The pathogenesis of vitiligo involves interplay between intrinsic and extrinsic melanocyte defects, innate immune inflammation, and T-cell–mediated melanocyte destruction. The goal of treatment is to not only halt disease progression but also promote repigmentation through melanocyte regeneration, proliferation, and migration. Treatment strategies that address all aspects of disease pathogenesis and repigmentation are likely to have greatest efficacy, a strategy that may require combination therapies. Current treatments generally involve nontargeted suppression of autoimmunity, whereas emerging treatments are likely to use a more targeted approach based on in-depth understanding of disease pathogenesis, which may provide higher efficacy with a good safety profile.
Key points
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Vitiligo results from the destruction of epidermal melanocytes by autoreactive cytotoxic T cells.
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Melanocyte-specific autoimmunity in vitiligo is a result of interplay among multiple factors, including genetic predisposition, environmental triggers, melanocyte stress, and innate and adaptive immune responses.
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An optimal treatment strategy in vitiligo would stabilize melanocytes, suppress the autoimmune response, and restore immune tolerance as well as stimulate melanocyte regeneration, proliferation, and migration to lesional skin.
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A better understanding of the key pathways involved in vitiligo onset and progression will enable developing treatments that have greater efficacy and a good safety profile.
Introduction
Vitiligo is a common, disfiguring autoimmune disease that negatively affects patients’ self-esteem and quality of life. Existing vitiligo treatments, which are used off-label, are general, nontargeted immunosuppressants that provide only modest efficacy. Developing safe and effective treatments requires a better understanding of disease pathogenesis to identify new therapeutic targets. Vitiligo is caused by a dynamic interplay between genetic and environmental risks that initiates an autoimmune attack on melanocytes in the skin.
Introduction
Vitiligo is a common, disfiguring autoimmune disease that negatively affects patients’ self-esteem and quality of life. Existing vitiligo treatments, which are used off-label, are general, nontargeted immunosuppressants that provide only modest efficacy. Developing safe and effective treatments requires a better understanding of disease pathogenesis to identify new therapeutic targets. Vitiligo is caused by a dynamic interplay between genetic and environmental risks that initiates an autoimmune attack on melanocytes in the skin.
Vitiligo pathogenesis
Genetics
The observation that vitiligo was more prevalent in the immediate relatives of patients with vitiligo provided early evidence of its heritability. Although vitiligo affects approximately 1% of the general population, the risk of a patient’s sibling developing the disease is 6% and for an identical twin it is 23%. In addition, patients with vitiligo and their relatives have an increased risk of developing other autoimmune diseases, including autoimmune thyroiditis, type 1 diabetes mellitus, pernicious anemia, and Addison disease, suggesting that vitiligo is also an autoimmune disease. These early observations were later confirmed by genome-wide association studies, which identified numerous common genetic variants in vitiligo patients encoding for components of both the innate immune system (NLRP1, IFIH1, CASP7, C1QTNF6, and TRIF) and adaptive immune system (FOXP3, BACH2, CD80, CCR6, PTPN22, interleukin [IL]-2R, α-GZMB, and HLA classes I and II) (see also Richard Spritz and Genevieve Andersen’s article, “ Genetics of Vitiligo ,” in this issue).
Oxidative Stress
Accumulating evidence suggests that melanocytes from vitiligo patients have intrinsic defects that reduce their capacity to manage cellular stress (reviewed by Harris ). Epidermal cells, including melanocytes, are constantly exposed to environmental stressors, such as ultraviolet (UV) radiation and various chemicals, which can increase production of reactive oxygen species (ROS). Although healthy melanocytes are capable of mitigating these stressors, melanocytes from vitiligo patients seem more vulnerable. For example, melanocytes from perilesional vitiligo skin demonstrate a dilated endoplasmic reticulum and abnormalities in their mitochondria and melanosome structure, all of which are characteristic of elevated cellular stress. High concentrations of epidermal H 2 O 2 level and a decreased level of catalase, a critical enzyme that protects cells from oxidative damage, have been observed in skin of patients with vitiligo.
Environment
The earliest triggering events that lead to vitiligo are not fully understood. Multiple studies suggest that a combination of melanocyte intrinsic defects and exposure to specific environmental factors may play a central role in disease onset. This was evident in a group of factory workers who developed vitiligo after exposure to monobenzone, an organic chemical phenol, in their gloves. Later studies confirmed that a history of exposure to other phenolic and catecholic chemicals found in dyes (especially hair dyes), resins/adhesives, and leather was associated with vitiligo.
Melanogenesis is a multistep process through which the melanocyte produces melanin. Tyrosinase is a rate-limiting enzyme in this process that controls the production of melanin through oxidation of the amino acid tyrosine, a naturally occurring phenol (reviewed by d’Ischia and colleagues and discussed further by John E. Harris’s article, “ Chemical-Induced Vitiligo ,” in this issue). In vitro studies demonstrated that chemical phenols can act as tyrosine analogs within the melanocyte, precipitating high levels of cellular stress. This stress may include increased production of ROS and triggering of the unfolded protein response, which in turn activates innate inflammation.
Innate Immunity
As discussed previously, genome-wide association studies in vitiligo patients implicated multiple susceptibility loci related to the genes that control the innate immunity. This likely causes dysregulated innate activation in response to melanocyte stress, demonstrated through recruitment of innate populations like natural killer cells and production and release of high levels of proinflammatory proteins and cytokines, including heat shock proteins (HSPs), IL-1β, IL-6, and IL-8 (reviewed in Refs. ). Among larger HSP molecules, inducible HSP70 (HSP70i) is unique, because it can be secreted to chaperone peptides specific to the originating host cells. Recently, HSP70i has been shown to be important for vitiligo pathogenesis in a mouse model through induction of inflammatory dendritic cells, which themselves may be cytotoxic or carry and present melanocyte-specific antigens to T cells in lymphoid tissues. This has been proposed to be a key cross-talk step between innate and adaptive immunity, leading to the T-cell–mediated autoimmune destruction of melanocytes.
Adaptive Immunity
Ultimately, cytotoxic CD8 + T cells are responsible for the destruction of melanocytes. Cytokines secreted within the skin act as an early signal to help these autoreactive T cells locate stressed melanocytes. This is probably important because the epidermis is not vascularized, so active mechanisms are required to help them efficiently locate melanocytes. Chemokines are small, secreted proteins that act as chemoattractants to guide T-cell migration. Interferon (IFN)-γ and IFN-γ–induced chemokines (CXCL9 and C-X-C Motif Chemokine Ligand 10 [CXCL 10]) are highly expressed in the skin and blood of patients with vitiligo as well as in a mouse model. In addition, IFN-γ and CXCL10 are required for both disease progression and maintenance in a mouse model of the disease. Recently, a separate study demonstrated not only that serum CXCL10 was higher in patients with vitiligo compared with healthy controls but also that its level was associated with disease activity and significantly decreased after successful treatment, suggesting it may be used as a biomarker to monitor the disease activity and treatment response.
Emerging treatments
Based on current understanding of vitiligo pathogenesis, a successful strategy to treat vitiligo should incorporate 3 distinct approaches: reducing melanocyte stress, regulating the autoimmune response, and stimulating melanocyte regeneration. Existing treatments partially address these needs; however, emerging therapies may do this in a more targeted way, and combination therapies may synergize to produce a better overall response ( Fig. 1 ).
Reducing Melanocyte Stress
The apparent reduction of catalase enzyme in the epidermis of vitiligo patients as well as elevated levels of ROS in lesional skin prompted the hypothesis that treating patients with antioxidants or otherwise controlling ROS might be an effective treatment strategy. Pseudocatalase describes a treatment cream comprised of any number of metal ions capable of converting H 2 O 2 , a common ROS, into water and oxygen. Early studies using pseudocatalase combined with phototherapy for vitiligo patients seemed promising ; however, they were either not controlled or not blinded, and subsequent studies have not reproduced positive results. It is unclear if this strategy could be optimized or otherwise improved for the development of future therapies.
Oral or topical natural health products, vitamins, and supplements have been suggested as possible therapies based on their antioxidant and anti-inflammatory properties (reviewed by Pearl E. Grimes and Rama Nashawati’s article, “ The Role of Diet and Supplements in Vitiligo Management ,” in this issue). The herbal supplement Gingko biloba has been tested in 2 small trials and reported to promote some improvement. The plant extract Polypodium leucotomos reportedly improved responses to narrow band (NB)-UVB in a small group of vitiligo patients compared with placebo. One group tested NB-UVB with or without supplementation by an antioxidant pool that included α-lipoic acid, vitamin C, vitamin E, and polyunsaturated fatty acids. They reported greater efficacy in patients who received a combination of NB-UVB plus antioxidants. Larger, controlled trials need to be conducted to determine if adding antioxidants is a beneficial strategy to add to patient management.
Regulating Autoimmunity
Over the past decade, significant progress has been made in the development of immunomodulators to treat inflammatory skin disease, including more targeted treatments. Recent advances in understanding of the immunopathogenesis of vitiligo have helped identify novel immune targets to develop and test new vitiligo treatments.
Inducible heat shock protein 70
One group reported a role for HSP70i in vitiligo pathogenesis, suggesting that it was released by stressed melanocytes and initiated innate inflammation within the skin. They then found that mutating the protein made it less immunogenic and seemed to even induce tolerance when expressed in the skin of a mouse model, preventing the onset of disease. They proposed future testing this as a new treatment of vitiligo, although DNA delivery of a mutant protein in patient skin may take some time to develop and demonstrate safety.
Interferon-γ/CXCL10
The authors previously reported that the IFN-γ/CXCL10 axis is a critical signaling pathway required for both the progression and maintenance of vitiligo and hypothesized that targeting this pathway could be an effective treatment strategy. A variety of antibodies and small molecule inhibitors have already been developed to target components of this pathway (including IFN-γ, CXCL10, and the CXCL10 receptor CXCR3) and were found safe in early-phase clinical trials for treatment of other autoimmune diseases, including psoriasis, rheumatoid arthritis, and Crohn disease. Most of these trials failed to reach their efficacy endpoint, likely because IFN-γ is not a major driving cytokine in those diseases. Recent findings in patients and a mouse model suggest, however, that vitiligo is an optimal disease to test those investigational drugs.
Janus kinase–signal transducer and activator of transcription signaling
Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling is essential to transmit extracellular signals of many cytokines, including IFN-γ, to the nucleus. After ligation of the cytokine receptor, JAKs phosphorylate STAT proteins, which become activated and induce transcription of target genes. There are 4 members of the JAK family, including JAK1, JAK2, JAK3, and tyrosine kinase 2. Among these, JAK1 and JAK2 are directly involved in IFN-γ signaling, which activate STAT1 and thus induce the transcription of IFN-γ–induced genes, including CXCL10 ( Fig. 2 ) (reviewed by Villarino and colleagues ).
Several small molecule JAK inhibitors with distinct selectivity have been tested in patients or are under development. A patient with generalized vitiligo was reported to respond to treatment with oral tofacitinib, a JAK 1/3 inhibitor approved for the treatment of moderate to severe rheumatoid arthritis. Ruxolitinib, another JAK inhibitor with JAK 1/2 selectivity, is currently approved by the Food and Drug Administration (FDA) for the treatment of intermediate-risk or high-risk myelofibrosis and polycythemia vera. The authors and colleagues reported that a patient with vitiligo developed rapid repigmentation on his face and trunk after initiating oral ruxolitinib. The treatment response from these inhibitors did not seem durable, because patients lost the repigmentation after discontinuing treatment (Dr B. King, personal communication, April, 2016).
Similar to all other immunosuppressive drugs, tofacitinib and ruxolitinib may have adverse effects, including opportunistic infections and rare malignancies. In addition, ruxolitinib may induce blood abnormalities, including thrombocytopenia, anemia, and neutropenia. Topical formulation of these drugs may provide therapeutic benefit without increasing the risk of adverse events. Currently, an open-label, phase 2, proof-of-concept clinical trial is recruiting participants to test the efficacy of topical ruxolitinib 1.5% in the treatment of vitiligo.
In addition to JAK inhibitors, STAT inhibitors could potentially have similar effects. So far, 7 members have been identified in this family; however, only STAT1 as a homodimer has been implicated in IFN-γ signaling (reviewed by Villarino and colleagues ). A previous in vitro study reported that statins, which lower cholesterol via inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, inhibited STAT1 function. In addition, a vitiligo patient was reported to improve after taking oral simvastatin. A recent study tested systemic simvastatin in a mouse model of vitiligo and found it effective in both preventing and reversing disease. A small pilot clinical trial the authors conducted to test the efficacy of high-dose (80 mg daily) oral simvastatin in patients with generalized vitiligo did not reach its primary efficacy endpoint. Adverse effects of simvastatin limit dosing in humans, which may be responsible for the disparate results between the mouse model and vitiligo patients. An ongoing study is currently recruiting patients to evaluate the benefits of combining atorvastatin and UVB for the treatment of active vitiligo, and future studies could test topical simvastatin as a way to increase local concentrations without toxicity.
Immune checkpoints
Successful application of immunotherapy to treat metastatic melanoma via blockade of inhibitory checkpoints has gained recent attention. Immune checkpoints are molecules that modulate T-cell responses to inflammation and include cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), among others. The treatment response of melanoma patients to immune checkpoint inhibitors correlates with the development of vitiligo. Some investigators have hypothesized that activating these surface receptors could restore tolerance in vitiligo patients.
Abatacept is a fusion protein composed of the fragment crystallizable (Fc) region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4. It is currently approved by the FDA for the treatment of moderate to severe rheumatoid arthritis. Recently, an open-label, single-arm, pilot study was initiated to test the efficacy of abatacept in patients with vitiligo. Additionally, PD-1 ligand (a PD-1 agonist) is currently under development and is being tested in preclinical phases of inflammatory bowel disease and psoriasis.
Stimulating Melanocyte Regeneration
α-Melanocyte–stimulating hormone
Phototherapy is currently first-line therapy for vitiligo, especially in patients with widespread disease (reviewed by Samia Esmat and colleagues’ article, “ Phototherapy and Combination Therapies for Vitiligo ,” in this issue). Although the mechanism of its therapeutic effects are not completely understood, repigmentation from phototherapy is probably due to its ability to induce immunosuppression and also to the induction of melanocyte stem cell differentiation and proliferation. α-Melanocyte–stimulating hormone (α-MSH) is a naturally occurring hormone that stimulates melanogenesis (reviewed by Videira and colleagues ). Afamelanotide, a synthetic analog of α-MSH, is currently approved by the European Medicines Agency to mitigate photosensitivity in erythropoietic protoporphyria and thus may also improve the efficacy of phototherapy for vitiligo. Recently, a randomized comparative multicenter trial was conducted to test the safety and efficacy of an afamelanotide subcutaneous implant in combination with NB-UVB in adults with generalized vitiligo. The combination therapy was somewhat well tolerated, although side effects included nausea and skin hyperpigmentation, which led some subjects to withdraw from the trial. The treatment resulted in faster and increased total repigmentation compared with NB-UVB monotherapy. This response was most evident in patients with darker skin (Fitzpatrick skin types IV to VI). It is currently unknown whether afamelanotide monotherapy would have any benefit in the treatment of vitiligo.
Wnt signaling
A recent study reported that melanocytes from vitiligo patients had defective Wnt signaling, a pathway that promotes the differentiation of melanocyte precursors in skin. The investigators hypothesized that this impaired signaling contributed to disease pathogenesis and, in particular, inhibited melanocyte regeneration and repigmentation during treatment. Studies using explanted human skin ex vivo suggested that Wnt activators could enhance melanocyte differentiation. Thus, therapeutic Wnt activation could potentially serve as an adjunctive therapy for vitiligo that supports melanocyte regeneration.
Selective sunscreen
Despite being the most effective current treatment of vitiligo, patient access to phototherapy is a challenge. To receive therapy, patients typically attend a specialized clinic 2 to 3 times weekly for up to 1 to 2 years to achieve a satisfactory response. Although sun exposure is an inexpensive alternative to phototherapy, it is difficult to monitor exposure, and nontherapeutic wavelengths of light can be erythematogenic and dose limiting. Recently, a topical formulation of dimethicone 1% was reported to selectively block wavelengths of sunlight below 300 nm, permitting therapeutic wavelengths in the NB-UVB range (approximately 311–312 nm) to penetrate. A small double-blind placebo-controlled study found that application of this cream followed by sun exposure was safe and effective at inducing repigmentation in lesional skin. This needs to be confirmed in larger clinical trials, however, and, as the investigators acknowledged, its use would be limited by inadequate sunlight during certain times of the year or involvement of body areas that cannot be exposed in public. In addition, potentially harmful UVA light is not blocked by this cream; thus, this approach may not be as safe as NB-UVB phototherapy.
Related posts:
The Medical Treatment of Vitiligo
Quality of Life, Burden of Disease, Co-morbidities, and Systemic Effects in Vitiligo Patients
Skin Cancer Risk (Nonmelanoma Skin Cancers/Melanoma) in Vitiligo Patients
Phototherapy and Combination Therapies for Vitiligo
Surgical Therapies for Vitiligo
Genetics of Vitiligo
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