In this study, we assessed the potential relevance of serum drug levels and ADAbs on various aspects of clinical response to adalimumab treatment in pSpA. The major findings are that (1) trough serum adalimumab levels were heterogeneous but did not correlate with clinical response to treatment or relapse after anti-TNF treatment discontinuation, (2) antiadalimumab ADAbs were found in one-fourth of the patients but also did not correlate with clinical response to treatment or relapse after discontinuation of the TNF inhibitor and (3) low-titre ADAbs could be masked by circulating adalimumab, but ‘unmasked’ ADAbs showed no clear relationship with clinical efficacy.
More and more research is being done to address the immunogenicity of TNF inhibitors in various IMIDs, including SpA, because the development of ADAbs towards these TNF inhibitors are assumed to play a major role in loss of response to treatment. The mechanism behind this is thought to be either an increased clearance of the drug or neutralization of the active component of the compound[
6,
7]. This hypothesis is supported by researchers in several studies of infliximab and adalimumab who reported that treatment failure occurred more often in patients who tested positive for ADAbs[
10‐
14]. However, there is also evidence which is not in line with this concept; in other studies of infliximab, investigators did not find a relation between ADAbs and response to treatment[
17,
18]. Moreover, in one of the studies in which researchers found serum trough infliximab levels to be significantly higher in responders than in nonresponders, although statistical significance was reached, the difference between these groups was very low (8.2 μg/ml vs. 6.3 μg/ml, respectively)[
12]. Whether such a small difference is really clinically relevant is questionable. ADAbs towards etanercept have not been found, nor is there an association between serum drug levels and clinical effect[
19]. Likewise, for golimumab, there is no clear relation between ADAbs and clinical efficacy[
20,
21]. Furthermore, in a recent meta-analysis of various TNF inhibitors[
22] and the clinical experience of there being no difference in efficacy or drug survival between the various TNF inhibitors[
23,
24], the authors also questioned the clinical relevance of anti-TNF ADAbs.
Several factors could be examined to develop an explanation of these differences between the various studies. First, not all TNF inhibitors are assumed to be equally immunogenic. For example, the soluble dimeric fusion protein etanercept has a less immunogenic structure because only the fusion part of the molecule can contain immunogenic epitopes. Also, it is administered more frequently than the other TNF inhibitors, thereby possibly creating more drug interference in ADAb detection[
19]. However, this does not explain why researchers in different studies of the same TNF inhibitor (for example, infliximab) have come to different conclusions[
10‐
14,
17,
18]. Second, there may be differences among the different SpA subtypes. However, even in studies of both the same disease and the same TNF inhibitor (for example, infliximab in AS), contradicting conclusions have been drawn[
10‐
12,
17,
18]. Hence, this could also not explain why we and others[
21] did not find a clinical association with anti-TNF drug levels or ADAbs in pSpA, whereas researchers in another study did conclude that these factors had clinical relevance[
15]. Third, there is some variation in the size and duration of the studies, but this did not influence the results with regard to whether ADAbs did or did not have clinical relevance[
10‐
21]. Fourth, the use of DMARDs, especially methotrexate, has been described to decrease the immunogenicity of TNF inhibitor trough, a mechanism which is not yet understood[
8,
9,
14,
31]. However, this is not in line with the finding that the addition of methotrexate in the management of SpA does not have an impact on the efficacy of the treatment[
23,
24,
32] or on drug survival of the TNF inhibitor[
23,
24]. In our present study, we indeed found fewer of ADAbs in patients using DMARDs; however, this difference was no longer present when we analysed the ‘unmasked ADAbs’. Fifth, the detection of ADAbs is also influenced by the assay used. However, the method used in our present study is the same as that used in other studies[
15,
16], making it unlikely that this is the explanation for the differences in results. Seventh, the timing of the samples also influences the measurement of ADAbs because the assays are sensitive to drug interference, even when measured before the next administration of the drug, when the drug levels are the lowest[
8,
9]. Indeed, we show here that when antiadalimumab ADAbs were measured at follow-up, after discontinuation of the TNF inhibitor, more patients tested positive than when antiadalimumab ADAbs were measured at the end of treatment. Previous researchers have reported that anti-TNF ADAb titres can decrease and increase over time, and vice versa[
10,
15,
33], causing a gradual increase in incidence over time when ADAb status is presented cumulatively, but not when assessed at each time point independently[
33]. This shows that the timing of the measurement can influence the interpretation of ADAb status, making it very difficult to make strong conclusions about the relationship with clinical response and to apply ADAb measurement in clinical practise.
The limited number of patients is a limitation of our study. We thus cannot exclude that clinical correlation with serum adalimumab levels and/or ADAbs would be found in larger patient cohorts. However, this would imply that this association is weak and thus not relevant anyway for treatment monitoring in individual patients. Also, in one small study in which researchers investigated whether the serum trough infliximab levels modified therapeutic decisions in the management of AS, no improvement in the control of disease activity was found[
34]. Similar efficacy and drug survival of TNF inhibitors—those that induce ADAbs and those which do not[
23,
24] —also raise questions about the relevance of testing the immunogenicity of these drugs. Although testing immunogenicity in clinical trials is standard practise and may yield interesting scientific insights, the real added value of the presence or absence of ADAbs in an individual patient in clinical practise remains to be demonstrated.