Paradoxical Expansion of Th1 and Th17 Lymphocytes in Rheumatoid Arthritis Following Infliximab Treatment: a Possible Explanation for a Lack of Clinical Response.
OBJECTIVE
The immunogenicity of anti-TNF-α drugs may affect their safety and efficacy. Infliximab (IFX), a chimeric monoclonal antibody, induces antibody formation in up to 60% of cases. Some studies have suggested the involvement of a Th1 response to TNFα blockers following immunization, but the triggering of Th17 responses has never been reported. The aim of this study is to investigate whether the immunogenicity of IFX affects the Th1, Th17 and Treg compartments in rheumatoid arthritis (RA) patients failing IFX therapy, and verify whether this may be responsible for treatment failure.


METHODS
The study involved 55 patients with RA (15 treatment-naïve patients; 20 IFX responders; 20 IFX non-responders) and 10 healthy controls. PBMCs were cultured in the presence/absence of IFX, and the variations in the percentage of Th1, Th17 and Treg lymphocytes following IFX treatment were analysed.


RESULTS
IFX-specific Th1 and Th17 responses and an increase in IL-21 production were observed in patients failing IFX (p < 0.01, p < 0.05, and p < 0.01 respectively). In contrast, IFX incubation reduced significantly Th1 and Th17 responses and IL-21 production (p < 0.05) in successfully-treated subjects, but did not affect these responses in healthy controls or treatment-naïve patients.


CONCLUSIONS
RA patients may have impaired peripheral tolerance, which could favour the development of an aberrant immunological response to biological drugs. The loss of therapeutic effectiveness of IFX and the onset of adverse events may be due to a paradoxical activation of Th17 or Th1 lymphocytes following sensitisation, thus worsening the patients' inflammatory status.
Rheumatology Unit, Department of Internal Medicine, L. Sacco University Hospital, Milan, Italy.
Rossella
R
Talotta
L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Via GB Grassi 74, 20157, Milan, Italy.
Angela
A
Berzi
Rheumatology Unit, Department of Internal Medicine, L. Sacco University Hospital, Milan, Italy.
Fabiola
F
Atzeni
Rheumatology Unit, Department of Internal Medicine, L. Sacco University Hospital, Milan, Italy.
Alberto
A
Batticciotto
Department of Physiopathology and Transplantation, University of Milan, Milan, Italy.|Don C. Gnocchi Foundation, IRCCS, Milan, Italy.
Mario
M
Clerici
Rheumatology Unit, Department of Internal Medicine, L. Sacco University Hospital, Milan, Italy.
Piercarlo
P
Sarzi-Puttini
L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Via GB Grassi 74, 20157, Milan, Italy. daria.trabattoni@unimi.it.
Daria
D
Trabattoni
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D000069285:Infliximab / Q000008:administration & dosage*; D007378:Interleukins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000098546:Interleukin-21
D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000098546:Interleukin-21
Rheumatoid arthritis; Th1 lymphocytes; Th17 lymphocytes; immunogenicity; infliximab