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To the Editor:

I would like to thank Dr. Park for his interest in our work, and agree that there is increasing evidence that the type I IFN signature may be predictive of therapeutic response to certain treatments. We found in 2 independent cohorts that the type I IFN signature negatively predicts the clinical response to rituximab treatment in patients with RA. The correlation between the type I IFN signature at baseline and the clinical response to rituximab was recently confirmed in a third cohort (1). It should be noted, however, that we did not observe a significant correlation between disease activity at baseline and the type I IFN signature, which is consistent with other studies (1–3).

The relationship between the type I IFN signature and the response to anti-TNF therapy appears to be more complex. We did not find evidence of modulation of the expression of type I IFN response genes after infliximab treatment in RA patients, although infliximab could induce up-regulation of the type I IFN genes in a subset of patients with a poor clinical response to treatment (4). In spondylarthritis, infliximab treatment induced a temporary decrease in type I IFN activity, but levels returned to baseline after 12 weeks of treatment (5). Etanercept treatment, however, led to a small increase in type I IFN activity after 12 weeks (5). Taken together, results of studies in patients with RA, spondylarthritis, Sjögren's syndrome, and inflammatory myopathies indicate that the effect of anti-TNF therapy on type I IFN–related genes is not universal and may depend on the specific disease, the type of TNF inhibitor, and the clinical response to treatment (6).

It should also be noted that in addition to the distinction between type I IFN and type II IFN (IFNγ), the family of type I IFN consists of multiple subtypes of IFNα, a single IFNβ, and some less-characterized family members, such as IFNϵ, IFNκ, and IFNω. These IFN subtypes have potentially subtle differential effects, which may also differ in various compartments of the body and among different diseases. Whereas, for instance, IFNα appears to have a predominantly pathogenic role in systemic lupus erythematosus, IFNβ is probably mainly antiinflammatory in RA. The interpretation of various studies of the type I signature in relation to the clinical response to treatment is further complicated by the fact that the type I IFN signature is not always synonymous with the presence of type I IFN specifically.

Keeping all these caveats in mind, Dr. Park's suggestion to study the effects of antimalarial agents in RA patients with a type I IFN signature who do not respond to rituximab is of interest and worth studying. Initial evidence from in vitro studies suggests that these agents may inhibit type I IFN–regulated genes (7).

Acknowledgements

Dr. Tak has received consulting fees from Roche and Genentech (less than $10,000) and owns stock in Arthrogen.

  • 1
    Vosslamber S, Raterman HG, van der Pouw Kraan TC, Schreurs MW, von Blomberg BM, Nurmohamed MT, et al. Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis. Ann Rheum Dis 2011; 70: 11539.
  • 2
    Cantaert T, van Baarsen LG, Wijbrandts CA, Thurlings RM, van de Sande MG, Bos C, et al. Type I interferons have no major influence on humoral autoimmunity in rheumatoid arthritis. Rheumatology (Oxford) 2010; 49: 15666.
  • 3
    Van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM, et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 2007; 66: 100814.
  • 4
    Van Baarsen LG, Wijbrandts CA, Rustenburg F, Cantaert T, van der Pouw Kraan TC, Baeten DL, et al. Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment. Arthritis Res Ther 2010; 12: R11.
  • 5
    Cantaert T, De RL, Mavragani CP, Wijbrandts CA, Niewold TB, Niers T, et al. Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor α blockade. Ann Rheum Dis 2009; 68: 10229.
  • 6
    Cantaert T, Baeten D, Tak PP, van Baarsen LG. Type I IFN and TNFα cross-regulation in immune-mediated inflammatory disease: basic concepts and clinical relevance. Arthritis Res Ther 2010; 12: 219.
  • 7
    Martinson JA, Montoya CJ, Usuga X, Ronquillo R, Landay AL, Desai SN. Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell α interferon: implication for T-cell activation. Antimicrob Agents Chemother 2010; 54: 87181.

Paul P. Tak MD, PhD*, * Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.