Vitiligo is a skin disease characterized by selective loss of melanocytes followed by depigmentation in the affected areas of the skin.1 The disease, which has a complex pathogenesis, can have a serious psychosocial impact on patients.1 Although management of vitiligo is complex, there are safe, effective treatments available and promising emerging therapies.1,2 In a recent AJMC® Peer Exchange™, experts who specialize in treating patients with vitiligo were joined by professionals from the insurance industry to explore the clinical and economic burden of vitiligo, review treatment paradigms and standard-of-care therapies, and discuss unmet needs and future directions in treatment. The session was moderated by Jeffrey D. Dunn, PharmD, MBA, chief clinical officer at Cooperative Benefits Group in Salt Lake City, Utah.
Disease Burden
Vitiligo is a chronic, acquired disease of the skin and mucous membranes that is characterized by sharply demarcated, milky white, depigmented macules and patches, with neat borders and variable dimensions and distribution.3,4 There are 2 forms of the disease: segmental and nonsegmental.1,5 Segmental vitiligo is characterized by unilateral, localized distribution of lesions. It is more common in younger children, and often has rapid onset and stabilization with early hair follicle involvement. Nonsegmental vitiligo is characterized by bilateral distribution of lesions on the body, with progressive onset and multiple flare-ups, later hair follicle involvement, and an unpredictable course.6
Vitiligo has been dismissed as a cosmetic disease.7 However, patients may experience a severe impact on quality of life because the disorder can be psychologically devastating.3,7-9 Vitiligo lesions, which typically occur in exposed areas of the skin such as the hands and face, are often mistaken for an infectious disease, which contributes to the stigma experienced by patients.1,3,7-9 Furthermore, the lesions may have a strong negative impact on patients’ self-esteem and perception of self,3 and patients may experience psychological problems such as depression, anxiety, and shame, which can result in social isolation.1,7 In fact, recent systematic reviews of the available evidence for the psychosocial burden in vitiligo found that depression and anxiety were the most commonly reported psychological disorders; feelings of stigmatization, adjustment disorders, sleep disturbance, relationship difficulties such as sexual dysfunction, and avoidance or restriction behavior were the most prevalent psychosocial comorbidities; female sex, visible or genital lesions, age younger than 30 years (particularly adolescents), and greater body surface area involvement were factors associated with a significantly higher psychosocial burden; and lesion concealment was the most common coping strategy.9,10 Importantly, most interventions significantly improved quality of life for patients.10 Therefore, it is important to assess quality of life during consultations and refer patients to psychological help, if needed.1,3,9
Finally, vitiligo carries a significant economic burden as management of the disease is associated with high direct and indirect costs.7 Costs include those for prescription and OTC medications, medical office visits, phototherapy, lost workdays, public avoidance, and impaired quality of life.11 Because patients with insurance are more likely to receive treatment, it is important that payers understand that early treatment of vitiligo lesions has better results, as well as benefits via early detection of associated autoimmune diseases.7,12
Epidemiology and Pathogenesis
The average age of onset follows a bimodal pattern, with early onset at a mean of 7.3 years and late onset at a mean of 40.5 years; the overall mean (SD) age of onset is 31.8 (20.2) years.13,14 Although vitiligo can occur in individuals of all genetic backgrounds, the prevalence varies widely across geographic areas, ranging from a low of 0.06% to a high of 2.28%.1,15 In the United States, the prevalence of vitiligo varies between 0.76% based on clinician adjudication and 1.38% based on self-report.16 The incidence and prevalence of segmental vitiligo is not well established1; however, it is less common than nonsegmental vitiligo and affects between 5% and 16% of patients.17,18
Vitiligo has a complex multifactorial pathogenesis.4 However, the exact mechanisms that integrate the genetic susceptibility of each individual with melanocyte auto-aggression and failure of immune tolerance mechanisms are not fully elucidated.19 The most common theory for the pathogenesis of vitiligo is that a convergence of immunological and nonimmunological factors ultimately leads to the development of the disease. Patients with a background of genetic susceptibility and intrinsic skin abnormalities are more susceptible to oxidative stress damage, which triggers the release of various factors that activate the immune system and lead to melanocyte loss.4
There is strong evidence for the importance of genetic factors in the development of vitiligo; however, these influences are complex and the genetic risk is not absolute.1 The disease tends to aggregate in families, as approximately 20% of patients have at least 1 first-degree relative with vitiligo, and the relative risk of vitiligo for first-degree relatives is increased.20 However, monozygotic twins have only a 23% concordance rate, highlighting the importance of additional stochastic or environmental factors in the development of the disease.21 There are nearly 50 different genetic loci that confer a vitiligo risk, with relevant genes involved in the innate and adaptive immune system, melanogenesis, and apoptosis. Furthermore, several of these genes are associated with other pigmentary and autoinflammatory disorders, as well as autoimmune disorders such as thyroid disease, type 1 diabetes, and rheumatoid arthritis.22
Intrinsic alterations in the skin of patients with vitiligo include a thicker epidermis with a reduced number of basal melanocytes and the presence of degenerated keratinocytes with swollen mitochondria, increased levels of reactive oxygen species (ROS), and reduced E-cadherin expression. The melanocytes have a senescent phenotype with high intracellular ROS levels, reduced antioxidant activity, abnormalities in mitochondrial function, and release of senescence-associated proteins. The fibroblasts have a myofibroblast phenotype, increased intracellular ROS, and mediators that contribute to the downregulation of E-cadherin. Finally, there is a decrease in microbial diversity, possibly due to the altered microenvironment of the skin.4
In this background of intrinsic skin alterations together with genetic susceptibility, additional environmental stress causes widespread alterations in the antioxidant system.1 Oxidative stress leads to the secretion of interferon-γ (IFN-γ) by natural killer (NK) cells and innate lymphoid cells (ILCs).4 The increase in IFN-γ levels has several effects, starting with the release of CXCL9 and CXCL10, which recruit CD8+ T cells, and MMP9, which contributes to the detachment of melanocytes from the basal layer, from damaged keratinocytes. Damaged melanocytes release damage-associated molecular patterns, heat shock protein 70, and HMGB1, which further activates NK cells and ILCs, acting as a positive feedback loop, and activates dendritic cells, further potentiating the development of a specific immune response through the activation of autoreactive CD8+ T cells. Following this autoimmune reaction, a portion of T cells remains in the skin as resident memory T cells (TRM), which may be responsible for the recurrence of vitiligo following repigmentation.1,4
Diagnosis and Assessment
The diagnosis of vitiligo is generally straightforward and made clinically based on appearance of the characteristic lesions. It usually does not require confirmatory laboratory tests, and a skin biopsy is only used to exclude other disorders. The diagnosis may be facilitated by use of a handheld UV irradiation device that emits UVA, commonly referred to as a Wood lamp. Under the Wood lamp, the vitiligo lesions emit a bright blue-white fluorescence and appear sharply demarcated, which helps identify focal melanocyte loss and detect areas of depigmentation that may not be visible to the eye.3,6,23
Physicians should reserve enough time for a careful initial assessment of a patient with vitiligo. The evaluation entails a detailed history and complete skin examination to assess disease severity and individual prognostic factors. An assessment form created by the Vitiligo European Task Force summarizes the personal and family history elements of the clinical examination items and may be useful for evaluation. It is important to routinely ask patients about family history of vitiligo and premature hair graying and about personal and family history of thyroid disease or other autoimmune diseases. Aspects that should be assessed include the skin phototype, disease duration, extent, activity, rate of progression or spread of lesions, presence of the Koebner phenomenon, presence of halo nevi, previous treatments (including their type, duration, and effectiveness), previous episodes of repigmentation, and occupational history/exposure to chemicals.6
Finally, the quality of life of patients with vitiligo should be assessed regularly. Assessment tools used in the research setting include the Short Form-12, the Dermatology Life Quality Index, the Vitiligo Impact Scale, the Vitiligo-Specific Health-Related Quality of Life Instrument, and the Vitiligo Impact Patient Scale.1 All patients with vitiligo should be offered psychological support and counseling.23
Stakeholder Insights
More than 1 million individuals in the United States have vitiligo. However, “it is very hard to know the exact incidence and prevalence of vitiligo in the population,” said David Rosmarin, MD, vice chair of education and research at Tufts Medical Center in Boston, Massachusetts. This is because many patients do not seek care for their disease. They may not be aware of it or may have received a misdiagnosis. Therefore, some patients may be missed when the incidence and prevalence are calculated. The reason for the reported differences in incidence is not well understood, as vitiligo can affect any individual. However, “how it affects somebody in terms of their quality of life may vary greatly depending on the culture and some of the subgroups,” Rosmarin said. He underscored that it is the burden on mental health that clinicians are particularly concerned about when it comes to vitiligo. Although some individuals adapt to their disease, perhaps because it is less noticeable on fair skin or because they are older, others find that it has a significant impact on their quality of life.
Brett King, MD, PhD, associate professor of dermatology at Yale School of Medicine in New Haven, Connecticut, emphasized the social impact of the disease. “Imagine having white spots all over [your] face or having white spots just surrounding your eyes, having big raccoon eyes, having white spots all over your arms and your hands,” he said. Other individuals may react negatively to these lesions, thinking they are infectious, and avoid touching them. In other words, vitiligo is associated with stigma. Therefore, patients can find day-to-day life challenging. There are data showing the impact that the disease has on work productivity, life decisions, and quality of life.
In terms of the economic burden of vitiligo, David Epstein, MD, MBA, an independent consultant, shared that from the payer perspective, this is not being tracked because most medications are not expensive. Dunn agreed and said that the challenge, from the payer perspective, will be how to manage the direct costs once new treatments are approved. But from the perspective of the patient, there certainly is an economic impact associated with the treatment, Rosmarin said, especially with phototherapy sessions, which may require patients to miss work.
The fact that vitiligo is an autoimmune disease was emphasized by Rosmarin and King. A further clinical clue about the autoimmune nature of vitiligo is the fact that it is sometimes associated with autoimmune thyroid disease, King said. The autoimmune nature of vitiligo also points to the other causative aspect of the disease, which is the genetic predisposition that is probably present in all patients. This genetic predisposition is likely what explains the well-documented association between autoimmune thyroid disease and vitiligo, which is also seen in patients with other autoimmune skin diseases. Finally, although emerging data suggest there is systemic inflammation in vitiligo, it is not clear whether patients are predisposed to any other internal organ disease, King said.
Although several tools are used in the research setting to assess quality of life of patients with vitiligo, there are no standardized tools used in clinical practice, Rosmarin said. Clinicians typically ask questions, such as whether patients have switched to different clothing or changed their going-out habits or whether they feel people are staring at them, to determine how the disease is affecting patients. Furthermore, Rosmarin wished there were better tools to assess quality of life of patients with vitiligo in the research setting as well.
Management of Vitiligo
Several guidelines have been published for the treatment of patients with vitiligo.23-26 As most of the therapeutic options are time-consuming and require long-term follow-up, management of vitiligo requires a personalized treatment approach that considers the preferences of the patient. The choice of treatment depends on factors including the subtype of vitiligo, as well as the extent, distribution, and activity of the disease. The patient’s age, phototype, effect on quality of life, and motivation for treatment also play a role in the decision-making process.1
The areas that have the best response to treatment are the face, neck, trunk, and midextremities, whereas the lips and distal extremities are more resistant. The repigmentation starts at the periphery of the lesions in a perifollicular pattern, and at least 2 to 3 months of continued treatment is necessary to determine efficacy for the individual patient.1
Commonly used treatments for vitiligo are topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). TCSs can be used for patients with limited lesions that are not on the face. The first choice should be a less potent TCS, and treatment should be no longer than 3 months if administered daily, or 6 months if following a discontinuous scheme. TCIs are as effective as TCSs on facial lesions and have less severe adverse effects.24
UV light–based therapy is associated with an improved outcome when combined with an additional therapy. Phototherapy treatments include narrowband UV-B (NBUVB) and psoralen and UVA (PUVA). NBUVB is indicated for generalized nonsegmental vitiligo, with total body treatments being suggested for lesions involving more than 15% to 20% of the body area, whereas targeted phototherapies are indicated for localized and small lesions.24
The combination of phototherapy and TCS and TCI treatments appears safe and leads to better results. Additionally, phototherapy should be used for 3 to 4 weeks following surgical procedures to enhance repigmentation. There is less evidence for combining phototherapy with antioxidant therapy; however, it might be beneficial. The only therapy for which combination with phototherapy is not recommended is therapy with vitamin D analogues.24
Systemic steroid treatment may also be used in some cases. Patients experiencing rapid disease progression may be treated with systemic oral minipulse steroids, a treatment that consists of twice-a-week corticosteroid administration.24 For patients with more resistant vitiligo, options include surgical grafting as a third-line therapy and depigmenting treatments as a fourth-line therapy.1
Additionally, patients should be offered advice on cosmetic camouflage by a cosmetician or a specialized nurse, as this can be beneficial for patients with vitiligo lesions in exposed areas. Cosmetic camouflage includes foundation-based cosmetics and self-tanning products containing dihydroxyacetone. Patients may also opt to have cosmetic tattoos, especially on the lips and nipples.1,24
Stakeholder Insights
Although there are other agents available, the main 3 therapies used in the front line are TCSs, TCIs, and phototherapy, which can be used alone or in combination, Rosmarin said. Corticosteroids are inexpensive but can be difficult to use for prolonged periods, which are typically needed for repigmentation. Calcineurin inhibitors generally work well for repigmentation of the face. However, as it is a large molecule, it does not work as well on other parts of the body. Phototherapy is also very effective, as it stimulates the melanocytes to migrate back to the lesion and calms the immune system. However, it can be inconvenient for patients to go to the clinic 3 times a week for treatments, especially if they live far away and must miss work.
Treatment goals vary by patient, Rosmarin said. Some patients just want to get a diagnosis and they do not want any treatment. Others experience severe anxiety about spread of the lesions and want to stop progression, which is easier to do than repigmenting. For some patients, the goal is to repigment at least some areas. Finally, the goal can also be repigmentation maintenance, which may be helped by twice-a-week application of a TCI. Vitiligo is a chronic disease with no permanent cure, and new spots may appear at any time. Existing and emerging therapies manage the underlying cause of an overactive immune system but do not cure the disease.
On the other hand, it is possible to achieve remission without continued treatment, King noted, which is not the case for other autoimmune diseases such as psoriasis. Furthermore, once repigmentation has been achieved, it is also likely that patients will be less motivated to continue treatment as diligently, which ends up also being a cost-saving mechanism. King emphasized that it is important for patients, providers, and payers to understand that vitiligo treatment is a monthslong process. There are data indicating that a significant proportion of patients achieves success in 6 months, but others need up to a year.
In terms of insurance coverage, some payers will not cover even the diagnosis of vitiligo, although this is rare. As for treatment, corticosteroids are generally covered and do not require prior authorization, Rosmarin said. However, both Rosmarin and King expressed that coverage for calcineurin inhibitors and phototherapy varies depending on the payer and the plan and is frequently denied.
From the payer perspective, vitiligo is acknowledged as a disease and assessed in a way similar to other diseases, with a focus on the standard of care, Epstein said. Coverage for the management of vitiligo is based on the opinions from experts and key opinion leaders. The main concern of payers at this moment is the potential manipulation of information from the manufacturer side. Dunn concurred with the idea that payers view vitiligo as a disease and not merely a cosmetic problem. Part of the problem, in his view, is that right now most of the therapies used to treat vitiligo are relatively inexpensive, as there are a lot of generic medications available; however, as more expensive options become available, there will be a need to work with providers to determine the best use for these medications. Together, they must determine who are the appropriate patients for the new medications and how to assess whether the new medications are working. Both agreed that there will probably be a need to use payer tools to control costs, such as initial authorization followed by reauthorization after a period, with physician attestation as to progress.
King agreed that it is important to have documentation that patients are getting better with treatment. This is also important from the physician and patient point of view, as neither would normally want to continue a treatment that is not working. He further said that payers and formulary managers will need to be thoughtful about which patients are likely to get better and which are not, and to develop decision trees around those parameters. A key question will be the appropriate amount of time to determine whether a patient is having a meaningful clinical response to treatment; that is, what percentage of skin repigmentation in a set period would be the cutoff for continuing treatment.
Emerging Therapies and Unmet Needs in Vitiligo
There are various agents being tested for the treatment of patients with vitiligo, including calcineurin inhibitors, MC1R agonists, antioxidants, metabolism inhibitors, cytokine inhibitors, and kinase inhibitors.27 The most promising new therapies are the Janus kinase (JAK) inhibitors tofacitinib and ruxolitinib.
Tofacitinib
Oral tofacitinib, a JAK 1/3 inhibitor, demonstrated promising repigmentation results in case studies and a retrospective observational study. The addition of NBUVB therapy seems to improve its efficacy. It is well tolerated in most patients, and adverse events include respiratory tract infections, diarrhea, arthralgia, weight gain, and mild lipid and liver enzyme elevation. In rare cases it can lead to malignancies.2
Ruxolitinib
Ruxolitinib is a JAK 1/2 inhibitor that has been tested in 2 phase 2 clinical trials (NCT02809976 and NCT03099304) and is being evaluated in 3 phase 3 trials (NCT04052425, NCT04057573, and NCT04530344).28 The phase 2 trials’ results showed that ruxolitinib may be a good option for vitiligo management as patients had substantial repigmentation and good dose tolerance.28 Furthermore, results from the phase 3 trials presented at the 2022 American Academy of Dermatology Annual Meeting showed that approximately half the patients treated with ruxolitinib cream achieved at least 75% improvement in the facial lesions at 52 weeks, leading to FDA approval of ruxolitinib cream (Opzelura) in July 2022.29,30
Stakeholder Insights
Dunn explained that, in a setting where there are various options that work, from the payers’ perspective there is a fiduciary responsibility to encourage the use of the most cost-effective therapy first. Therefore, there may be a need for payers to influence the first therapy choice without overstepping their bounds in determining whether a drug works. On the other hand, King said the fact that vitiligo is an autoimmune disease that responds to JAK inhibitors, as do other autoimmune diseases, may also be a factor in the decision algorithm; using the more expensive treatment might lead to less expenditure over the lifetime of the patient. Epstein stressed that payers would be looking at specialists, key opinion leaders, and specialty societies to make these determinations and indicate when these drugs would best be used in the front line. There will need to be collaboration between specialists to determine the best treatment for each patient and minimize burden, King said. On the other hand, Epstein noted that the safety profiles of some of the new agents will also have to be considered.
In terms of managing costs, payers used to focus on disease states. However, that focus has switched dramatically to the drugs, Epstein explained. So, for JAK inhibitors, the focus of payers will not be on the use of this agent in vitiligo but on how to manage the use of JAK inhibitors more broadly. This change is putting pressure on insurance purchasers, which eventually gets passed down to patients through deductibles, coinsurance, and premiums. This is a challenge because patient affordability is likely to become an issue, Dunn said.
Rosmarin and King suggested that the fact that none of these therapies are specifically approved for the treatment of vitiligo is influencing their coverage and that approval of a new agent would change this scenario because they would be significantly less expensive than the new agent. Dunn suggested that a step approach, where patients must try a generic medication before getting approval for a biologic agent, may be a solution. However, Rosmarin cautioned that although a step approach may be reasonable for treatment of facial lesions, which respond well to calcineurin inhibitors, it would not be advisable for other areas such as the hands, which are notoriously challenging to treat. Therefore, the newer agents might be more adequate as first-line therapies for the extremities, genitals, and trunk.
Considering this, it is possible that payers may restrict coverage for the treatment of sensitive areas such as the head, neck, and hands, Epstein said. King agreed that this might make sense; however, he cautioned that these decisions should be driven by data. Physicians will always advocate for the patient to get the treatment, because having vitiligo in any part of the body can be debilitating. However, if the data say a certain treatment works well in one location but not so well in another, then it is reasonable that it should be covered for the locations where it works. Physicians would then have to make the argument if they want to use it for the location where it does not typically work as well.
On the other hand, this approach may be challenging to implement with the introduction of new agents such as ruxolitinib. Ruxolitinib has shown a significant effect in all areas of the body, with a greater effect on the face. This is not surprising, as all therapies work better on the face. If payers cover ruxolitinib treatment only for facial lesions, because that is where it is more effective, then patients would lose access to the best medication available for repigmentation of other areas, Rosmarin explained. However, he agrees that starting with a generic medication before introducing a JAK inhibitor may be the way forward, with the key being that these requirements are data driven.
The greatest unmet need for patients was the lack of an FDA-approved treatment for vitiligo, Rosmarin said. Vitiligo is a difficult disease to treat. Whereas all it takes for the disease to develop is an overactive immune system that destroys the melanocytes, treatment is a 2-step process. The immune system must be regulated so that there is a more hospitable environment for the melanocytes, which then must be coaxed to migrate back to the lesions. Treatment can often facilitate both processes.
JAK inhibitors, especially ruxolitinib, have shown the greatest promise for patients with vitiligo, Rosmarin said. Results from 2 phase 3 trials have shown that after 1 year of treatment with ruxolitinib cream, patients regain 75% or more of pigmentation on the face and 50% or more on the whole body. Furthermore, its safety profile is also promising, and it was approved for the treatment of atopic dermatitis in September 2021. The choice of JAK inhibitors for vitiligo was deliberate, King explained. JAK inhibitors disrupt the signaling pathway that induces the T cells to attack and destroy the melanocytes. Therefore, there are ample data to support the use of JAK inhibitors in vitiligo.
King mentioned the concept behind the REVEAL trial (NCT04338581) that is testing an antibody of IL-15, which is necessary for the survival of TRMs. Targeting IL-15 would dampen or even abolish the survival signal, which could lead to a durable disease remission without ongoing treatment. Although this provocative concept is not ready to be used in practice, it could revolutionize the field if it is safe and effective. Rosmarin added that depending on what the data show, there is a possibility that a combination of therapies including the IL-15 antibody at the end might be the best option for some patients.
In the next 5 years, it is expected that there will be several new agents approved for vitiligo, which will change how the disease is managed and will have implications for all stakeholders. This has already started with the approval of ruxolitinib cream and will probably be followed by oral JAK inhibitors and then other novel agents. Rosmarin concluded by saying, “There is going to be some work to do to decide how these different treatments fit into the paradigm, and we just don’t know that yet, but it’s important to be data driven and follow that pathway so we can make those best decisions for patients.”
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