Presence of antidrug antibody associated with lower drug levels in patients with noninfectious uveitis: JAMA
The tumor necrosis factor a inhibitors (TNFis) infliximab and adalimumab have been shown to be effective in treating noninfectious uveitis (NIU). TNFis are typically used in cases refractory to conventional immunomodulatory therapy, in more severe presentations, or as a primary treatment for certain etiologies such as Behçet disease. Despite the effectiveness of TNFis, few studies to date have investigated antidrug antibodies (ADAs) in patients with NIU, which can result in lower circulating drug levels and potential loss of medication efficacy. The goal of this study by Sunil Bellur et al was to investigate the frequency of ADAs and their association with circulating drug levels, clinical response, and concurrent treatment with antimetabolites in patients receiving adalimumab or infliximab for NIU.
This single-site, retrospective cross-sectional study was conducted at the National Eye Institute in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Patients with a diagnosis of NIU treated with either adalimumab or infliximab who underwent ADA testing from September 2017 to July 2021 were included. Serum drug level testing with reflex testing for ADA levels was performed. The main outcome was the association between drug levels and ADAs, clinical response, and concurrent antimetabolite use in patients treated with TNFis for NIU.
Of 54 patients included in the study, 42 received adalimumab and 12 received infliximab. In the adalimumab group, mean (SD) drug level was 9.72 (6.82) μg/mL, mean (SD) ADA level was 84.2 (172.9) arbitrary units/mL, and ADA frequency was 35.7% (15 of 42 patients).
Mean drug level was lower in those with ADAs compared with those without ADAs (P < .001). There was a higher mean drug level with concurrent antimetabolite use compared with monotherapy (P = .06).
Multivariable modeling showed that a 1−arbitrary unit increase in ADAs was associated with a –0.02 μg/mL difference in mean drug level (P < .001). Favorable clinical response was associated with a threshold drug level above 2.7 μg/mL or an antibody level below 15.2 μg/mL. The mean (SD) drug level in the infliximab group was 27.02 (18.15) μg/mL, and no ADAs were detected.
Study results suggest that the presence of ADAs is associated with lower mean drug level and that higher ADA levels may be associated with increased risk of TNFi treatment failure. The rate of ADA formation is an important therapeutic consideration when using TNFis in patients with NIU. Data regarding ADAs is mostly derived from rheumatologic disease, and to date, there remains a paucity of data regarding the frequency and implications of ADAs following TNFi treatment for NIU.
This study highlights the importance of recognizing the formation of ADAs and its association with TNFi therapy in patients with NIU. The presence of ADAs was associated with lower drug levels; however, their presence was not always associated with therapy failure. Results from multivariable models suggest that drug level is associated not only with the presence of ADAs but also with the quantity of ADAs. As a result, patients with sufficiently high ADA levels may be expected to have essentially no effective circulating drug and loss of response to TNFi therapy. These findings support consideration of drug and antibody level testing in patients receiving adalimumab who are experiencing therapy failure. Failure due to ADA formation is suggested if serum drug level is low or undetectable and ADA levels are elevated, in which case intraclass or interclass switching can be considered. Further prospective studies are needed to clarify the role of TDM and the association of ADAs with TNFi treatment in patients with NIU.
Source: Sunil Bellur, Matthew McHarg, Wijak Kongwattananon; JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2022.5584
