POS0345 ADALIMUMAB SERUM DRUG LEVELS AND ANTI-DRUG ANTIBODIES: ASSOCIATION TO DISEASE ACTIVITY AND DRUG SURVIVAL IN INFLAMMATORY ARTHRITIS PATIENTS

Abstract

BackgroundLack of response to TNF-inhibitors (TNFi) can be caused by subtherapeutic drug levels and anti-drug antibodies (ADAb). Therapeutic-drug-monitoring (TDM) can help clinicians tailor treatment and may improve effectiveness, safety and cost-effectiveness of TNFi. For TDM to be validated as a clinical tool, therapeutic ranges must be identified.ObjectivesTo explore the association between adalimumab serum drug level, treatment response and drug survival in patients with inflammatory arthritis, with the intention to identify a therapeutic range. In addition, to assess frequency and clinical implications of ADAb formation.MethodsPatients with a clinical diagnosis of rheumatoid arthritis (RA), spondyloarthritis (SpA) or psoriatic arthritis (PsA) starting treatment with adalimumab and enrolled in the observational NOR-DMARD study were included. Treatment response at 3 months was defined as EULAR good or moderate response in RA/PsA and ASDAS Major or Clinically Important Improvement in SpA. Serum drug levels and ADAb at 3 months were measured using an in-house fluorescence method, with ADAb measured in patients with serum drug levels < 3mg/L. Comparisons of serum drug level and ADAb formation between diagnosis groups was done by Mann-Whitney U and χ2 test, respectively. Multivariate logistic regression analyses were used to assess serum drug level and treatment response and Cox proportional hazard regression analyses were used to assess drug survival and serum drug level, ADAb formation and methotrexate use, all analyses adjusted for age, sex and previous use of bDMARDs.ResultsA total of 343 patients (98 RA, 70 PsA, 177 SpA) were included (median age 46.0 years [SD 14.1], 182 [53%] female). 123/340 (36%) patients used methotrexate as co-medication. The median serum drug level at 3 months was 7.3 mg/L (IQR 3.7-10.3) and 34 (10 %) patients developed ADAb, these findings were comparable across diagnoses, (Figure 1A). Serum drug levels at 3 months were higher in responders (7.8 mg/L [IQR 5.4-10.5]) than in non-responders (6 mg/L [IQR 2.6-9.6]), p=0.0014.Percent distribution of responders at 3 months stratified by serum adalimumab levels by percentile distribution suggested that the therapeutic ranges were 6 -12 mg/L for RA/PsA and >1.4 mg/L SpA, with no upper cut-off detected in SpA, (Figure 1B and C).RA and PsA patients with serum adalimumab > 6 mg/L had higher odds for response to therapy at 3 months (Odds Ratio [OR] 2.2 [95% CI 1.1 – 4.5], p=0.026), and lower treatment discontinuation rate (Hazard Ratio [HR] 0.43 [95% CI 0.27-0.80], p= 0.006). No additional benefit was found with serum drug levels >12 mg/L.SpA patients with serum adalimumab level >1.4 mg/L had higher odds for response (OR 4.7 [95% CI 1.4-15], p=0.01) Further, in these patients treatment discontinuation was seen at a lower rate (HR 0.35 [95% CI 0.17-0.73], p= 0.005).Patients with ADAb at 3 months discontinued treatment at a higher rate (HR 3.4 [95% CI 2.1-5.3], p=<0.001).In RA/PsA patients, co-medication with methotrexate was associated with higher serum drug levels (8.4 mg/L [IQR 5.3-10.9] vs 5.8 mg/L [IQR 1.2-8.7], p=0.0003), lower rate of ADAb (6% vs 22 %, p<0.0001) and better drug survival (HR for drug discontinuation 0.50 [95% CI 0.29-0.87] p= 0.013).ConclusionThis study is the first to explore associations between adalimumab serum levels and clinical outcomes across all inflammatory arthritides. Higher adalimumab drug levels were associated with clinical response at 3 months and long-term drug survival. This study suggests 6 - and 1.4 mg/L as lower target adalimumab levels for RA/PsA and SpA respectively and contributes to the development of TDM algorithms for adalimumab in arthritis patients.Figure 1.Serum adalimumab levels at 3 months. A) Violin plot. Each data point is a participant, and the solid orange line show the group median.B) and C) Percent distri bution of responders at 3 months stratified by serum adalimumab levels. Adalimumab groups are divided by percentile distribution.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsIngrid Jyssum: None declared, Johanna Elin Gehin: None declared, Eirik kristianslund: None declared, Joseph Sexton: None declared, David Worren: None declared, Yi Hu Speakers bureau: Boehringer, Tore K. Kvien Speakers bureau: Grünenthal,Sandoz, UCB, Consultant of: AbbVie,Amgen,Celltrion,Gilead,Novartis,Pfizer,Sandoz, UCB, Grant/research support from: AbbVie,Amgen, BMS,Galapagos,Novartis,Pfizer, UCB, Espen A Haavardsholm Speakers bureau: Pfizer, UCB, Consultant of: AbbVie,Boehringer-Ingelheim,Eli Lilly,Gilead, Nils Bolstad: None declared, Silje Watterdal Syversen: None declared, Guro Løvik Goll Speakers bureau: AbbVie/Abbott,Galapagos, Pfizer, UCB., Consultant of: AbbVie/Abbott, Galapagos, Pfizer, UCB.