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

Abstract

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 FoxP3ϩCD4ϩ Treg cells were assessed 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 erythematosus (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 expansion 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.

Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response

“…Related studies have reported the increase in T reg cell levels 1 year after TCZ administration in a small population [ 20 ], for 3 months [ 15 ] and for 6 months [ 12 ]. Though definitions of T reg cells in our study, using only cell surface markers without stimulatory modification for cells in vitro , were different from those in these previous studies, our results showed the same trends as previously reported.…”

The Interplay Between Monocytes/Macrophages and CD4+ T Cell Subsets in Rheumatoid Arthritis

“…Previously underappreciated mechanisms of existing therapeutics may contribute to their efficacy by (in)directly targeting monocytes/macrophages. For example, multiple studies have shown that blockade of IL-6 signaling via monoclonal antibody to the IL-6 receptor (tocilizumab) can boost Treg frequencies ( 194 – 198 ), but additional mechanisms of action may include reduction in CD69 + CD14 + and CD16 + CD14 + monocyte frequencies ( 197 ), induction of monocyte apoptosis, and inhibition of monocytic IL-6 mRNA expression ( 199 ). Despite the widespread uptake and high efficacy of TNFα inhibitor drugs in RA, the underlying mechanisms of action are not firmly established [reviewed in Ref.…”

Altered Immunoregulation in Rheumatoid Arthritis: The Role of Regulatory T Cells and Proinflammatory Th17 Cells and Therapeutic Implications

“…Concerning Treg cells, progressive increase of their proportion starting from the first month of therapy with subsequent stability overtime in the 12-month follow-up has been described in all the available studies [ 22 , 112 , 113 ] except one that reported a surprising reduction of circulating Treg cells induced by tocilizumab in early RA [ 110 ].…”