Rheumatoid Arthritis

Adalimumab Serum Levels Not Predictive of Response to Next Anti-Rheumatic Drug

Emily Pond
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It is unclear whether disease control prevents RA-related bone loss, but data suggest it does in patients with early RA and high disease activity.1 Two systemic analyses of RA studies concluded that biologic DMARDs reduce generalized and localized bone loss.2,19 However, few studies were phase 3 trials, and most measured markers of bone turnover.2,19 High-quality trials that measure BMD change or fracture risk are needed. Bisphosphonates, denosumab, and parathyroid hormone are agents approved for osteoporosis and glucocorticoid-induced osteoporosis. Bisphosphonates and denosumab appear to have similar efficacy at preserving BMD.1 In some RA studies, denosumab also prevented and repaired erosions.2 The ACR guidelines for glucocorticoid-induced osteoporosis categorize patients as having low, moderate, or high fracture risk.18 They recommend calcium (1000 to 1200 mg/d) and vitamin D (600 to 800 IU/d) supplements for all patients, plus an osteoporosis agent (preferably an oral bisphosphonate) for patients with moderate to high fracture risk.

It is unclear whether disease control prevents RA-related bone loss, but data suggest it does in patients with early RA and high disease activity.1 Two systemic analyses of RA studies concluded that biologic DMARDs reduce generalized and localized bone loss.2,19 However, few studies were phase 3 trials, and most measured markers of bone turnover.2,19 High-quality trials that measure BMD change or fracture risk are needed. Bisphosphonates, denosumab, and parathyroid hormone are agents approved for osteoporosis and glucocorticoid-induced osteoporosis. Bisphosphonates and denosumab appear to have similar efficacy at preserving BMD.1 In some RA studies, denosumab also prevented and repaired erosions.2

The ACR guidelines for glucocorticoid-induced osteoporosis categorize patients as having low, moderate, or high fracture risk.18 They recommend calcium (1000 to 1200 mg/d) and vitamin D (600 to 800 IU/d) supplements for all patients, plus an osteoporosis agent (preferably an oral bisphosphonate) for patients with moderate to high fracture risk.

Results from this diagnostic test accuracy study suggest that adalimumab serum levels may not be reliable indicators of response to other bDMARDs after adalimumab failure.

In a cohort of patients with rheumatoid arthritis (RA), neither adalimumab serum levels nor anti-adalimumab antibodies were predictive of response to other biological disease-modifying anti-rheumatic drugs (bDMARDs), according to study data published in the Annals of Rheumatic Disease.

The researchers investigated the predictive value of anti-adalimumab antibody and adalimumab serum levels for European League Against Rheumatism (EULAR) clinical response to subsequent treatment with a second bDMARD (tumour necrosis factor inhibition (TNFi) or non-TNFi) after discontinuing adalimumab because of treatment failure.

The study enrolled patients with RA who had received treatment with adalimumab and subsequently another TNFi or non-TNFi drug at participating rheumatology centers in Denmark between 2012 and 2018. Eligible participants had discontinued adalimumab after >3 months of treatment due to lack of efficacy. Eligible participants also had available serum samples taken between ≥8 weeks after starting and ≤2 weeks after discontinuing adalimumab. Patients without viable serum samples were excluded. The primary outcome measure was the association between adalimumab serum levels and response to the first bDMARD after adalimumab. Treatment response was defined per the EULAR criteria for “good” clinical response. The area under the receiver operating characteristic (AUROC) curve was used to determine the predictive values of adalimumab serum levels and antibodies against adalimumab. 

The study cohort comprised 137 patients with RA, among whom 94 (68.6%) were women. Mean age was 64.4 ± 13.2 years. Antibodies against adalimumab were detected in 39 patients (28.5%), and 35 patients (25.5%) had adalimumab serum levels >5 μg/mL. Overall, 47 patients switched to another TNFi after adalimumab, while 90 switched to a non-TNFi agent. Among patients who received a second TNFi, 36% achieved “good” clinical response, compared with 23.4% in the non-TNFi group. No clear predictive value of adalimumab serum levels could be identified for either TNFi or non-TNFi response. Area under the receiver operating characteristic (AUROC) values for adalimumab serum levels predicting TNFi and non-TNFi response were each 0.50, suggesting that adalimumab serum levels could not be used to distinguish responders from non-responders. Antibodies against adalimumab were also not significantly predictive for response in either the TNFi (sensitivity: 18%; specificity: 75%) or non-TNFi (sensitivity: 33%; specificity: 70%) groups. The AUROC values for antibodies predicting TNFi and non-TNFi response were 0.46 and 0.52, respectively, again suggesting no ability to distinguish between response and non-response.  

These data challenge prior study results, which suggest that patients with anti-adalimumab antibodies may not respond to other tumor necrosis factor inhibitors (TNFis).

As study limitations, investigators noted that serum samples were not taken at standardized times for each patient, which may have limited the association between serum data and drug response. Further study is necessary to clarify the relationship between adalimumab serum levels and later response to other bDMARDs.

“For now, a rheumatologists’ decision to switch to a TNFi/non-TNFi treatment after adalimumab failure should not be led by the idea that one could be more effective than the other,” investigators wrote. “[R]heumatologists should let their decision be led by other important variables such as possible side effects, local protocol, economical aspects and patient preferences.”

Reference

Ulijn E, den Broeder N, Wientjes M, et al. Therapeutic drug monitoring of adalimumab in RA: no predictive value of adalimumab serum levels and anti-adalimumab antibodies for prediction of response to the next bDMARD. Ann Rheum Dis. 2020;79(7):867-873.

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