Study points to new vitiligo treatment options

Acta Eruditorum

Abby Van Voorhees

Dr. Van Voorhees is the physician editor of Dermatology World. She interviews the author of a recent study each month.

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In this month’s Acta Eruditorum column, Physician Editor Abby S. Van Voorhees, MD, talks with John Harris, MD, PhD, about his recent Science Translational Medicine article, “CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo.”

Dr. Van Voorhees: Vitiligo is definitely a disease in need of better treatment options. Here we have a disease where immune cells that were intended to protect the skin instead attack the skin. Can you bring us up to date on these T cells and how we’ve thought that they function?

Dr. Harris: There is good evidence that vitiligo is an overactive response meant to protect us from melanoma, and patients with vitiligo have threefold lower incidence of the tumor. Vitiligo patients have increased numbers of melanocyte-specific, cytotoxic CD8+ T cells in their blood and skin. These cells are the professional killers of the immune system, which target self-cells that have either been infected by a virus or transformed into a tumor. CD8+ T cells can be seen infiltrating the epidermis in lesional skin of vitiligo patients in close proximity to dying melanocytes. In experiments using skin from vitiligo patients, they are necessary and sufficient to induce melanocyte death. However, the skin is a large organ, and the signals that direct their migration from the blood into the skin, and then to efficiently find melanocytes in the epidermis, are unknown. We thought that interfering with this process might be a good strategy to develop new treatments.

Dr. Van Voorhees: Are there any FDA-approved treatments for vitiligo? Let’s review the standard therapies.

Dr. Harris: The only FDA-approved treatment for vitiligo is monobenzone, a topical medication used by those with extensive disease to remove the remaining pigment with the goal of producing a more even appearance. However, it is appropriate only for a minority of patients. Off-label treatments used to repigment the skin focus on suppressing the autoimmune response to prevent melanocyte destruction and allow their regeneration. Phototherapy, particularly narrow-band UVB, can be effective for over half of patients who undergo treatment, however it requires one to two years of therapy two or three times per week, and is only useful for those who live close to a treatment center and whose schedule permits this regular interruption. Topical treatments include steroids and calcineurin inhibitors, which can be effective for some patients with focal disease. With all vitiligo treatments, non-hair-bearing skin, like that on the wrists, hands, and feet, is very slow to respond. Melanocyte transplantation is an exciting new therapy for those with stable vitiligo and may be effective in those locations; however, it is mostly limited to patients with the segmental variant of vitiligo.

Some concerns have been raised about skin cancer risk with phototherapy, however existing data suggest that, unlike with PUVA treatment, narrow-band UVB does not increase cancer risk. Topical steroids carry the risk of atrophy with continued use and, rarely, suppression of the adrenal axis. Calcineurin inhibitors appear to be safer than steroids, but are expensive and a little less effective. All of these therapies are non-targeted, acting as general immunosuppressants to prevent autoimmunity in vitiligo, but at the same time affect all other immune responses as well. A more targeted therapeutic approach, as used in psoriasis with the newer biologics, would potentially be safer and more effective.[pagebreak]

Dr. Van Voorhees: Do we know if those white patches are active sites of immunosuppression or are they a result of a transient insult that causes whiteness as a result of melanocyte death?

Dr. Harris: White patches in the skin represent areas where the melanocytes have been destroyed by T cells, starting as small macules that expand over time to become large patches. These patches can stabilize, without expanding or repigmenting. For a long time we assumed that stable patches were “burned out,” representing inactivity with no T cell destruction or melanocyte regeneration at all. However even these patches can repigment with treatment, suggesting that there is active autoimmunity in that skin preventing the ability of melanocytes to regenerate and repigment the skin. Results from our study support this concept.

Dr. Van Voorhees: Tell us about the results of your study.

Dr. Harris: In our search to develop new treatments for vitiligo, we were inspired by the recently effective biologic therapies for psoriasis that target cytokines that drive the autoimmune response. Biologic treatments for psoriasis, in particular the anti-TNF-γ therapies, have been tested in vitiligo patients but are ineffective. We hypothesized that vitiligo is driven by a different pathway of cytokines than psoriasis. We began by looking at gene expression within lesional skin of vitiligo patients and our mouse model to identify which cytokine pathways are active. Consistent with our hypothesis, the Th17 pathway was silent in the samples, while IFN-γ and its targets were significantly elevated, representing a focused Th1-type response.

Included in this panel of IFN-γ-induced genes in lesional skin were the chemokines CXCL9, CXCL10, and CXCL11. Since these chemokines are responsible for promoting directed migration of T cells to peripheral tissues, we investigated whether they were responsible for promoting autoreactive T cell migration to the skin during vitiligo. Long story short, we found that CXCL10 was present in human vitiligo serum and skin, and its receptor CXCR3 was expressed on melanocyte-specific T cells in the blood and skin. This was also true in the mouse, and we found that interfering with this pathway using either genetically modified mice or a CXCL10-neutralizing antibody prevented the onset of vitiligo. The real surprise was that neutralizing CXCL10 in mice with widespread depigmentation reversed disease, allowing perifollicular repigmentation of the skin as we see in successfully treated patients with vitiligo. This is consistent with the hypothesis that white patches in vitiligo require active autoimmunity to keep them that way, and offers a new approach for developing targeted therapy for vitiligo, as seen in psoriasis.[pagebreak]

Dr. Van Voorhees: So why don’t the biologics that we use in psoriasis work on this disease if it also is a Th1 disease?

Dr. Harris: For many years psoriasis was thought to be a Th1-mediated disease, primarily based on the presence of T cells in the skin and some expression of interferons, however there were many aspects of the disease that didn’t fit this designation. Th1-dominant diseases, like autoimmune thyroiditis and type 1 diabetes, are targeted and asymptomatic with minimal inflammation, similar to anti-viral immune responses. However psoriasis is highly inflammatory, recruiting neutrophils and activating production of antimicrobial peptides and epidermal thickening, more consistent with anti-bacterial responses. Following the discovery of the antibacterial Th17 pathway and the cytokines that drive it, psoriasis has been reclassified as a Th17-dominant disease, a designation supported by the many highly effective biologics that target this pathway.

Dr. Van Voorhees: What are the treatment possibilities that come out of this work?

Dr. Harris: There are currently no FDA-approved treatments that target the IFN-γ-CXCL10-CXCR3 cytokine pathway, however there are a number that are in the therapeutic pipeline from a number of pharmaceutical companies. There are antibodies against IFN-γ, CXCL10, and CXCR3, as well as small molecule inhibitors of CXCR3, which block their function. Many have already been tested in Phase I clinical studies with good safety profiles. They were primarily developed for psoriasis and inflammatory bowel disease due to some elevation of this pathway in target tissues, however they have not been effective in clinical trials, probably due to Th17-dominance in these diseases. Considering the evidence that vitiligo is primarily driven by the IFN-γ-CXCL10 pathway, we are hopeful that these treatments will translate into safe and effective targeted treatments for vitiligo.

Dr. Harris is assistant professor of medicine at the University of Massachusetts in the division of dermatology. His article appeared in the Feb. 12 issue of Science Translational Medicine; Sci Transl Med 6, 223ra23 (2014). doi: 10.1126/scitranslmed.3007811.