**5. Conclusions**

The results revealed a heterogeneous function of CD4+ T-lymphocytes subsets in the early clinical stages of RA with potential pathogenic relevance:

The numbers of circulating Th1, Th2 or Th17 CD4+T-lymphocytes subsets in the early clinical stages of RA show two different profiles of cytokine producing CD4<sup>+</sup> T-lymphocyte subsets associated to a response or not associated to the MTX treatment of the RA patients.

The pattern of IL-17+, IFNγ<sup>+</sup> and IL-4<sup>+</sup> CD4<sup>+</sup> T production detected in new-onset DMARD-naïve RA patients could be modified by MTX treatment.

Results may offer a way of identifying which patients will respond, or not, to MTX treatment.

**Author Contributions:** M.Á.-M. and J.M.S. were responsible for the study conception and design, J.M.S. and A.M.G. for the data acquisition, and M.Á.-M., J.M.S., D.D., C.B., A.M., A.P., L.R., A.I.S. and F.A. for the data analysis and interpretation. J.M.S., M.Á.-M., C.B. and I.S. drafted the manuscript. All authors read and approved the final manuscript.

**Funding:** This work was partially supported by grants from the Fondo de Investigación de la Seguridad Social, Instituto de Salud Carlos III (PI18/01726), Spain and the Programa de Actividades de I+D de la Comunidad de Madrid en Biomedicina (MITIC-CM, S2017/BMD-3804), Madrid, Spain.

**Acknowledgments:** The authors would like to thank all the medical doctors, nurses and technical staff of the Immune System Diseases-Rheumatology Service of the Hospital Universitario Principe de Asturias and the Department of Medicine of the University of Alcalá for their careful and generous collaboration while doing this work.

**Conflicts of Interest:** The authors declare no conflict of interest.
