Highlights
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Antiadalimumab antibodies occur frequently, ∼50% by 8 years.
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Antibodies are associated with lower adalimumab levels and active disease.
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Concomitant immunosuppression may reduce risk of antibody formation.
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Weekly dosing is associated with reduced risk of antibody formation.
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Monitoring enables treatment escalation or safe discontinuation.
Purpose
To determine the incidence, effect on adalimumab drug levels, and clinical consequences of antiadalimumab antibody formation, and to assess potential risk factors.
Design
Retrospective clinical cohort study.
Participants
One hundred twenty-eight patients treated with adalimumab who underwent antiadalimumab antibody monitoring.
Methods
Beginning October 2023, regularly scheduled antiadalimumab antibody and adalimumab level testing was begun. Using staggered entry analysis, anchored observation to treatment initiation, incidence was calculated. Time-updated models evaluated risk factors for antiadalimumab antibody formation.
Main Outcome
Incidence of antiadalimumab antibodies.
Results
Antiadalimumab antibodies developed in 37 of 128 patients for a rate of 0.077 per person-year (PY) (95% confidence interval [CI] 0.055/PY, 0.104/PY). Median serum adalimumab concentrations were significantly lower in antiadalimumab antibody-positive blood samples (2.6 µg/mL; interquartile range 0.8, 7.0) than in antibody-negative samples (10.2 µg/mL; interquartile range 6.9, 15.1), P <.00001. In time-updated analyses, there was a suggestion that concomitant immunosuppression was associated with a reduced risk of antiadalimumab antibodies (odds ratio [OR] 0.64; 95% CI 0.37, 1.10; P =.10) and weekly adalimumab dosing was associated with a reduced risk (OR 0.62; 95% CI 0.42, 0.91; P =.01). Antiadalimumab antibodies were associated with active ocular inflammation (OR 3.68; 95% CI 1.99, 6.82; P <.00001).
Conclusions
Antiadalimumab antibodies occur commonly among patients treated with long-term adalimumab, with a cumulative incidence of nearly 50% by 8 years of therapy. Antibody formation was associated with lower serum adalimumab levels and active ocular inflammation.
INTRODUCTION
A dalimumab is a recombinant human monoclonal antibody targeting tumor necrosis factor-α. It is the only FDA-approved biologic agent for the treatment of noninfectious intermediate, posterior, and panuveitis. ,,, The ADVISE trial compared adalimumab to conventional immunosuppression with either antimetabolites or calcineurin inhibitors and demonstrated that adalimumab was more effective than conventional immunosuppression in achieving successful corticosteroid-sparing at 6 months and successful corticosteroid discontinuation at 12 months in patients with uveitis, suggesting that adalimumab was at least faster in achieving important clinical outcomes. Although adalimumab is effective, treatment failure may occur and antidrug antibodies have been identified as one mechanism of reduced therapeutic response. Cordero-Coma et al linked the presence of antiadalimumab antibodies to undetectable serum drug levels and treatment failure, and subsequent studies have supported this association. ,,,,,,,,, However, most prior studies relied on selective testing among patients with inadequate therapeutic response, limiting interpretation of the frequency of antibody formation in treated populations. ,,,,,,,
In October 2023, the Ocular Immunology Division at the Wilmer Eye Institute initiated an antiadalimumab monitoring protocol as part of clinical care for patients receiving adalimumab. Antibody assays and adalimumab drug level testing were performed regularly among patients receiving adalimumab irrespective of inflammatory status. Herein, we report the results of this program.
METHODS
Study population. We reviewed the clinical and laboratory records of patients with inflammatory ocular disease who were treated with adalimumab and seen in the Johns Hopkins Ocular Immunology Division during the study period from October 1, 2023, when routine testing was initiated, to March 1, 2025. Patients were identified using the institutional clinical management software SlicerDicer (Epic). All patients receiving adalimumab at any point during the study interval were included, independent of the date adalimumab was initiated. The study was performed with the approval of the Johns Hopkins University School of Medicine Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. Patients’ uveitis was classified using the standardization of uveitis nomenclature system, and specific disease entities were diagnosed using the standardization of uveitis nomenclature criteria. ,
Monitoring protocol. As mentioned, beginning in October 2023, a standard monitoring protocol of serum antiadalimumab antibodies and serum adalimumab levels was implemented in our division. For patients initiating adalimumab, serologic testing was performed at one, three, and 6 months after starting therapy, and then every 6 months thereafter. For patients already receiving adalimumab when the protocol was introduced, testing was performed at the first visit after implementation of the protocol, then at three and 6 months, and every 6 months thereafter. Patients planning to resume adalimumab therapy after prior exposure and discontinuation were tested before restarting adalimumab; those without baseline antiadalimumab antibodies were monitored on the same schedule as new users. Patients who tested positive for antiadalimumab antibodies underwent retesting at 1 month after the initial positive result, with subsequent testing every 3 months thereafter.
To facilitate adherence to testing, patients were not instructed to delay or time injections to permit testing during trough conditions. Prior studies in inflammatory bowel disease and rheumatologic populations have demonstrated comparable applicability of nontrough sampling for adalimumab pharmacokinetics and immunogenicity, supporting this approach. ,,
Laboratory assays. Testing was performed through Labcorp or Quest Diagnostics according to provider order and insurance requirements. LabCorp utilized an electrochemiluminescence immunoassay, and Quest Diagnostics employed a drug-tolerant ELISA-based method. These platforms vary in quantitation limits for serum adalimumab levels and antibody reporting units. Antiadalimumab antibodies positivity was determined according to laboratory-specific manufacturer thresholds.
Data collection. Patient records were reviewed retrospectively, and data were entered into a customized database. Data collected included demographics, ocular diagnosis, systemic inflammatory disease if present, date of adalimumab initiation, concomitant immunosuppressive therapy, systemic corticosteroid use, and adalimumab dosing frequency. Concomitant immunosuppression included methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, or tacrolimus. We also longitudinally recorded: episodes of treatment interruption (defined as a lapse in dosing greater than 30 days), changes in adalimumab dosing frequency, initiation or cessation of concomitant immunosuppressive therapy, and disease activity. Antiadalimumab antibody status and serum adalimumab concentration are systemic biomarkers and cannot be assigned to individual eyes. Disease activity therefore, was recorded as active or inactive at the patient level, defined as the presence of active inflammation in at least one eye, based on the treating uveitis specialist’s clinical assessment using both clinical examination and appropriate imaging. ,
Outcomes. The primary outcome was development of antiadalimumab antibodies in the serum. Secondary outcomes included serum levels of adalimumab and active ocular inflammation. Risk factors for antiadalimumab antibodies included concomitant immunosuppression, concomitant oral corticosteroid use, and adalimumab dosing frequency (every 2 weeks, the FDA-approved dosing interval, vs weekly).
Statistical analysis. Baseline characteristics were summarized using means or medians for continuous variables and proportions for categorical variables. Time to antibody development was estimated using Kaplan–Meier methods and staggered entries to anchor events to the date of adalimumab initiation. Risk factors for antiadalimumab antibody development were evaluated using time-updated models with exposures measured at the time the monitoring protocol was initiated for each patient. Time-updated models incorporated changes in dosing frequency, concomitant immunosuppressive drug therapy, and treatment interruptions. Associations between visit-level factors and active disease at the end of a visit were evaluated using univariate and multivariate logistic regression models, with odds ratios (OR) and 95% confidence intervals (CI) reported. Adalimumab serum drug levels were reported as median drug level and interquartile range (IQR).
RESULTS
Characteristics of the study population. During the time of study, 252 patients treated with adalimumab were identified, of whom 128 (50.8%) underwent protocol-driven antiadalimumab antibody testing. These 128 patients comprise the study population. The demographic and clinical characteristics of the tested and not-tested patients are summarized in Table 1 . The mean age at adalimumab initiation in the tested group was 43.5 ± 17.9 years, the majority were women (68.0%), and the majority were white, non-Hispanic (59.4%). The most common uveitis anatomical classes were anterior uveitis (28.9%) and posterior uveitis (26.6%). Among the tested patients, 33.6% were receiving concomitant 2nd agent immunosuppression at the time of enrollment. Patients tested and not tested were similar in baseline characteristics, with two exceptions that should be taken into account when considering generalizability: tested patients were more likely to have a systemic disease (21.9% vs 10.5%; P =.03), and tested patients were more often on weekly adalimumab therapy (18.8% vs 5.6%; P =.004).
TABLE 1
Demographic and Clinical Profile of the Study Cohort Stratified by Antiadalimumab Antibody Testing Status.
| Characteristic | Tested ( N = 128) | Not Tested ( N = 124) | P Value |
|---|---|---|---|
| Demographics | |||
| Age at adalimumab initiation, mean ± SD (y) | 43.5, 17.9 | 44.6, 18.1 | .64 |
| Female sex, n (%) | 87 (68.0) | 83 (66.9) | .89 |
| Race, n (%) | |||
| • White non-Hispanic | 76 (59.4) | 79 (63.7) | .65 |
| • Black non-Hispanic | 34 (26.6) | 32 (25.8) | |
| • Hispanic | 10 (7.8) | 5 (4.0) | |
| • Asian | 8 (6.2) | 8 (6.4) | |
| Bilateral disease, n (%) | 110 (85.9) | 103 (83.1) | .60 |
| Ocular diagnosis class | |||
| Anterior uveitis | 37 (28.9) | 26 (21.0) | .10 |
| Anterior and intermediate uveitis | 7 (5.5) | 5 (4.0) | |
| Intermediate uveitis | 5 (3.9) | 15 (12.1) | |
| Posterior uveitis | 34 (26.6) | 43 (34.7) | |
| Panuveitis | 21 (16.4) | 17 (13.7) | |
| Scleritis | 12 (9.4) | 12 (9.7) | |
| Idiopathic orbital inflammatory syndrome | 7 (5.5) | 4 (3.2) | |
| Ulcerative keratitis | 5 (3.9) | 2 (1.6) | |
| Systemic disease association, n (%) | |||
| None | 100 (78.1) | 111 (89.5) | .03 |
| Spondyloarthritis | 6 (4.7) | 3 (2.4) | |
| Behçet’s disease | 2 (1.6) | 1 (0.8) | |
| Inflammatory Bowel disease | 3 (2.3) | 1 (0.8) | |
| Juvenile idiopathic arthritis | 3 (2.3) | 2 (1.6) | |
| Systemic lupus erythematosus | 0 (0) | 1 (0.8) | |
| Sarcoidosis | 13 (10.2) | 2 (1.6) | |
| Rheumatoid arthritis | 1 (0.8) | 3 (2.4) | |
| Treatment | |||
| Concomitant immunosuppressive therapy, n (%) | 43 (33.6) | 41 (33.1) | .99 |
| Prednisone use, n (%) | 33 (25.8) | 30 (24.2) | .88 |
| Adalimumab frequency: every 2 wk, n (%) | 97 (75.8) | 114 (91.4) | .35 |
| Adalimumab frequency: every wk n (%) | 24 (18.8) | 7 (5.6) | .004 |
| History of ADA interruption, n (%) | 22 (17.2) | 13 (10.5) | .15 |
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