James P. Strassner

Suction blistering the lesional skin of vitiligo patients reveals useful biomarkers of disease activity

Background: Vitiligo is an autoimmune disease of the skin with limited treatment options; there is an urgent need to identify and validate biomarkers of disease activity to support vitiligo clinical studies. Objective: To investigate potential biomarkers of disease activity directly in the skin of vitiligo subjects and healthy subjects. Methods: Patient skin was sampled via a modified suction‐blister technique, allowing for minimally invasive, objective assessment of cytokines and T‐cell infiltrates in the interstitial skin fluid. Potential biomarkers were first defined and later validated in separate study groups. Results: In screening and validation, CD8+ T‐cell number and C‐X‐C motif chemokine ligand (CXCL) 9 protein concentration were significantly elevated in active lesional compared to nonlesional skin. CXCL9 protein concentration achieved greater sensitivity and specificity by receiver operating characteristic analysis. Suction blistering also allowed for phenotyping of the T‐cell infiltrate, which overwhelmingly expresses C‐X‐C motif chemokine receptor 3. Limitations: A small number of patients were enrolled for the study, and only a single patient was used to define the treatment response. Conclusion: Measuring CXCL9 directly in the skin might be effective in clinical trials as an early marker of treatment response. Additionally, use of the modified suction‐blister technique supports investigation of inflammatory skin diseases using powerful tools like flow cytometry and protein quantification.

Understanding mechanisms of autoimmunity through translational research in vitiligo.

Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells. Once the autoimmune T cell response is established, the IFN-γ-STAT1-CXCL10 signaling axis becomes the primary inflammatory pathway driving both progression and maintenance of vitiligo. This pathway is a tempting target for both existing and developing pharmaceuticals, but further detailing how melanocytes signal their own demise may also lead to new therapeutic targets. Research in vitiligo may be the future key to understand the pathogenesis of organ-specific autoimmunity, as vitiligo is common, reversible, progresses over the life of the individual, has been relatively well-defined, and is quite easy to study using translational and clinical approaches. What is revealed in these studies can lead to innovative treatments and also help elucidate the principles that underlie similar organ-specific autoimmune diseases, especially in cases where the target organ is less accessible.

Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure

Background: Vitiligo is an autoimmune disease in which cutaneous depigmentation occurs. Existing therapies are often inadequate. Prior reports have shown benefit of the Janus kinase (JAK) inhibitors. Objective: To evaluate the efficacy of the JAK 1/3 inhibitor tofacitinib in the treatment of vitiligo. Method: This is a retrospective case series of 10 consecutive patients with vitiligo treated with tofacitinib. Severity of disease was assessed by body surface area of depigmentation. Results: Ten consecutive patients were treated with tofacitinib. Five patients achieved some repigmentation at sites of either sunlight exposure or low‐dose narrowband ultraviolet B phototherapy. Suction blister sampling revealed that the autoimmune response was inhibited during treatment in both responding and nonresponding lesions, suggesting that light rather than immunosuppression was primarily required for melanocyte regeneration. Limitations: Limitations include the small size of the study population, retrospective nature of the study, and lack of a control group. Conclusion: Treatment of vitiligo with JAK inhibitors appears to require light exposure. In contrast to treatment with phototherapy alone, repigmentation during treatment with JAK inhibitors may require only low‐level light. Maintenance of repigmentation may be achieved with JAK inhibitor monotherapy. These results support a model wherein JAK inhibitors suppress T cell mediators of vitiligo and light exposure is necessary for stimulation of melanocyte regeneration.

Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo

Human and mouse resident memory T cells are present in vitiligo lesions, and blocking IL-15 signaling provides long-lasting reversal of disease in a mouse model of vitiligo. Forcing memory T cells to forget In vitiligo, autoreactive T cells attack melanocytes, leading to white spots on the skin. Depigmentation typically recurs upon cessation of treatment, so new therapies are needed for permanent patient relief. Richmond and colleagues reasoned that targeting tissue-resident memory T cells may allow for durable therapy. They observed that T cells from patient lesional samples expressed the receptor for IL-15, an important survival cytokine. T cells in a mouse model of vitiligo also expressed the IL-15 receptor, and blocking IL-15 signaling with an antibody was able to reverse disease symptoms. A clinical trial to test this therapy is now in the works. Vitiligo is an autoimmune disease of the skin mediated by CD8+ T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (TRM) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)–deficient mice reportedly have impaired TRM formation, and IL-15 promotes TRM function ex vivo. We found that both human and mouse TRM express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits TRM production of interferon-γ (IFNγ), and long-term treatment depletes TRM from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving TRM.

Melanocytes in psoriasis: convicted culprit or bullied bystander?

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