The advent of biologic therapies, particularly tumor necrosis factor (TNF)-α inhibitor, has transformed the treatment landscape of ankylosing spondylitis (AS). However, the clinical benefits of these therapies may be compromised by the development of anti-drug antibodies (ADAs), which can neutralize drug efficacy and accelerate clearance. Identifying modifiable risk factors for ADA formation is therefore central to optimizing long-term biologic response.

In this issue of the Journal of Rheumatic Diseases, Kim et al. [1] present a prospective, real-world investigation into the immunogenicity of the infliximab biosimilar CT-P13 in patients with AS. Their study explores not only the incidence of ADA formation but also potential risk factors, highlighting smoking as an independent contributor to high ADA titers at 54 weeks. This important work adds to the growing body of evidence that seeks to individualize biologic therapy through immunologic monitoring and lifestyle modification.

The immunogenicity of TNF-α inhibitor—especially monoclonal antibodies such as infliximab—is well-established across autoimmune diseases. ADA formation has been associated with reduced drug levels, diminished clinical response, and increased treatment discontinuation. A meta-analysis by Moots et al. [2] reported immunogenicity rates of up to 40% with originator infliximab and similar rates for its biosimilar CT-P13.

While immunogenicity may be expected to a degree with any protein-based therapy, inter-individual variability in ADA formation raises critical questions about underlying risk factors. The current study offers timely insight by prospectively assessing serum infliximab and ADA levels, correlating them with clinical and demographic features over a 54-week period.

Notably, despite the rise in ADA titers, clinical response in the study—assessed by BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index)—was largely maintained, suggesting that not all ADAs are functionally neutralizing or clinically relevant. This underscores the heterogeneity in ADA impact and supports the cautious interpretation of ADA and drug levels in clinical practice. While routine monitoring may not be necessary for all patients, such testing could prove useful in selected scenarios, such as secondary loss of response. Limitations in assay standardization, however, remain an important barrier to implementation.

Smoking has consistently been linked to increased ADA formation across rheumatic diseases. The current study reinforces this association in AS, supporting prior findings in rheumatoid arthritis (RA) and spondyloarthritis (SpA) [3,4]. Smoking-induced immune dysregulation, including enhanced antigen presentation and impaired regulatory B cell function, may drive this effect. These results further highlight the importance of integrating smoking cessation strategies into AS management not only for cardiovascular and pulmonary health but also to maintain biologic treatment efficacy.

While smoking is the only significant risk factor identified in Kim et al. [1]’s study, prior literature suggests that a broader array of variables should be taken into account when evaluating ADA formation.

Fully human monoclonal antibodies (e.g., adalimumab) tend to be less immunogenic than chimeric agents like infliximab. Thus, drug selection may inherently affect ADA risk.

Specific HLA-DRB1 alleles have been implicated in increased ADA formation [5]. Carriage of HLA-DRB1*03:01 and *11:01 alleles was significantly associated with higher risk of ADA development [6].

Female patients often exhibit more robust humoral immune responses, potentially contributing to higher ADA prevalence, although this was not explored in Kim et al. [1]’s analysis.

Intermittent TNF-α inhibitor exposure has been linked to greater immunogenicity compared to continuous dosing [7]. Given the multifactorial nature of ADA formation, future studies should consider a multivariate approach, incorporating clinical, immunological, and genetic variables.

Although the present study did not evaluate radiographic progression outcomes directly, it sets the stage for future longitudinal research to link ADA titers with objective clinical endpoints.

Importantly, this study supports the integration of smoking cessation counseling into routine AS management not only for general health but also to reduce the risk of biologic treatment failure.

In RA, methotrexate (MTX) co-administration is a well-known strategy to reduce ADA formation. However the evidence does not support routine use of MTX for this purpose in AS. Studies by Haibel et al. [8] have demonstrated that MTX provides minimal additive benefit in axial disease [8,9]. While MTX may still be used in cases of peripheral SpA or overlapping manifestations, it is not currently recommended solely for the prevention of ADA formation in axial SpA [10].

Nevertheless, a recent multicenter randomized trial [11] reported that MTX reduces immunogenicity and improves long-term maintenance of adalimumab therapy in patients with axial SpA, suggesting that further research is warranted.

This study by Kim et al. [1] contributes meaningful evidence to the immunogenicity profile of CT-P13 in AS and underscores smoking as a modifiable risk factor for ADA development. By situating these findings within the broader literature, the study also invites further investigation into additional host- and therapy-related predictors of immunogenicity. As we move toward more personalized care in AS, immunologic monitoring and lifestyle interventions may play an increasingly important role in optimizing biologic therapy.