD and UC patients with inadequate disease control on conventional therapy; the safety of the two treatment approaches was comparable.
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increased risk of malignancy with Adalimumab combination therapy compared with monotherapy for crohn s disease
Gastroenterology, 2014Co-Authors: Mark T Osterman, William J Sandborn, Jean-frederic Colombel, Anne M Robinson, Roopal Thakkar, Paul F Pollack, Winnie Lau, Bidan Huang, James D LewisAbstract:Background & Aims Few studies have assessed the risk of malignancy from anti-tumor necrosis factor monotherapy or combination therapy for Crohn's disease (CD). We determined the relative risk of malignancy in patients with CD who received Adalimumab monotherapy, compared with the general population. We also compared the risk of malignancy associated with combination Adalimumab and immunomodulator therapy with that of Adalimumab monotherapy. Methods We performed a pooled analysis of data from 1594 patients with CD who participated in clinical trials of Adalimumab (CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE studies; 3050 patient-years of exposure). We calculated rates of malignancy among patients; the expected rates of malignancy, based on the general population, were derived from the Surveillance, Epidemiology, and End Results registry and National Cancer Institute survey. Results Compared with the general population, patients receiving Adalimumab monotherapy did not have a greater than expected incidence of nonmelanoma skin cancer (NMSC) or other cancers, whereas those receiving combination therapy had a greater than expected incidence of malignancies other than NMSC (standardized incidence ratio, 3.04; 95% confidence interval [CI], 1.66-5.10) and of NMSC (standardized incidence ratio, 4.59; 95% CI, 2.51-7.70). Compared with patients receiving Adalimumab monotherapy, those patients receiving combination therapy had an increased risk of malignancy other than NMSC (relative risk, 2.82; 95% CI, 1.07-7.44) and of NMSC (relative risk, 3.46; 95% CI, 1.08-11.06). Conclusions In patients with CD, the incidence of malignancy with Adalimumab monotherapy was not greater than that of the general population. Co-administration of immunomodulator therapy and Adalimumab was associated with an increased risk of NMSC and other cancers.
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Adalimumab induces deep remission in patients with crohn s disease
Clinical Gastroenterology and Hepatology, 2014Co-Authors: Jean-frederic Colombel, William J Sandborn, Paul Rutgeerts, Anne M Robinson, Roopal Thakkar, Anne Camez, Paul F Pollack, Mei Yang, N Chen, Parvez MulaniAbstract:Background & Aims Patients with moderate to severe ileocolonic Crohn's disease (CD) who received Adalimumab induction and maintenance therapy had greater rates of mucosal healing than patients who received placebo after Adalimumab induction therapy in a 52-week trial (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing). We investigated whether this treatment also induced deep remission—a composite clinical and endoscopic end point. Methods Rates of deep remission, defined as the absence of mucosal ulceration and CD Activity Index scores less than 150, were compared between patients given continuous Adalimumab and those given only induction therapy followed by placebo. We assessed the relationships between deep remission and other outcomes among patients who received Adalimumab. The outcomes of patients with deep remission were compared with those of patients with only the absence of mucosal ulceration or only clinical remission. Results Rates of deep remission were 16% in patients given Adalimumab vs 10% in those given placebo (P = .34) at week 12, and 19% vs 0% (P Conclusions In an exploratory study of patients with moderate to severe ileocolonic CD who received Adalimumab induction and maintenance therapy, patients achieving deep remission appeared to have better 1-year outcomes than those not achieving deep remission. These findings should be validated in large, prospective trials. ClinicalTrials.gov number: NCT00348283.
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Adalimumab induces and maintains mucosal healing in patients with crohn s disease data from the extend trial
Gastroenterology, 2012Co-Authors: Paul Rutgeerts, William J Sandborn, Gert Van Assche, Jean-frederic Colombel, Walter Reinisch, Douglas C Wolf, Andreas Lazar, Karel Geboes, Ashish Kumar, Anne CamezAbstract:Background & Aims We investigated the efficacy of Adalimumab for inducing and maintaining mucosal healing in patients with Crohn's disease (CD). Methods A randomized, double-blind, placebo-controlled trial (extend the safety and efficacy of Adalimumab through endoscopic healing [EXTEND]) evaluated Adalimumab for induction and maintenance of mucosal healing in 135 adults with moderate to severe ileocolonic CD. The baseline degree of mucosal ulceration was documented by ileocolonoscopy. All patients received induction therapy (subcutaneous Adalimumab 160/80 mg at weeks 0/2). At week 4, patients were randomly assigned to groups given 40 mg Adalimumab or placebo every other week through week 52. Open-label Adalimumab was given to patients with flares or no response, starting at week 8. Mucosal healing was reassessed by ileocolonoscopy at weeks 12 and 52. Results Twenty-seven percent of patients receiving Adalimumab had mucosal healing at week 12 (the primary end point) versus 13% given placebo ( P = .056). At week 52, rates of mucosal healing were 24% and 0, respectively ( P P = .006) and 28% and 3%, respectively, at week 52 ( P P = .021) and 52 (33% vs 9%; P = .001). Five serious (1 during induction and 4 during open-label therapy) and 3 opportunistic infections (1 in each group during double-blind therapy and 1 during open-label therapy) were reported (n = 135). Conclusions Following induction therapy with Adalimumab, patients with moderately to severely active CD who continue to receive Adalimumab are more likely to achieve mucosal healing than those given placebo.
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Adalimumab induces and maintains clinical remission in patients with moderate to severe ulcerative colitis
Gastroenterology, 2012Co-Authors: William J Sandborn, Geert R Dhaens, Gert Van Assche, Jean-frederic Colombel, Walter Reinisch, Douglas C Wolf, Martina Kron, Mary Beth Tighe, Andreas Lazar, Roopal ThakkarAbstract:Background & Aims Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor (TNF)-α. Its efficacy as maintenance therapy for patients with ulcerative colitis has not been studied in a controlled, double-blind trial. Methods Ulcerative colitis long-term remission and maintenance with Adalimumab 2 (ULTRA 2) was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of Adalimumab in induction and maintenance of clinical remission in 494 patients with moderate-to-severe ulcerative colitis who received concurrent treatment with oral corticosteroids or immunosuppressants. Patients were stratified based on prior exposure to TNF-α antagonists (either had or had not been previously treated with anti–TNF-α) and randomly assigned to groups given Adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week or placebo. Primary end points were remission at weeks 8 and 52. Results Overall rates of clinical remission at week 8 were 16.5% on Adalimumab and 9.3% on placebo ( P = .019); corresponding values for week 52 were 17.3% and 8.5% ( P = .004). Among anti–TNF-α naive patients, rates of remission at week 8 were 21.3% on Adalimumab and 11% on placebo ( P = .017); corresponding values for week 52 were 22% and 12.4% ( P = .029). Among patients who had previously received anti-TNF agents, rates of remission at week 8 were 9.2% on Adalimumab and 6.9% on placebo ( P = .559); corresponding values for week 52 were 10.2% and 3% ( P = .039). Serious adverse events occurred in 12% of patients given Adalimumab or placebo. Serious infections developed in 1.6% of patients given Adalimumab and 1.9% given placebo. In the group given Adalimumab, 1 patient developed squamous cell carcinoma and 1 developed gastric cancer. Conclusions Adalimumab was safe and more effective than placebo in inducing and maintaining clinical remission in patients with moderate-to-severe ulcerative colitis who did not have an adequate response to conventional therapy with steroids or immunosuppressants.
Michael T. Nurmohamed - One of the best experts on this subject based on the ideXlab platform.
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dynamics of circulating tnf during Adalimumab treatment using a drug tolerant tnf assay
Science Translational Medicine, 2019Co-Authors: Lea C Berkhout, Michael T. Nurmohamed, Margreet Hart, Ronald F Van Vollenhoven, Merel J Lami, J Ruwaard, Pleuni Ooijevaarde Heer, Karien Bloem, Maarten Boers, Daniel AlvarezAbstract:Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody Adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during Adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive Adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of Adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with Adalimumab and could be recovered as inactive 3:1 Adalimumab-TNF complexes. No quantitative association was found between TNF and Adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during Adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward Adalimumab treatment.
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key findings towards optimising Adalimumab treatment the concentration effect curve
Annals of the Rheumatic Diseases, 2015Co-Authors: Mieke F Pouw, Desiree Van Der Kleij, Charlotte L. M. Krieckaert, Theo Rispens, Michael T. Nurmohamed, Lucien A Aarden, Gertjan WolbinkAbstract:Objective To determine a concentration–effect curve of Adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for Adalimumab concentrations. Methods In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg Adalimumab subcutaneously every other week. The relationship between Adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration–effect curve. A receiver–operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on Adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration–effect curve and a concentration table. Results Clinical efficacy improved with increasing Adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5–8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and Adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on Adalimumab monotherapy had a median Adalimumab level of 4.1 μg/mL (IQR 1.3–7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3–10.6, p Conclusions Adalimumab trough levels in a range of 5–8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.
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anti infliximab and anti Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti tumour necrosis factor naive patients a cohort study
Annals of the Rheumatic Diseases, 2010Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Ben A. C. Dijkmans, Paul P. Tak, W F Lems, Gertjan WolbinkAbstract:Objective To investigate how antibodies against anti-TNF agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). Methods: This cohort study consisted of 235 RA patients, all treated with Adalimumab. At baseline fifty-two patients (22%) were previously treated with infliximab ("switchers"), and 183(78%) were anti-TNF naive. Disease activity (using the DAS28score) and presence of antibodies against infliximab and Adalimumab was assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. Results After 28 weeks of Adalimumab therapy the decrease in DAS28 (ΔDAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). ΔDAS28 was 1.8±1.4 in patients without anti-Adalimumab and 0.6±1.3 in patients with anti-Adalimumab (P Conclusion Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF therapy should be offered to RA-patients who fail on initial treatment with anti-TNF, in the absence of anti-biological antibodies.
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Anti-infliximab and anti-Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study
Annals of the rheumatic diseases, 2009Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Willem F. Lems, Ben A. C. Dijkmans, Paul P. Tak, Gertjan WolbinkAbstract:To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). This cohort study consisted of 235 patients with RA, all treated with Adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab ('switchers'), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and Adalimumab were assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. After 28 weeks of Adalimumab treatment the decrease in DAS28 (Delta DAS28) for the 235 patients was 1.6+/-1.5 (mean+/-SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). Delta DAS28 was 1.8+/-1.4 in patients without anti-Adalimumab and 0.6+/-1.3 in patients with anti-Adalimumab (p<0.0001). Thirty-three of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-Adalimumab than anti-TNF naive patients (11 (33%) vs 32 (18%); p=0.039). Delta DAS28 was greater for anti-TNF naive patients (1.7+/-1.5) than for switchers without anti-infliximab antibodies (Delta DAS28=0.9+/-1.4) (p=0.009). Delta DAS28 for switchers with anti-infliximab was 1.2+/-1.3 and did not differ significantly from anti-TNF naive patients (p=0.262). Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF treatment should be offered to patients with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.
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clinical response to Adalimumab relationship to anti Adalimumab antibodies and serum Adalimumab concentrations in rheumatoid arthritis
Annals of the Rheumatic Diseases, 2007Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Willem F. Lems, Ben A. C. Dijkmans, Paul P. Tak, Gertjan WolbinkAbstract:Background: A substantial proportion of patients with rheumatoid arthritis (RA) do not respond, or lose initial response, to Adalimumab treatment. One explanation for non-response is that patients develop anti-Adalimumab antibodies. Objectives: To evaluate the incidence of formation of antibody against Adalimumab and the association with serum Adalimumab concentrations and clinical response. Methods: In a cohort of 121 consecutive patients with RA treated with Adalimumab, serum Adalimumab concentrations and antibodies against Adalimumab were measured together with clinical response variables before and up to 28 weeks after the start of treatment. Results: Anti-Adalimumab antibodies were detected in 21 patients (17%) during 28 weeks of treatment. EULAR non-responders had antibodies significantly more often than good responders (34% vs 5%; p = 0.032). Patients with antibodies showed less improvement in disease activity (mean (SD) delta DAS28 0.65 (1.35)) than patients without antibodies (mean delta DAS28 1.70 (1.35)) (p = 0.001). Patients with antibodies during follow-up had lower serum Adalimumab concentrations at 28 weeks than patients without antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/l, range 2.0–33.0, respectively; p Conclusions: Serum antibodies against Adalimumab are associated with lower serum Adalimumab concentrations and non-response to Adalimumab treatment.
Lucien A Aarden - One of the best experts on this subject based on the ideXlab platform.
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key findings towards optimising Adalimumab treatment the concentration effect curve
Annals of the Rheumatic Diseases, 2015Co-Authors: Mieke F Pouw, Desiree Van Der Kleij, Charlotte L. M. Krieckaert, Theo Rispens, Michael T. Nurmohamed, Lucien A Aarden, Gertjan WolbinkAbstract:Objective To determine a concentration–effect curve of Adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for Adalimumab concentrations. Methods In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg Adalimumab subcutaneously every other week. The relationship between Adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration–effect curve. A receiver–operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on Adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration–effect curve and a concentration table. Results Clinical efficacy improved with increasing Adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5–8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and Adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on Adalimumab monotherapy had a median Adalimumab level of 4.1 μg/mL (IQR 1.3–7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3–10.6, p Conclusions Adalimumab trough levels in a range of 5–8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.
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Adalimumab elicits a restricted anti idiotypic antibody response in autoimmune patients resulting in functional neutralisation
Annals of the Rheumatic Diseases, 2013Co-Authors: Pauline A Van Schouwenburg, Theo Rispens, Margreet Hart, Lotte A Van De Stadt, Rob N De Jong, Esther E L Van Buren, Simone Kruithof, Els R De Groot, Marieke S Van Ham, Lucien A AardenAbstract:Objectives Millions of patients worldwide are treated with therapeutic monoclonal antibodies. These biological therapeutics can be immunogenic, resulting in anti-drug antibody formation which leads to loss of response. Fully human biological agents, such as the anti-tumour necrosis factor α (anti-TNFα) antibody Adalimumab, are considered to be weakly immunogenic, but anti-Adalimumab antibodies (AAA) were recently detected in more than half of treated patients with rheumatoid arthritis (RA) within 28 weeks of treatment. A study was undertaken to determine the mechanism by which AAA lead to loss of response. Methods The specificity of the repertoire of AAA was investigated in a cohort of 50 AAA-positive RA patients. Inhibition experiments using TNFα and patient-derived anti-Adalimumab monoclonal antibodies were performed. Results The antibody response against Adalimumab is highly restricted: Fab fragments of a single monoclonal antibody specific for the idiotype of Adalimumab inhibited 98.65% (25th–75th percentiles: 98.25–99.90) of the total anti-Adalimumab reactivity in serum from 50 AAA-positive patients. The anti-Adalimumab response was confined to the TNFα binding region of Adalimumab, thereby neutralising its therapeutic efficacy. In line with this restricted specificity, small immune complexes were found in the circulation of AAA-forming patients. Conclusions The humoral immune response against Adalimumab is highly restricted and limited to the idiotype of the therapeutic antibody. All antibodies result in functional neutralisation of the drug, thereby providing a mechanism by which AAA formation leads to clinical non-response.
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a novel method for the detection of antibodies to Adalimumab in the presence of drug reveals hidden immunogenicity in rheumatoid arthritis patients
Journal of Immunological Methods, 2010Co-Authors: Pauline A Van Schouwenburg, Gertjan Wolbink, Lucien A Aarden, G. M. Bartelds, Margreet Hart, Diana WoutersAbstract:Production of anti drug antibodies (ADA) in Adalimumab treated RA patients is associated with reduced serum Adalimumab levels and less clinical response. However, most current assays to measure ADA are unable to detect ADA in complex with Adalimumab. Thus, ADA is only measured if antibody production exceeds drug levels in the serum, meaning that ADA formation is underestimated. The aim of this study is to develop a method to detect ADA in the presence of drug. A pH-shift-anti-idiotype Antigen binding test (PIA) was used to enable ADA measurement in the presence of Adalimumab. ADA-Adalimumab complexes were dissociated by acid treatment and addition of excess rabbit anti-idiotype-F(ab) before neutralization. Rabbit anti-idiotype-F(ab) blocks reformation of ADA-drug complexes by competing with patient ADA for Adalimumab binding. Released ADA are measured by an antigen binding test (ABT). The PIA enabled detection of ADA in the presence of large excess of Adalimumab and was used to measure ADA in 30 Adalimumab treated rheumatoid arthritis (RA) patients during the first 28 weeks of treatment. It revealed ADA in 21 out of 30 tested patients, while the ABT detected ADA in only 5 patients. Indicating that an immunogenic reaction towards Adalimumab is present in the majority of Adalimumab treated patients.
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anti infliximab and anti Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti tumour necrosis factor naive patients a cohort study
Annals of the Rheumatic Diseases, 2010Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Ben A. C. Dijkmans, Paul P. Tak, W F Lems, Gertjan WolbinkAbstract:Objective To investigate how antibodies against anti-TNF agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). Methods: This cohort study consisted of 235 RA patients, all treated with Adalimumab. At baseline fifty-two patients (22%) were previously treated with infliximab ("switchers"), and 183(78%) were anti-TNF naive. Disease activity (using the DAS28score) and presence of antibodies against infliximab and Adalimumab was assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. Results After 28 weeks of Adalimumab therapy the decrease in DAS28 (ΔDAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). ΔDAS28 was 1.8±1.4 in patients without anti-Adalimumab and 0.6±1.3 in patients with anti-Adalimumab (P Conclusion Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF therapy should be offered to RA-patients who fail on initial treatment with anti-TNF, in the absence of anti-biological antibodies.
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Anti-infliximab and anti-Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study
Annals of the rheumatic diseases, 2009Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Willem F. Lems, Ben A. C. Dijkmans, Paul P. Tak, Gertjan WolbinkAbstract:To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). This cohort study consisted of 235 patients with RA, all treated with Adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab ('switchers'), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and Adalimumab were assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. After 28 weeks of Adalimumab treatment the decrease in DAS28 (Delta DAS28) for the 235 patients was 1.6+/-1.5 (mean+/-SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). Delta DAS28 was 1.8+/-1.4 in patients without anti-Adalimumab and 0.6+/-1.3 in patients with anti-Adalimumab (p<0.0001). Thirty-three of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-Adalimumab than anti-TNF naive patients (11 (33%) vs 32 (18%); p=0.039). Delta DAS28 was greater for anti-TNF naive patients (1.7+/-1.5) than for switchers without anti-infliximab antibodies (Delta DAS28=0.9+/-1.4) (p=0.009). Delta DAS28 for switchers with anti-infliximab was 1.2+/-1.3 and did not differ significantly from anti-TNF naive patients (p=0.262). Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF treatment should be offered to patients with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.
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a novel method for the detection of antibodies to Adalimumab in the presence of drug reveals hidden immunogenicity in rheumatoid arthritis patients
Journal of Immunological Methods, 2010Co-Authors: Pauline A Van Schouwenburg, Gertjan Wolbink, Lucien A Aarden, G. M. Bartelds, Margreet Hart, Diana WoutersAbstract:Production of anti drug antibodies (ADA) in Adalimumab treated RA patients is associated with reduced serum Adalimumab levels and less clinical response. However, most current assays to measure ADA are unable to detect ADA in complex with Adalimumab. Thus, ADA is only measured if antibody production exceeds drug levels in the serum, meaning that ADA formation is underestimated. The aim of this study is to develop a method to detect ADA in the presence of drug. A pH-shift-anti-idiotype Antigen binding test (PIA) was used to enable ADA measurement in the presence of Adalimumab. ADA-Adalimumab complexes were dissociated by acid treatment and addition of excess rabbit anti-idiotype-F(ab) before neutralization. Rabbit anti-idiotype-F(ab) blocks reformation of ADA-drug complexes by competing with patient ADA for Adalimumab binding. Released ADA are measured by an antigen binding test (ABT). The PIA enabled detection of ADA in the presence of large excess of Adalimumab and was used to measure ADA in 30 Adalimumab treated rheumatoid arthritis (RA) patients during the first 28 weeks of treatment. It revealed ADA in 21 out of 30 tested patients, while the ABT detected ADA in only 5 patients. Indicating that an immunogenic reaction towards Adalimumab is present in the majority of Adalimumab treated patients.
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anti infliximab and anti Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti tumour necrosis factor naive patients a cohort study
Annals of the Rheumatic Diseases, 2010Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Ben A. C. Dijkmans, Paul P. Tak, W F Lems, Gertjan WolbinkAbstract:Objective To investigate how antibodies against anti-TNF agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). Methods: This cohort study consisted of 235 RA patients, all treated with Adalimumab. At baseline fifty-two patients (22%) were previously treated with infliximab ("switchers"), and 183(78%) were anti-TNF naive. Disease activity (using the DAS28score) and presence of antibodies against infliximab and Adalimumab was assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. Results After 28 weeks of Adalimumab therapy the decrease in DAS28 (ΔDAS28) for the 235 patients was 1.6±1.5 (mean±SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). ΔDAS28 was 1.8±1.4 in patients without anti-Adalimumab and 0.6±1.3 in patients with anti-Adalimumab (P Conclusion Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF therapy should be offered to RA-patients who fail on initial treatment with anti-TNF, in the absence of anti-biological antibodies.
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Anti-infliximab and anti-Adalimumab antibodies in relation to response to Adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study
Annals of the rheumatic diseases, 2009Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Willem F. Lems, Ben A. C. Dijkmans, Paul P. Tak, Gertjan WolbinkAbstract:To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to Adalimumab in rheumatoid arthritis (RA). This cohort study consisted of 235 patients with RA, all treated with Adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab ('switchers'), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and Adalimumab were assessed. Clinical response to Adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-Adalimumab antibody status. After 28 weeks of Adalimumab treatment the decrease in DAS28 (Delta DAS28) for the 235 patients was 1.6+/-1.5 (mean+/-SD). Anti-Adalimumab antibodies were detected in 46 patients (20%). Delta DAS28 was 1.8+/-1.4 in patients without anti-Adalimumab and 0.6+/-1.3 in patients with anti-Adalimumab (p<0.0001). Thirty-three of the 52 switchers (63%) had anti-infliximab antibodies. Patients with anti-infliximab more often developed anti-Adalimumab than anti-TNF naive patients (11 (33%) vs 32 (18%); p=0.039). Delta DAS28 was greater for anti-TNF naive patients (1.7+/-1.5) than for switchers without anti-infliximab antibodies (Delta DAS28=0.9+/-1.4) (p=0.009). Delta DAS28 for switchers with anti-infliximab was 1.2+/-1.3 and did not differ significantly from anti-TNF naive patients (p=0.262). Switchers with anti-infliximab antibodies more often develop antibodies against Adalimumab than anti-TNF naive patients. Response to Adalimumab was limited in switchers without anti-infliximab antibodies, which raises the question whether a second anti-TNF treatment should be offered to patients with RA for whom an initial treatment with an anti-TNF blocker fails, in the absence of anti-biological antibodies.
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clinical response to Adalimumab relationship to anti Adalimumab antibodies and serum Adalimumab concentrations in rheumatoid arthritis
Annals of the Rheumatic Diseases, 2007Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Willem F. Lems, Ben A. C. Dijkmans, Paul P. Tak, Gertjan WolbinkAbstract:Background: A substantial proportion of patients with rheumatoid arthritis (RA) do not respond, or lose initial response, to Adalimumab treatment. One explanation for non-response is that patients develop anti-Adalimumab antibodies. Objectives: To evaluate the incidence of formation of antibody against Adalimumab and the association with serum Adalimumab concentrations and clinical response. Methods: In a cohort of 121 consecutive patients with RA treated with Adalimumab, serum Adalimumab concentrations and antibodies against Adalimumab were measured together with clinical response variables before and up to 28 weeks after the start of treatment. Results: Anti-Adalimumab antibodies were detected in 21 patients (17%) during 28 weeks of treatment. EULAR non-responders had antibodies significantly more often than good responders (34% vs 5%; p = 0.032). Patients with antibodies showed less improvement in disease activity (mean (SD) delta DAS28 0.65 (1.35)) than patients without antibodies (mean delta DAS28 1.70 (1.35)) (p = 0.001). Patients with antibodies during follow-up had lower serum Adalimumab concentrations at 28 weeks than patients without antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/l, range 2.0–33.0, respectively; p Conclusions: Serum antibodies against Adalimumab are associated with lower serum Adalimumab concentrations and non-response to Adalimumab treatment.
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Clinical response to Adalimumab: relationship to anti-Adalimumab antibodies and serum Adalimumab concentrations in rheumatoid arthritis
Annals of the rheumatic diseases, 2007Co-Authors: G. M. Bartelds, Michael T. Nurmohamed, Lucien A Aarden, S O Stapel, Carla A. Wijbrandts, Willem F. Lems, Ben A. C. Dijkmans, Paul P. Tak, Gertjan WolbinkAbstract:A substantial proportion of patients with rheumatoid arthritis (RA) do not respond, or lose initial response, to Adalimumab treatment. One explanation for non-response is that patients develop anti-Adalimumab antibodies. To evaluate the incidence of formation of antibody against Adalimumab and the association with serum Adalimumab concentrations and clinical response. In a cohort of 121 consecutive patients with RA treated with Adalimumab, serum Adalimumab concentrations and antibodies against Adalimumab were measured together with clinical response variables before and up to 28 weeks after the start of treatment. Anti-Adalimumab antibodies were detected in 21 patients (17%) during 28 weeks of treatment. EULAR non-responders had antibodies significantly more often than good responders (34% vs 5%; p = 0.032). Patients with antibodies showed less improvement in disease activity (mean (SD) delta DAS28 0.65 (1.35)) than patients without antibodies (mean delta DAS28 1.70 (1.35)) (p = 0.001). Patients with antibodies during follow-up had lower serum Adalimumab concentrations at 28 weeks than patients without antibodies (median 1.2 mg/l, range 0.0-5.6 vs median 11.0 mg/l, range 2.0-33.0, respectively; p<0.001). Good responders had higher serum Adalimumab concentrations than moderate responders (p = 0.021) and non-responders (p = 0.001). Concomitant methotrexate use was lower in the group with anti-Adalimumab antibodies (52%) than in the group without antibodies (84%) (p = 0.003). Serum antibodies against Adalimumab are associated with lower serum Adalimumab concentrations and non-response to Adalimumab treatment.
