Th9 Cells May Play a Role in Immunogenicity of Reference Infliximab

A newly published study found that the prevalence of T helper (Th) lymphocytes, specifically Th9 cells, is higher in patients who have rheumatoid arthritis (RA), and that these cells may also be involved in immune responses against reference infliximab in patients with RA. Activated Th9 cells (which are responsible for secreting IL-9 and are present in higher numbers in the bloodstream and synovial membranes of patients with RA) following treatment with reference infliximab could contribute to inflammation and a subsequent loss of treatment efficacy. However, biosimilar infliximab does not appear to activate the same cells.

The study sought to evaluate whether Th9 cells mediate drug immunogenicity, and compared the immunogenicity of reference infliximab (Remicade) and its biosimilar (Remsima) among patients with RA who were classified as responders or inadequate responders to the reference product.

The study involved 55 patients with RA and a control group of 10 healthy volunteers. Of the 55 patients with RA, 15 were treatment naïve, 20 were receiving reference infliximab and were classified as responders, and 20 had switched from reference infliximab to other biologics, either due to adverse events or a lack of efficacy, and were classified as inadequate responders.

The researchers found that the baseline percentage of Th9 cells was higher among treatment naïve patients than in the control group or the group treated for RA, which, the authors say, indicates that activation of Th9 cells is a characteristic of RA that can be altered through treatment.

The researchers found that stimulation with reference infliximab increased the percentage of Th9 cells expressing the transcription factor PU.1 and interferon-regulatory factor 4 in the group of inadequate responders only. They further investigated whether Th9 cells could be activated by a specific stimulus on memory cells in patients who had discontinued reference infliximab because of inefficacy or adverse events. This additional investigation found that these cell pools were increased in the inadequate responder group when reference infliximab was added, a finding that indicates that these cell pools could result in a change in percentage of PU.1 and IRF4-expressing, IL-9-secreting cells.

A repeated experiment using biosimilar infliximab did not significantly increase the percentage of IL-9-secreting cells in the treatment naïve group, or the group of responding patients with RA. Notably, the addition of the biosimilar also did not increase the percentage of such cells in the inadequate responder group, as had been observed with the reference infliximab.

The authors explain that while the production of anti-drug antibodies (ADAs) is the most widely accepted mechanism for a drug-induced immune response, activation of other immune pathways may be responsible for the failure of a biologic treatment. Th9 lymphocytes, they say, may direct an immune response toward autoimmunity or inflammation.

This study, the authors conclude, provides new insight into the immunogenicity of anti—tumor necrosis factor agents. However, follow up confirmatory studies will be necessary to rule out method bias in this study, which used only single batches of both the reference and biosimilar infliximab products. Additional limitations of the study include a small patient population and concomitant treatment with methotrexate or steroids, which may have influenced the results.