In the absence of clear guidelines for the management of lymphocytosis in RA and PsA patients under anti-TNF-α therapy, the biologic therapy was interrupted in the five patients presenting a lymphocytosis and a monoclonal TCRγ chain repertoire. Within 3 months following the interruption of TNF-α inhibitor a significant decrease in the lymphocytes level, until physiological values, was observed, whereas in the patients who did not interrupt biologic therapy the number of lymphocytes remained stable (Fig.
1). In one of these patients, in which a rechallenge with biologic therapy was necessary as a consequence of RA flare up, it was possible to observe the reappearance of lymphocytosis. Analysis of the data with Naranjo algorithm gave a probability score result for causality of 6 thus indicating a probable anti-TNF-α induced event [
26]. Despite the persistence of lymphocyte expansion and the probable link with anti-TNF-α agents, as previously reported in anecdotal cases (19–21), none of the patients developed clinical or laboratory signs of progression toward malignancy at 1-year follow-up. Consequently, this haematologic abnormality appears as a benign reversible drug-related laboratory finding other than a serious adverse event, at least for the observation period. In RA patients, the risk of developing hematologic tumors is higher than in the healthy population [
27]. In particular large granular lymphocytosis is frequently associated with RA and other autoimmune diseases [
28]. Reversible T lymphoproliferation in RA patients under anti-TNF-α therapy has been occasionally described in case reports. Sometimes the number of CD8
pos T cells is altered [
20], but more frequently CD4
pos is the main T cell subset to be affected. The lymphocyte expansion may be either monoclonal [
19] or polyclonal [
21]. Reversible lymphoproliferation has also been described as a consequence of CMV reactivation [
29]. However, the cause for reversible lymphoproliferation in these patients has not yet been identified, it is known that TNF-α can limit T cell expansion and induce apoptosis in both naïve and memory T cells [
30], consequently TNF-α blocking agents may lead to a dysregulation of these biologic mechanisms, thus resulting in T cell expansion and/or prolonged survival. Moreover, in addition to anti-TNF-α biologic treatment, the role of steroids in promoting lymphoproliferation can not be forgotten. Recent studies have demonstrated that steroids are able to significantly reduce circulating T regulatory cells [
31], thus adding fuel to the hypothesis that immunosuppressive therapy may in certain conditions induce T cell expansion. The higher risk of lymphoma in RA patients treated with TNF-α inhibitors has been suggested but not clearly demonstrated. Several factors may hinder a definitive correlation between anti-TNF-α therapy and lymphoma development, among which the selection of the population enrolled in different studies or national registries and the inter individual variability of the immune system exposed to TNF-α. In fact, being a double sword tool, TNF-α may play a defensive role by stimulating NK and cytotoxic T lymphocytes, but can also be “offensive” acting as mediator of cancer development through chronic inflammation promotion [
13]. Thus, in theory, TNF-α antagonists may either promote or inhibit cancer growth [
32]. The onset of B-cell lineage lymphomas and hepatosplenic T cell lymphoma (HSTCL) has been observed in patients with Crohn’s disease who received anti-TNF-α agents mainly in association to thiopurines [
33‐
35]. Of note, in patients with psoriasis, an absolute lymphocytosis associated to γδ T cell lymphoma after treatment with anti-TNF-α has been observed [
36,
37].