Blood Lymphocyte Subsets for Early Identification of Non-Remission to TNF Inhibitors in Rheumatoid Arthritis

Abstract

Background: TNF inhibitors (TNFis) are widely used for the treatment of rheumatoid arthritis (RA), although the response rates to this therapy in patients with RA remains heterogeneous and < 50% achieve remission (REM). Objective: To analyze baseline peripheral blood leukocytes profiles in order to search for biomarkers identifying patients who will most likely not achieve REM under TNFi treatment. Methods: A prospective bi-center pilot study including 98 RA patients treated with TNFis and followed-up during 6 months. Patients were classified according to DAS28 as follows: those who achieved REM (DAS28 ≤ 2.6) and those who did not (DAS28 > 2.6) at 6 months after starting TNFis. These rates were also assessed by simplified disease activity index (SDAI ≤ 3.3 and SDAI > 3.3, respectively). Peripheral blood immune cells were studied by flow cytometry before treatment initiation. Results: At 6 months, 61 or 80% of patients did not achieve REM by DAS28 or SDAI, respectively. Basal leukocyte profiles differed between REM vs. non-REM patients. Non-REM patients showed lower percentages of total and naïve B cells at baseline than REM subjects. A B lymphocyte/CD4+ lymphocyte ratio (BL/CD4 ratio) <0.2 clearly associated with a higher probability of non-REM status based on DAS28 at 6 months (OR = 9.2, p = 0.006). These data were confirmed when patient response was evaluated by SDAI index. Conclusion: Our results strongly suggest that BL/CD4 ratio could be considered as a useful biomarker for the early identification of non-remitters to TNFi in clinical practice.

Low Serum BAFF Concentration Is Associated with Response to TNF Inhibitors in Seropositive Patients with Rheumatoid Arthritis

“…Leandro has deepened this controversy by suggesting that this variability could be due to the absence of a pattern in the B-cell compartment population in patients with RA [ 24 ]. Previous results from our research group and from other researchers have supported the hypothesis of the importance of B-cell dynamics in response to biological therapy [ 25 , 26 , 27 ]. Moreover, research from our group identified the role of BAFF in the development of immunogenicity and, therefore, in B-cell activation and its involvement in the response to TNFis [ 28 ].…”

“…With these findings, it could be hypothesised that in seropositive patients who are good responders, their disease is mediated by the chosen mechanism of action and could demonstrate less BAFF production by inflammatory cells and greater uptake by the specific receptor expressed on B cells [ 23 ]. This hypothesis has been reinforced by previous studies in which the proportion of B lymphocytes at baseline and 6 months after treatment with TNFis is different depending on the response to treatment [ 26 , 27 ].…”

Remission Induced by TNF Inhibitors Plus Methotrexate is Associated With Changes in Peripheral Naïve B Cells in Patients With Rheumatoid Arthritis

“…Different PBMC subsets were analyzed at baseline and after 6 months of TNFi treatment, in order to identify whether PBMC profile changes after TNFi therapy ( , 6-0 months). A previous analysis in our cohort of patients showed that a higher percentage of baseline B cells (especially naive B cells) was associated with attaining REM after 6 months of TNFi treatment (13).…”

“…In a previous study conducted by our group including the same cohort of patients, the correction of multiple comparisons using the Benjamini-Hochberg (BH) method with a predefined value FDR = 0.25 was applied (free software used MEV 2.0). This analysis demonstrated that the associations of either total or naive B lymphocytes with REM were not due to chance (13). Therefore, clinical follow-up analyses after initiation of TNFi therapy have been performed in these two subpopulations.…”

“…We have recently published that patients who did not achieve remission by Disease Activity Score-28 (DAS28) after 6 months of TNFi therapy showed lower percentages of total and naive B cells at baseline than remission (REM) subjects. However, to deepen into this field, more studies are needed (13).…”