EMERGING CONCEPTS FOR VITILIGO TREATMENT

In this review article, we will focus on the current concepts of the pathophysiology of vitiligo, as well as current treatment protocols. We discuss new treatment strategies including blocking interferon-gamma, or its downstream effectors like the Janus kinases (JAKs) using topical or systemic JAK inhibitors. Moreover, strategies for augmenting melanocyte proliferation, migration from hair follicles, and stem cell therapies are addressed. This information could serve to optimize the care of the vitiligo patient. Introduction Definition of Vitiligo Vitiligo is the formation of white macules on the skin as a result of the destruction of epidermal melanocytes. The close relatives of people suffering from vitiligo are at high risk of vitiligo and other autoimmune diseases. The comparative risk for first-degree relatives is nearly 6-18 fold high.

Also, the approximations for the heritability of vitiligo range at 46 percent in India to around 16 percent in China (Spritz, 2013). Other studies have revealed that the concordance for the disease among monozygotic twins is at 23 percent, enhancing the roles of genetic as well as non-genetic factors in the pathogenesis of the disease (Spritz, 2013). In itself, vitiligo has been known to have a notable history of detection and re-detection of major observations which are often ignored or even forgotten throughout time (Spritz, 2013). In a study conducted by Rothstein et al. (2017), 3 out of 11 patients were reported to have suffered from other autoimmune illnesses like the thyroid disease. The Importance of Vitiligo Numerous studies and evidence point out to the fact that vitiligo is more of a medical condition than a cosmetic condition.

Enough evidence shows that; Similar to other organ-specific diseases like psoriasis, type 1 diabetes as well as multiple sclerosis vitiligo is a serious autoimmune disorder which affects the epidermis of the skin-damaging the melanocytes as soon as it attacks (Sehgal & Srivastava, 2007). Besides, autoreactive cytotoxic T cells have a sihnificant role in causing the manifestation of vitiligo in humans. Furthermore, vitiligo is known to have a serious and permanent effect on the quality of life of an individual, particularly among younger individuals. Since vitiligo attacks younger individuals mostly before they reach 20 years, it results to stigmatization among these individuals at a very important time of their individual, psychological and professional development (Sehgal & Srivastava, 2007). A majority of such people, experience, stress, depression as well as anxiety which mostly brought about by their condition (Sehgal & Srivastava, 2007).

As a result, these individuals develop low self-esteem and withdraw themselves from the society. Furthermore, some ethnic groups banish the affected members of a family who fail in their social roles or may fail to fully interact with the rest of the society. These patches also display some form of symmetry like for instance patches may form on both knees and hands. The patches normally begin from the wrists, hands, mouth, feet or around the eyes. As well, this form of vitiligo may affect an individual at any age, implying that even an old individual may suffer from vitiligo. Although an individual may be suffering from the disease, there is a probability of fresh patches being observed over time. Also, the patches may affect any part of the body or specific regions of the body.

A differentiating feature of this type of vitiligo is depigmentation which occurs around the facial orifices and distal fingers. The disease may later affect other parts of the body leading to typical generalized vitiligo (Boniface et al. Studies have revealed that this form of vitiligo happens more frequently in the onset of vitiligo among adults. Also, acrofacial vitiligo affects the distal sections of the limbs as well as circumferential patterns on the orifices of the face. According to Karelson (2013), this subtype consists of around 3 to 12 percent of clinical research. The most common subgroup of Segmental Vitiligo is; Mono-segmental vitiligo This is considered as a widespread type of vitiligo. It is characterized by the appearance of either one or more white lesions which distribute themselves on one part of a person's body.

These lesions may display some progressive patterns like huge band Blaschko lines (Boniface et al. The etiology of the segmental vitiligo patters has remained elusive. In rare occasions, different segmental lesions take place simultaneously or fail to distribute themselves in a unilateral or bilateral manner. This reactive oxygen species may also develop a pro-inflammatory surrounding that influences the initiation of the immune system. Furthermore, vitiligo melanocytes may be as a result of the high intracellular oxidative stress, the present irregularities of signal transduction routes which are well-matched with a state of an impulsive senescence-like phenotype that has been induced by stress. This is described by the formation of numerous proteins in the secretory phenotypes that are associated with senescence, in addition to the formation of pro-inflammatory cytokines as cyclooxygenase-2, interleukin-6, matrix metalloproteinase, IGFBP7 and binding protein (Taïeb & Picardo, 2009).

Recent studies have also revealed that when melanocytes get exposed to chemical agents, the development of vitiligo is triggered which further triggers the disturbance of the compact apparatus of the endoplasmic reticulum resulting to the buildup of proteins that are not yet mature (Taïeb & Picardo, 2009). Consequently, the unfolded protein response is activated which later leads to a transient reduction of the synthesis of proteins maximizing the capability of the trafficking of proteins through the endoplasmic reticulum, protein folding transport as well as more protein derivative routes. Also, CCL5 and CXCL12 are added chemokines which take part in the homing of T cells to the skin that has been affected by vitiligo (Taïeb & Picardo, 2009). Furthermore, an increased in the level of oxidative stress as well as the destruction of the UPR activation or the routes which result to the death of cells in keratinocytes and melanocytes can stimulate the formation of pro-inflammatory cytokines with the activation of signals which are necessary for the stimulation of immune reaction in vitiligo.

Certainly, stimulation of the inherent immune system by activating the pathogen recognizing receptor is a vital process in host defense against pathogens (Taïeb & Picardo, 2009). However, it may be damaged in certain situations and may trigger autoimmunity in a patient that is genetically susceptible. Originally, the receptors specialize in the recognition of pathogens through molecular arrangements that are linked to pathogens (Taïeb & Picardo, 2009). Current Treatments It is crucial for clinicians to understand that the vitiligo disease is not simply cosmetic. Thus there are safe as well as effective current treatments for the disease. It is also necessary for them to identify both the common and rare characteristics of vitiligo and people with the active disease with its implications for future clinical management.

The current treatments for vitiligo include, • Topical and systemic immunosuppressants • Phototherapy and • Surgical techniques. All of these treatments work to prevent the disease from progressing, stabilize the development of the depigmented lesions and enhance the repigmentation of the skin. Systemic corticosteroids, on the other hand, act on the immune activity of the lesion as well as the T cells in outer circulation. Furthermore, apart from modulating the mediated immunity of T cells, corticosteroids also act to suppress the formation of autoantibody. Studies show that the serum of a patient with active vitiligo who have been administered with oral corticosteroids and displayed signs recovery were observed to have reduced cytotoxicity by the autoantibodies of the melanocytes as well as a minimized antibody titer to the surface antigen of the melanocyte (Khaitan & Kathuria, 2011).

For patients suffering from the rapidly advancing type of vitiligo, systemic corticosteroids are usually the first option for treatment. Systemic corticosteroids help in stopping the disease from progressing and triggers the process of repigmentation as the normal melanocytes from the outer areas of the lesions take over immediately the process of destruction of the melanocytes is captured. On the other hand, incoherent radiation can be released by different lighting systems and lamps. All the UVB phototherapy models should be utilized in combination with systemic or topical agents, therefore further broadening the treatment methods for patients with vitiligo (Castanedo-Cazares et al. Phototherapy with UVB comprises of the use of synthetic light minus the aide photosensitizing agents. This form of treatment is utilized in different dermatological conditions with the inclusion of atopic dermatitis, psoriasis among other dermatological disorders, lichen planus, graft-versus-host disease and seborrheic dermatitis and others (Adauwiyah & Suraiya, 2010).

UVB phototherapy in vitiligo normally leads to repigmentation, control of the disease and prevents the disease from progressing through its immune modulatory and immunosuppressive properties. Furthermore, other important considerations in the treatment of vitiligo include the extent of the body surface area that is involved. If there is a need for photoprotection of the different parts of the body or genital that seem sensitive, the incorporation of photosensitizing drugs, history of ultraviolet radiation exposure and the body surface area that was involved and other parameters. NB-UVB and BB-UVB treatments are administered through whole-body cabins which are equipped with the intended high-intensity light tubes either BB-UVB or NB-UVB. Ideally, the administration of NB-UVB should be conducted three times every week with a 24-hour treatment gap.

Besides, the period of treatment often extends to many months and may be narrowed down with time. This technique comprises of obtaining many circular grafts from the donor region which are taken with 3mm punches for the following transplantation to the area of reception (Gupta et al. This reception area is then prepared with equal sized punches in a design whose arrangement corresponds to the size of the graft by 2, 5 (Gupta et al. The adverse side effect of the technique is the production of unwanted cosmetic effects referred to as the cobblestone look which implies that the graft turns out to be a little elevated that the adjacent area of reception. Such an issue arises when the grafts with huge diameters are utilized.

However, such a result can resolve spontaneously and can as well as a treat with the use of electrofulguration. Cellular techniques Among the cellular techniques, there is the suspension of non-cultured cells of the epidermal layer of the skin. In this technique, a thin graft is obtained from the donating area using a razor blade or even a dermatome. Afterwards, the tissue fragment is placed in an incubator at 77-degree Celsius in a solution consisting of trypsin and ethylene dinitrilotetrascetic acid which isolates the dermis from the epidermal layer of the skin and ungroups the cells of the epidermis (Gupta et al. Following the centrifugation of the solution, a conc. Suspension of keratinocytes and melanocytes is obtained, then re-suspended in a small volume and later transplanted to the derma branded receiving area.

The biggest advantage of this method revolves around the fact that, there is a possibility of obtaining enough cells which can be used in treating large affected areas from a small fragment of the skin (Gupta et al. The method can result in the high rate of repigmentation when compared to methods that do not utilize culture cells. On the other hand, the dependence on a skilled team, huge costs and the dependence on special laboratory equipment serve as important disadvantages of this technique. Also, because the culture concentration contains mitogenic factors, a prolonged follow-up of people undergoing this form of treatment is crucial because of the theoretical possibility of post-transplantation malignant change. New Therapies for vitiligo The current therapies for vitiligo are inadequate in regards to their efficacy, and at times they may be linked with unwanted side effects.

As well, the level of involvement of the disease did not have an impact on the improvement of the facial vitiligo since the one patient who reported the highest affected body surface area experienced repigmentation of their facial skin. Also, the study showed that facial vitiligo responded well to ruxolitinib as compared to the rest of the body (Rothstein et al. Thus, there is a possibility that if ruxolitinib is applied to the skin near the eyelids may alleviate peripheral inflammation as well as it allows for periocular repigmentation. The most commonly noted adverse effect of the treatment was erythema of the skin among 72 percent of the patients undergoing treatment with ruxolitinib (Rothstein et al. Other patients experienced mild acne on their facial skin while another patient reported a worsened state of the existing facial acne.

Other patients reported a mild rise in the level of lipids (Liu et al. But no serious side effects were observed following this type of therapy. Patients who were given oral JAK inhibitors seemed to display repigmentation primarily in the areas that were exposed to the sun. As well, the study noted that the face, which is an area exposed to sunlight responded excellently to the treatment. A few important observations were noted including, the treatment of vitiligo by tofacitinib needs sun exposure whereby low doses are enough to attain repigmentation. Also, they may suggest the form of treatment that is suitable for a specific patient with vitiligo. In the study, the stem cells demonstrated the capacity to renew themselves as well as self –separating into melanocytes which are necessary for repigmentation to occur (Kumar et al.

Thus, the availability of stem cells in the glabrous skin that has formed lesions and can self-renew as well as separate into melanocytes is a source of hope for patients with vitiligo having lesions formed on the glabrous skin. But, it is rare and challenging to observe the repigmentation of the glabrous lesional skin with the available forms of treatment (Kumar et al. It is thus clear that the existing treatments are until now not efficient enough to trigger the differentiation of the dermal stem cells as well as their movement to the lesional epidermis. Inhibiting IFN-y like the Janus Kinases may turn out to be an efficient method of treating vitiligo. JAK inhibitors that have been accepted by the US Food and Drug Administration include; ruxolitinib and tofacitinib.

Patients who were given oral JAK inhibitors seemed to display repigmentation primarily in the areas that were exposed to the sun. Other new therapies involve augmenting melanocyte proliferation/migration with melanocyte stem cell therapy. The loss of melanocytes leads to a depigmentation on the visible layers of the skin. Repigmentation through melanocyte regeneration in vitiligo. Dermatol. Clin. 35 : 205-18 Boersma BR, Westerhof W, Bos JD. Repigmentation in vitiligo vulgaris by autologous minigrafting: Results in nineteen patients. Repigmentation patterns induced by NB-UVB and their relationship with melanocytic migration and proliferation in vitiligo. Photodermatol. Photoimmunol. Photomed. 32 : 269-75 Czajkowski, R. Acad. Dermatol. 76 : 736-44 Gupta, S. , Narang, T. , Olsson, M. Systemic Corticosteroids in Vitiligo. In Vitiligo-Management and Therapy. InTech. Kumar R, Parsad D, Rani S, Bhardwaj S, Srivastav N.