Clinical and immunological benefit of adjuvant therapy with thalidomide in the treatment of tuberculosis disease.

Abstract

Thalidomide has recently been approved by the US Food and Drug Administration for use in the treatment of erythema nodosum leprosum. However, the drug has since been found to be effective for several different conditions, such as Behçet's disease, chronic graft-versus-host disease, refractory rheumatoid arthritis, rash caused by systemic lupus erythematosus, aphthous ulcers, AIDS wasting syndrome, tuberculosis, and atypical mycobacteriosis. Although thalidomide has shown various anti-inflammatory and immunomodulating effects, its mechanism of action is still unknown. Moreover, thalidomide's most frequent use is based on its role in the inhibition of TNF-α, and the drug appeared to be beneficial in the treatment of disorders thought to involve TNF-α homeostasis [1–3]. However, two recent reports on the treatment of toxic epidermal necrolysis and aphthous ulcers [4,5] described an increase of TNF-α concentrations and soluble TNF-α receptors during thalidomide treatment, suggesting that thalidomide does not inhibit TNF-α production, and raising questions as to the nature of the interaction between thalidomide and TNF-α. We analysed the clinical and immunological role of adjuvant therapy with thalidomide in the treatment of tuberculosis disease, studying its in-vivo effect in patients affected by tuberculosis. We enrolled 15 patients with documented active tuberculosis: nine patients were HIV positive and six were HIV negative. All subjects received a standard anti-tuberculosis treatment according to the current World Health Organization treatment guidelines. Patients with positive clinical and microbiological responses were followed-up without further therapeutic interventions. Patients with signs and symptoms of persistent disease after at least 15 days of treatment were randomly assigned into two groups: the first continued the therapy without changes or with an adjunctive anti-tuberculosis drug, and the second added thalidomide (200 mg a day). Clinical characteristics of the patients are summarized in Table 1. The effect of thalidomide on clinical and microbiological response, cytokine production, CD4 T cell counts and HIV-1 viral load levels (for HIV-infected patients) was evaluated at days 0, 15, 30, 45, 60 and 90 of treatment.Table 1: Changes in clinical features of tuberculosis-affected patients according to the treatment group. An immunological evaluation of the patients before the introduction of thalidomide, gathered on the basis of their response to the standard anti-tuberculosis treatment, suggested that the patients with poor outcome, independent of HIV status, showed low levels of TNF-α production. On the contrary, type 1 (IL-2, INF-γ) and type 2 (IL-4, IL-10) cytokine analysis showed comparable levels of these cytokines among the different groups analysed. All patients treated with thalidomide showed a significant improvement in clinical conditions, including a reduction of fever, increase in body weight, improvement of radiological features, and negativization of Mycobacterium tuberculosis cultures after introduction of the drug (Table 1). In agreement with recently reported data [4,5], we observed an increase in TNF-α levels after the introduction of thalidomide in all patients, whether HIV positive or HIV negative. An increase in TNF-α levels was always followed by a concomitant improvement in clinical conditions. By contrast, those patients with poor outcome who were not designated to receive thalidomide continued to demonstrate clinical progression of the disease and remained with low levels of TNF-α and type 1 cytokines (Fig. 1).Fig. 1.: Different immunological pattern of cytokine production. ––, Responders; uu.uu.uu.uu.uu.uu., non-responders; –•–, thalidomide.After the use of thalidomide, cytokine production in treated patients became quite similar to that of those patients characterized by an effective control of tuberculosis (Fig. 1). We observed a progressive increase in type 1 cytokines (IL-2 and IFN-γ) without significant changes in type 2 cytokine (IL-4, IL-10) production levels. Among HIV-positive patients, no significant changes in HIV viral load were detected subsequent to the introduction of thalidomide. Our data illustrate the usefulness of thalidomide treatment in patients infected with M. tuberculosis with previously poor outcome, whether HIV positive or HIV negative. The association of thalidomide with standard anti-tuberculosis therapy resulted in an improvement of the clinical conditions with a rapid restoration of microbiological and immunological parameters in patients with a slow response to current anti-tuberculosis regimens. This clinical evolution has been strictly correlated to a significant increase in TNF-α, IFN-γ, and IL-2 levels. This study underlines some unexpected effects on the immune system induced by thalidomide. An increase in TNF-α levels after the introduction of thalidomide could be explained by an activation of T cell activity brought on by the drug. Thalidomide's principal action is likely to be in stimulating T lymphocytes , resulting in an increase in IL-2 and IFN-γ production. Andrea Goria Maria Cristina Rossia Giulia Marchettia Daria Trabattonib Chiara Moltenia Marta Cogliatib Alessandra Banderaa Mario Clericib Fabio Franzettia