ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 9, September 2014, pp 2638–2648 © 2014, American College of Rheumatology LETTERS DOI 10.1002/art.38714 Tocilizumab treatment leads to a rapid and sustained increase in Treg cell levels in rheumatoid arthritis patients: comment on the article by Thiolat et al To the Editor: In their recent article in Arthritis & Rheumatology, Thiolat and colleagues reported a significant expansion in the number of Treg cells in 15 rheumatoid arthritis (RA) patients after 3 months of treatment with tocilizumab (TCZ) (1). We have observed that the increase in Treg cell frequency occurs even sooner after the initiation of TCZ treatment (shortly after the first infusion) and is sustained over at least 12 months of regular drug administration. We studied 22 patients with active RA who were administered TCZ monthly (5 patients received 12 infusions, 4 received 8, 3 received 6, 3 received 4, and 7 received 2) along with disease-modifying antirheumatic drugs (DMARDs) at stable doses. Corticosteroids were not used throughout the study. Levels of CD25 high FoxP3+CD4+ Treg cells were as- sessed before every TCZ infusion. After the first infusion, Treg cell frequencies were significantly increased and the 28-joint Disease Activity Score (2) was decreased (Table 1); this increment was sustained over the subsequent months. Related studies have assessed Treg cell levels after 2 months (3) or 3 months (1,4) of TCZ administration. Our results show that a significant increase in Treg cell frequency occurs after only 1 infusion; furthermore, the increase remains stable over time. Whether TCZ or another drug(s) is the direct cause of the Treg cell expansion or whether this is the result of disease remission remains a matter of controversy. In this context, corticosteroids (used in moderate doses in previous studies) (4) are known to increase Treg cell levels in other systemic autoimmune diseases, e.g., systemic lupus erythema- tosus (5). In our patients (who did not receive corticosteroids during the study), DMARDs were administered at stable doses; therefore, it is quite unlikely that the Treg cell expan- sion could be attributed to these drugs. In conclusion, TCZ is expected to skew the Th17/Treg cell balance toward the protective Treg cell arm (6,7) The exact mechanism(s) behind this action, the duration of the increase in Treg cell frequency, and its clinical significance remain to be determined. Alexandros Sarantopoulos, MD, PhD Konstantinos Tselios, MD, PhD Ioannis Gkougkourelas, MD, PhD Marianna Pantoura, MSc Anastasia-Maria Georgiadou, MD Panagiota Boura, MD, PhD Aristotle University of Thessaloniki Hippokration General Hospital Thessaloniki, Greece 1. Thiolat A, Semerano L, Pers YM, Biton J, Lemeiter D, Portales P, et al. Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheumatol 2014;66:273–83. 2. Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. 3. Pesce B, Soto L, Sabugo F, Wurmann P, Cuchacovich M, Lopez MN, et al. Effect of interleukin-6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients. Clin Exp Rheumatol 2013;171:237–42. 4. Samson M, Audia S, Janikashvili N, Ciudad M, Trad M, Fraszczak J, et al. Inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum 2012;64:2499–503. 5. Tselios K, Sarantopoulos A, Gkougkourelas I, Boura P. CD4+CD25highFOXP3+ T regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study. Clin Exp Rheumatol. In press. 6. Tanaka T. Can IL-6 blockade rectify imbalance between Tregs and Th17 cells? Immunotherapy 2013;5:695–7. 7. Sarantopoulos A, Tselios K. Gkougkourelas I, Boura P. The impact of tocilizumab administration on innate-adaptive immune crosstalk [e-letter]. Blood 2011. URL: http://bloodjournal.hematologylibrary. org. Table 1. Variations in Treg cell frequency (as a proportion of CD4+ T cells and as absolute counts) and the DAS28 over 12 months in TCZ-treated rheumatoid arthritis patients* Infusion† Treg cells % of CD4+ T cells No./mm 3 DAS28 T0 (n = 22) 0.61  0.18 6.6  3.8 4.34  0.92 T1 (n = 22) 0.87  0.27 10.3  4.8 3.03  0.86 T2 (n = 15) 1.05  0.34 11.7  5.1 2.71  0.86 T3 (n = 15) 1.03  0.38 12.1  5.2 2.96  1.03 T4 (n = 12) 1.2  0.55 15.3  8 2.62  0.65 T5 (n = 12) 1.15  0.32 14.1  6.3 2.53  0.64 T6 (n = 9) 1.21  0.34 12.6  4.2 2.72  058 T7 (n = 9) 1.45  0.22 13.6  2.3 2.56  0.22 T8 (n = 5) 1.46  0.39 14.4  4.9 2.36  0.44 T9 (n = 5) 1.32  0.28 13.5  4.1 2.28  0.38 T10 (n = 5) 1.21  0.26 13.4  3 2.19  0.33 T11 (n = 5) 1.34  0.28 13.7  3.8 2.18  0.42 * Values are the mean  SD. DAS28 = 28-joint Disease Activity Score. † Tocilizumab (TCZ) infusions were administered once monthly (up to 12 infusions, starting at time 0 [T0]). 2638