Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo

Abstract

Tumour necrosis factor (TNF)-α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro- and anti-inflammatory properties and examine the effects of blocking its actions with TNF-α antagonist therapeutics in reports available in the literature. We found that TNF-α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF-α inhibition has proven useful for patients with progressive vitiligo, where TNF-α inhibition is able to quash cytotoxic T-cell-mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.

Figure 1

Effects of tumour necrosis factor (TNF)‐α inhibition in patients with progressive vitiligo (left) and in patients without vitiligo (right). In patients with progressive vitiligo (left), successful halting of depigmentation is observed with the use of TNF‐α inhibitors. In the skin of patients with progressive vitiligo, there is a surplus of cytotoxic T lymphocytes (CTLs) and a relative deficiency of regulatory T cells (Tregs) to suppress cytotoxic effects. With the addition of TNF‐α inhibitors, there is preferential inhibition of the effects of TNF‐α on CD8⁺ T‐cell activation and proliferation, resulting in reduced melanocyte destruction. In patients without vitiligo, a surplus of CTLs in the skin is not observed, and Treg numbers are normal. Thus, inhibiting TNF‐α instead preferentially inhibits the ability of TNF‐α to promote the activation and proliferation of Tregs, resulting in removal of the skin's innate protection against depigmentation and de novo vitiligo development (right). On the left, in progressive vitiligo, TNF‐α induces CTL activation and proliferation (Box 1), and upregulates expression of melanocyte cell‐surface molecules that result ultimately in melanocyte destruction (Box 2). With TNF‐α inhibitor therapy, CTL activation and proliferation is inhibited (Box 3), resulting in melanocyte survival and halted depigmentation (Box 4). On the right, in patients without vitiligo, an increase in cutaneous self‐reactive CTLs is not observed. Instead, immunological homeostasis exists, with a normal amount of Tregs suppressing effects of any self‐reactive CD8⁺ T cells. TNF‐α induces activation and proliferation of Tregs in the skin (Box 1). When TNF‐α is inhibited, Treg activation and proliferation are inhibited (Box 2), and self‐reactive cutaneous CD8⁺ T cells can destroy cutaneous melanocytes (Box 3), resulting in de novo vitiligo development (Box 4). ICAM, intercellular adhesion molecule; TNFR, TNF receptor.