In this study, we aimed to investigate whether BAFF contributes to immunogenicity associated to TNFi treatment in patients with RA. In our cohort, we found an association between baseline serum BAFF concentrations and the development of ADA within 6 months of TNFi treatment but this finding was restricted to patients older than 55. Furthermore, baseline serum BAFF levels ≥ 1034 pg/mL seemed to be the best threshold to predict the presence of ADA at 6 months of TNFi treatment in patients over 55 years old. We demonstrate for the first time that the contribution of BAFF to the development of ADA depends on the age. Moreover, the dose of concomitant MTX seems to also interact with BAFF concentration.
Immunogenicity related to treatment with TNFi is one of the causes that hampers the achievement of clinical response in patients with RA . The mechanisms underlying the development of ADA are not entirely clear. More studies are needed to understand why some patients develop ADA while others do not, and which factors amongst presence antibodies, antibody titres and other elements contribute to the loss of the biological action of TNFi, resulting in treatment failure. BAFF is believed to be one of the contributors on the development of immunogenicity [9, 10]. However, the role of BAFF in the mechanism behind the development of ADA has not been deeply investigated. Previous findings suggested that BAFF may have a role in the pathogenesis of RA [11, 12]. One possible explanation for the connection between BAFF and ADA development might be the role of BAFF in B cell maturation and survival, presumably also being the case for autoreactive B cell populations [13, 14]. We found ADA positive patients had higher serum BAFF concentrations prior to TNFi therapy initiation compared with patients who did not, but this association was restricted to patients who were older than 55 years. BAFF concentrations were unaltered after 6 months of TNFi treatment, which suggests that BAFF production is not likely to be affected by TNFi. A plausible explanation for the increased BAFF concentration in older patients who developed ADA could be the senescence of the B cell compartment. Several studies have demonstrated that blood cell populations as well as the cytokine network can be modified by aging. Production of interferons by CD4+ and CD8+ T cells is enhanced in aged individuals, and it is connected with BAFF mobilisation and release from monocytes, macrophages and dendritic cells [14–17]. Furthermore, immunosenescence during aging induces a decrease of B cells, especially plasma cells, starting at 40 years of age . Nevertheless, despite this ostensible contradiction, the phenomenon of immunogenicity associated to TNFi treatment is not likely to be weakened by aging; supportive of this notion was a study by Paul et al. in which production of ADA was not altered in relation to increasing age .
Different publications have demonstrated the usefulness of concomitant csDMARD use, particularly MTX, in preventing or decelerating immunogenicity and, consequently, promoting TNFi survival and TNFi efficacy [1, 20, 21]. The effect of concomitant MTX use in impeding immunogenicity receives increasing acknowledgement, with implications in clinical practice, but a proportion of patients still develop ADA despite use of MTX during TNFi therapy. Under further consideration, the dose of MTX could be an important factor [22, 23]. We herein observed that patients with RA who developed ADA at 6 months of treatment, significantly received lower doses of concomitant MTX compared with patients who did not develop ADA. Therefore, MTX had a significantly stronger dose-response effect on preventing the development of ADA.
Until now, the existence of a common denominator in the action mechanism between the preventive effect of MTX and the contributing role of BAFF has yet to be elucidated. MTX is known to lower numbers of B cells , which partially explains the association between using lower doses of concomitant MTX and ADA development in the present study, but the impact of MTX on BAFF levels is less clear. A study has demonstrated reductions of BAFF levels upon MTX therapy , which could possibly be supportive of a link between the two main observations in our study. However, other studies have shown associations between MTX use and elevated BAFF levels [24, 25] or even no association . Thus, deeper exploration is needed since current literature is inconclusive, but a link between MTX and BAFF levels related to the effect they exert on immunogenicity seems likely . In conformity with this notion, we found in the present study a plausible interaction between the dose of MTX and BAFF levels, which suggests that BAFF may be involved in MTX mechanism to reduce the development of ADA. However, neither our originally study design nor the chosen sample size have allowed us to evaluate this effect in the different age groups, and should be addressed in a different study.
Due to the negative effect of immunogenicity on therapy efficacy, it is an urgent demand to find biomarkers that will predict the development of ADA. We found that a baseline serum BAFF concentration of 1034 pg/mL or greater was strongly associated to the development of ADA in patients of over 55 years of age. To our knowledge, this is the first time that BAFF concentration is reported as a predictive biomarker of ADA development at 6 months of TNFi treatment. The measurement of serum BAFF concentration is easy to perform and could be a useful tool for making more effective and personalized decisions for patients with RA before embarking on a TNFi treatment.
This study had some limitations, which need to be kept in mind when interpreting the results. Due to the low number of patients included in the study, the influence of concomitant MTX use on the association between BAFF concentrations and the development of ADA at 6 months of TNFi treatment could not be properly evaluated. Therefore, further studies will be performed to stratify the analyses by concomitant use of MTX. Another limitation would be that the limited number of patients forced the selection of the median for the cut-off for the age, instead of stratification by age tertile or quartile.