Monitoring Drug and Antidrug Levels: A Rational Approach in Rheumatoid Arthritis Patients Treated with Biologic Agents Who Experience Inadequate Response While Being on a Stable Biologic Treatment

Abstract

Clinical response in patients with rheumatoid arthritis (RA) treated with biologic agents can be influenced by their pharmacokinetics and immunogenicity. The present study evaluated the concordance between serum drug and antidrug levels as well as the clinical response in RA patients treated with biological agents who experience their first disease exacerbation while being on a stable biologic treatment. 154 RA patients treated with rituximab (RTX), infliximab (IFX), adalimumab (ADL), or etanercept (ETN) were included. DAS28, SDAI, and EULAR response were assessed at baseline and reevaluated at precise time intervals. At the time of their first sign of inadequate response, patients were tested for both serum drug level and antidrug antibodies level. At the next reevaluation, patients retreated with RTX that had detectable drug level had a better EULAR response (P = 0.038) with lower DAS28 and SDAI scores (P = 0.01 and P = 0.03). The same tendency was observed in patients treated with IFX and ETN regarding EULAR response (P = 0.002 and P = 0.023), DAS28 score (P = 0.002 and P = 0.003), and SDAI score (P = 0.001 and P = 0.026). Detectable biologic drug levels correlated with a better clinical response in patients experiencing their first RA inadequate response while being on a stable biologic treatment with RTX, IFX, and ETN.

Biosimilars in rheumatology: current perspectives and lessons learnt

“…Moreover, data on reference TNF inhibitors, such as adalimumab and inflix imab, have already documented that ADAs and resulting drug levels are associated with better clinical responses in patients with RA. 37 This effect is generally accepted for inflammatory bowel diseases, in which patients are dosed according to the trough level of the drug, but this approach is not widely used in rheumatology practice. 38 …”

Biologic therapies in rheumatic diseases: drug and anti-drug antibody levels and clinical efficacy

“…In a third of cases such drugs are ineffective and this is due to primary treatment failure (drug inefficacy or serious side effects) or secondary treatment failure (drug loss of efficacy after initial good response). It has been shown that serum levels of ADA, ETN and IFX correlate with the clinical response in RA, while in ankylosing spondylitis (AS) data are controversial [1][2][3][4]. Similarly, anti-drug Ab levels inversely correlate with drugs levels and therapeutic response [4][5][6].…”

“…It has been shown that serum levels of ADA, ETN and IFX correlate with the clinical response in RA, while in ankylosing spondylitis (AS) data are controversial [1][2][3][4]. Similarly, anti-drug Ab levels inversely correlate with drugs levels and therapeutic response [4][5][6]. The mechanism of drug inactivation is linked to anti-drug Ab formation (against biological medications) which causes the neutralization of the drug and its increased clearance [5]: only 4% of patients with anti-adalimumab antibodies (anti-ADA Ab) achieved clinical remission compared to 34% anti-ADA Ab negative patients [6].…”

“…The mechanism of drug inactivation is linked to anti-drug Ab formation (against biological medications) which causes the neutralization of the drug and its increased clearance [5]: only 4% of patients with anti-adalimumab antibodies (anti-ADA Ab) achieved clinical remission compared to 34% anti-ADA Ab negative patients [6]. ETN has shown a less immunogenic effect with anti-etanercept antibodies (anti-ETN Ab) not detectable or present only in a low number of patients; as a consequence anti-ETN immune response has a minimal effect on clinical response [4,[7][8][9]. A clinically relevant impact of anti-drug Ab is described in about half of the patients receiving repeated TNFα monotherapy and therefore immune suppression by concomitant administration of metrotrexate (MTX) is indicated in RA and SpA patients [8,[10][11][12][13][14][15][16][17][18][19][20][21].…”

Quantification of active infliximab in human serum with liquid chromatography–tandem mass spectrometry using a tumor necrosis factor alpha -based pre-analytical sample purification and a stable isotopic labeled infliximab bio-similar as internal standard: A target-based, sensitive and cost-effective method

“…It is speculated that this is largely due to induction of immunogenicity where patients develop antiinfliximab antibodies (ATIs) that bind to IFX rendering it ineffective. Therapeutic drug monitoring of the biological active fraction of IFX in patients' serum has shown great promise to improve treatment outcomes in patients suffering from inflammatory autoimmune diseases [4][5][6][7].…”