Antibodies to infliximab and adalimumab in patients with rheumatoid arthritis in clinical remission:a cross-sectional study

Objective. To investigate if antibodies towards biological TNF-α inhibitors (anti-TNFi Abs) are present in patients with rheumatoid arthritis (RA) in clinical remission and to relate any anti-TNFi Abs to circulating level of TNF-α inhibitor (TNFi). Methods. Patients with RA, treated with infliximab or adalimumab, and in clinical remission (DAS28(CRP) < 2.6) were included from 6 out-patient clinics. In blood samples, presence of anti-TNFi Abs was determined by radioimmunoassay, and concentration of bioactive TNFi was measured by a cell-based reporter gene assay. Results. Anti-TNFi Abs were present in 8/44 patients (18%) treated with infliximab and 1/49 patients (2%) treated with adalimumab (p=0.012). In the former group, anti-TNFi Abs corresponded with low levels of TNFi (p=0.048). Anti-TNFi Ab-positive patients had shorter disease duration at initiation of TNFi therapy (p=0.023) but were similar for the rest of the compared parameters. Conclusions. In RA patients in clinical remission, anti-TNFi Abs occur frequently in patients treated with infliximab, while they occur rarely in patients treated with adalimumab. Presence of anti-infliximab Abs is accompanied by low or undetectable levels of infliximab. These data suggest that continued infliximab treatment may be redundant in a proportion of RA patients treated with infliximab and in clinical remission

Anti-Drug Antibodies, Drug Levels, Interleukin-6 and Soluble TNF Receptors in Rheumatoid Arthritis Patients during the First 6 Months of Treatment with Adalimumab or Infliximab:A Descriptive Cohort Study

OBJECTIVES:With the present study we wanted to explore the impact of treatment with a tumor necrosis factor-α -inhibitor (TNFi) on levels of soluble biomarkers in rheumatoid arthritis (RA) patients and to identify predictors of impaired drug levels and development of anti-TNFi antibodies (anti-TNFi Abs). METHODS:Blood samples from 26 patients with established RA were taken at baseline and following 6 months of treatment with adalimumab or infliximab. Samples were analyzed for levels of TNFi, interleukin (IL)-6, and soluble TNF-receptors 1 and -2 (sTNF-R1 and -2) and for presence of anti-TNFi Abs. Clinical and demographic data were recorded as well. RESULTS:During the initial 6 months treatment, DAS28(CRP) (Disease activity score in 28 joints using C-reactive protein) and levels of IL-6 and sTNF-R2 decreased significantly in patients without anti-TNFi Abs and in patients retaining detectable drug levels. The levels of other tested cytokines (TNF-α, TNF-β, IL-1ra, IL-1b, IL-8, IL-10, IL-12(p70), IL-13, IL-17A, IL-17F, and IL-33) were generally below detection limits. Higher baseline levels of IL-6 associated with undetectable levels of TNFi at follow-up. Anti-TNFi Abs were associated with decreased drug levels, but no predictors for anti-TNFi Ab development could be found. CONCLUSION:The effect of treatment with TNFi on RA disease activity depends on levels of active drug, and by presence of anti-TNFi Abs. In patients who retain detectable drug levels, and in the absence of anti-TNFi Abs, clinical outcome is improved during treatment, and circulating levels of IL-6 and sTNF-R2 decrease. Baseline levels of IL-6 may predict depletion of TNFi and may identify patients at risk of treatment failure

Changes in levels of IL-6, sTNF-R1 and sTNF-R2 following 6 months of treatment with adalimumab or infliximab.

<p>Level of IL-6 and sTNF-R1 and sTNF-R2 were determined in 26 patients with rheumatoid arthritis, 15 patients treated with adalimumab, and 11 patients treated with infliximab. Levels were determined prior to treatment (Baseline) and following 6 months of treatment (Follow-up). Levels of IL-6 (A) and sTNF-R2 (C) decreased significantly during treatment. *<i>p</i> < 0.05. Medians and interquartile ranges are shown.</p

Variables according to development of anti-TNFi Ab production following 6 months of treatment with adalimumab or infliximab.

<p>Variables according to development of anti-TNFi Ab production following 6 months of treatment with adalimumab or infliximab.</p

Serum TNFi levels in relation to antibodies against adalimumab and infliximab following six months of treatment.

<p>Antibodies towards the prescribed TNFi (anti-TNFi Abs) were measured in 26 patients with rheumatoid arthritis, using radioimmunoassay. Patients were treated with either adalimumab (A) or infliximab (B). Functional levels of TNFi were determined using reporter gene assays. Presence of anti-TNFi Abs correlated with lower levels of TNFi for both drugs *(<i>p</i> < 0.05). Medians and interquartile ranges are shown.</p

Flow diagram of the selection of patients in this study.

<p>Patients were recruited among all patients diagnosed with rheumatoid arthritis and treated with a TNFi, with serum samples available at the research biobank at the Parker Institute, Copenhagen University Hospital at Frederiksberg and Bispebjerg, Denmark. ^A Only patients treated with adalimumab or infliximab were included, as we did not have access to a reliable detection method regarding antibodies towards etanercept. ^B Vials were adequate only if they had not been previously thawed. At baseline, one vial of ≥ 3μl was required, and at 6 months follow-up 2 vials of ≥ 3 μl were required. ^C Missing samples due to inclusion in project not requiring 6 months sampling, termination of current treatment, or lost to follow-up.</p

Clinical variables and biomarkers according to whether TNFi was detectable in the patients’ blood following 6 months of treatment with adalimumab or infliximab.

<p>Clinical variables and biomarkers according to whether TNFi was detectable in the patients’ blood following 6 months of treatment with adalimumab or infliximab.</p

Baseline characteristics of the 26 rheumatoid arthritis patients included in the study.

<p>Baseline characteristics of the 26 rheumatoid arthritis patients included in the study.</p