Charlotte L. M. Krieckaert

Development of Antidrug Antibodies Against Adalimumab and Association With Disease Activity and Treatment Failure During Long-term Follow-up

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 in whom adalimumab 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.

Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner

Immunogenicity of adalimumab could impair important treatment outcome parameters in patients with rheumatoid arthritis (RA). Patients who developed antiadalimumab antibodies (AAA) during a 3 year time period achieved less often minimal disease activity or remission and treatment failure occurred more often compared with patients without AAA.1 There were remarkable baseline differences: patients developing AAA had more long-standing, severe disease and less often used concomitant medication including lower doses of methotrexate (MTX), compared with patients not developing AAA. In literature, a favourable effect of concomitant MTX use on the immunogenicity of adalimumab for several inflammatory conditions is suggested.2 To investigate which MTX dose is sufficient to reduce immunogenicity, patients of …

Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients

Objective To investigate the relationship between serum etanercept levels and clinical response. Methods In 292 etanercept-treated patients with rheumatoid arthritis clinical and pharmacological data were determined at baseline and after 1, 4 and 6 months of etanercept treatment. Differences in etanercept levels between good, moderate and European League Against Rheumatism (EULAR) non-responders were assessed after 6 months of therapy. Results After 6 months of therapy etanercept levels were significantly higher in good responders (median (IQR) 3.78 (2.53–5.17)) compared with both moderate 3.10 (2.12–4.47) and EULAR non-responders 2.80 (1.27–3.93) (all p<0.05). There was a significant association between clinical response and serum etanercept levels (regression coefficient 0.54, 95% CI 0.21 to 0.86, p=0.001). When patients were categorised into quartiles according to the height of etanercept levels, the lowest quartile (etanercept level <2.1 mg/l) comprised 40% of all non-responders. The highest quartile (etanercept level >4.7 mg/l) comprised 35% of all good EULAR responders. Anti-etanercept antibodies were detected in none of the sera. Conclusion The authors demonstrated that lower etanercept levels were associated with non-response. Therapeutic drug monitoring and the possibility of the adjusted dosing regimes in the selected groups of patients should be investigated further as a possible tool to optimise treatment with etanercept.

Key findings towards optimising adalimumab treatment: the concentration-effect curve.

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<0.001). 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.

The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review.

Therapeutic monoclonal antibodies have revolutionized the treatment of various inflammatory diseases. Immunogenicity against these antibodies has been shown to be clinically important: it is associated with shorter response duration because of diminishing concentrations in the blood and with infusion reactions. Concomitant immunomodulators in the form of methotrexate or azathioprine reduced the immunogenicity of therapeutic antibodies in rheumatoid arthritis, Crohn disease, and juvenile idiopathic arthritis. The occurrence of adverse events does not increase when immunomodulators are added to therapeutic antibodies. The mechanism whereby methotrexate and azathioprine influence immunogenicity remains unclear. Evidence-based consensus on prescribing concomitant immunomodulators is needed.

Comparison of Long-Term Clinical Outcome With Etanercept Treatment and Adalimumab Treatment of Rheumatoid Arthritis With Respect to Immunogenicity

OBJECTIVE To compare rates of sustained low and minimal disease activity and remission according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria during 3-year followup in rheumatoid arthritis (RA) patients treated with etanercept and adalimumab in routine care. METHODS Four hundred seven RA patients previously unexposed to tumor necrosis factor antagonists were treated with etanercept (n = 203) or adalimumab (n = 204) and assessed at 3- and later 6-month intervals. Treatment allocation was at the discretion of the treating rheumatologist. Clinical parameters were measured at each time point, as were anti-adalimumab antibodies in adalimumab-treated patients. Achievement of clinical outcome was defined as the occurrence of sustained (at least 12 consecutive months) low disease activity (28-joint Disease Activity Score [DAS28] <3.2), minimal disease activity (DAS28 <2.6), or ACR/EULAR remission based on the Simplified Disease Activity Index (SDAI). Non-overlapping response rates were calculated. RESULTS Among the adalimumab group, 13% reached sustained low disease activity but not sustained minimal disease activity, 15% reached sustained minimal disease activity but not sustained remission according to the SDAI, and 16% reached sustained ACR/EULAR remission. In the etanercept group the corresponding rates were 16%, 11%, and 12%, respectively (P = 0.42, overall test for linear trend). Adalimumab-treated patients without anti-adalimumab antibodies (n = 150 [74%]) had the best outcomes, and adalimumab-treated patients with anti-adalimumab antibodies the worst, with outcomes in etanercept-treated patients in between (P < 0.0001). Differences were most apparent in the sustained SDAI remission and sustained minimal disease activity categories. For example, 40% of anti-adalimumab antibody-negative patients, 23% of etanercept-treated patients, and 4% of anti-adalimumab antibody-positive patients achieved at least sustained minimal disease activity. CONCLUSION Overall, etanercept and adalimumab treatment appear similar in inducing a good long-term clinical outcome. However, in the case of adalimumab this is strongly dependent on the presence or absence of anti-adalimumab antibodies.

Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up

Background Immunogenicity influences adalimumab levels and therefore clinical response in patients with rheumatic diseases. Objectives To study the relationship between clinical response, adalimumab levels and antidrug antibodies (ADAb) in ankylosing spondylitis (AS). Methods Observational cohort study of 115 consecutive AS patients treated with adalimumab in the Netherlands (n=85) and Taiwan (n=30), monitored during 24 weeks. Adalimumab levels and ADAb titres were determined using an ELISA and an antigen binding test (ABT), respectively, designed by Sanquin Research, Amsterdam. Response to adalimumab treatment was defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) response, and disease activity was measured using the Ankylosing Spondylitis Disease Activity Score using C-reactive protein (CRP) (ASDAS). Results At baseline, median BASDAI (IQR) was 6.4 (4.5–7.6) and mean ASDAS (SD) was 3.5 (1.0). After 24 weeks, 49 (42.6%) patients were BASDAI50 responders and mean ASDAS (SD) for responders was 1.5 (1.0) vs 2.6 (1.0) for non-responders (p<0.001). Thirty-one (27.0%) patients had detectable ADAb. After 24 weeks, adalimumab levels (mg/L) (IQR) were significantly higher in ADAb-negative patients than in ADAb-positive patients (12.7 (8.2–18.0) vs 1.2 (0.0–2.0), (p<0.001)). A significant association was demonstrated between adalimumab levels and ASDAS (p=0.02; RC −1.1; 95% CI −2.0 to −0.2). Eleven (9.6%) patients had no detectable adalimumab levels and high detectable ADAb titres (>100 AU/mL). In these patients, CRP and erythrocyte sedimentation rate remained elevated during treatment. Conclusions Adalimumab levels are related to clinical response in AS patients measured with ASDAS and are influenced by ADAb detectable with an ABT.

Immunogenicity of biological therapeutics: from assay to patient.

Purpose of reviewTo give an overview of the current knowledge on assay techniques and clinical implications of immunogenicity of biological therapeutics. Recent findingsAssay techniques for the measurement of immunogenicity have improved, expanding the understanding of the immune response against biological therapeutics. Knowledge on the clinical effect of immunogenicity enables the treatment of patients in a targeted fashion, as a step towards personalized medicine. SummaryBiological medications are able to induce an antidrug immune response. Immunogenicity impairs clinical response and is associated with adverse events. Several confounding factors influence the measurement of immunogenicity, including drug interference and background problems. Concomitant administration of methotrexate lowers the frequency and amount of antibodies formed, whereby the efficacy of biologicals is improved. Algorithms for therapeutic drug monitoring could aid in adapting treatment strategies in a controlled setting.

Changes in bone mineral density during long-term treatment with adalimumab in patients with rheumatoid arthritis: a cohort study

OBJECTIVE To investigate the effect of long-term adalimumab treatment on BMD of the lumbar spine, total hip and hands in patients with RA. METHODS In 184 established RA patients treated with adalimumab for at least 1 year, BMD measurements of the total hip and lumbar spine were performed using dual-energy X-ray absorptiometry. Metacarpal cortex BMD was measured using digital X-ray radiogrammetry. RESULTS After 1 year of treatment, BMD of the hip and lumbar spine remained stable, while BMD of the hands decreased significantly by -1.41% (P < 0.0001). After a mean follow-up of 4.0 (s.d. 1.0) years, mean BMD change per year was -0.58% and 0.07% for the hip and lumbar spine, respectively (overall P-value of hip was <0.0001 and spine was 0.67). Predictors for BMD loss of the hip were anti-CCP positivity, non-use of bisphosphonates at baseline and BMI. In European League Against Rheumatism (EULAR) non-responders at 52 weeks, BMD change of the hip and spine was -1.25% and 1.08%, respectively, for moderate responders -0.61% and -1.87%, respectively, and in EULAR good responders, BMD remained stable: -0.02% and 0.06%, respectively. BMD of the hands decreased in non-, moderate and good responders (-2.85%, -1.47% and -1.26%, respectively). CONCLUSION In patients with severe, established RA, loss of BMD in the spine was arrested over 4 years of adalimumab treatment, whereas BMD of the hands and hip continued to decrease after 1 and 4 years, respectively. The changes in BMD are related to disease activity, underlining the importance of monitoring disease activity.

Anti-adalimumab antibodies and adalimumab concentrations in psoriatic arthritis; an association with disease activity at 28 and 52 weeks of follow-up

Objectives To investigate the relationship between antidrug antibodies (ADA), adalimumab concentrations and clinical response in patients with psoriatic arthritis (PsA) during 52 weeks of follow-up. Methods This prospective cohort study included 103 consecutive patients with PsA. Disease Activity Score of 28 joints (DAS28), Erythrocyte Sedimentation Rate, C reactive protein and Psoriasis Area and Severity Index were assessed. Adalimumab concentrations and ADA were measured in serum trough samples, using an ELISA and a radio immunoassay, respectively. Results Adalimumab concentrations were significantly lower at 28 and 52 weeks in patients with detectable ADA compared with patients without detectable ADA (at week 28: 1.3 mg/L (IQR 0.0–3.2) versus 8.7 mg/L (IQR 5.7–11.5), p<0.001; at week 52: 0.9 mg/L (IQR 0.0–2.9) vs 9.4 mg/L (IQR 5.7–12.1), p=0.0001). DAS28 at 28 weeks (2.16 vs 2.95, p=0.023) and 52 weeks (2.19 vs 2.95, p=0.024) showed a significant difference; patients with detectable ADA had a poorer clinical outcome than patients without. Conclusions Patients with detectable ADA had lower adalimumab concentrations and a significantly poorer clinical outcome compared with patients in whom ADA were not detected.