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Davinder Parsad1, Sanjeev Kandhari2, Rachita Dhurat3, Bela Shah4, Imran Majid5, Harikishan Kumar Yadalla6, Jagdish Sakhiya7, Shital Poojary8, P Jagadish9, Pravin D Banotkar10, Ravindra Babu11, YM Shivakumar12, SK Bose13, Saleem Jamadar14, Monal Shah15, Bharat Tank16, Ravindra Dhabhai17, Sanjay Kumar Mittal18, Premanshu Bhushan19, Akshi Pandita19, Vaibhav Barve20
1 From the Department of Dermatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Kandhari's Skin and Dental Clinic, Srinagar, Jammu and Kashmir, India
3 Department of Dermatology, LTMMC, Sion Hospital, Srinagar, Jammu and Kashmir, India
4 Department of Dermatology, B. J Medical College and Civil Hospital, Srinagar, Jammu and Kashmir, India
5 Cutis Clinic, Srinagar, Jammu and Kashmir, India
6 Department of Dermatology, Venereology and Leprosy, Rajarajeshwari Medical College, Surat, Gujarat, India
7 Sakhiya Skin Clinic, Surat, Gujarat, India
8 Department of Dermatology, KJ Somaiya Medical College, Bengaluru, Karnataka, India
9 Cuticare Centre, Bengaluru, Karnataka, India
10 Saifee Hospital, Bengaluru, Karnataka, India
11 Raga Clinic, Bengaluru, Karnataka, India
12 Inchara Skin Clinic, Mysore, Karnataka, India
13 Indraprastha Apollo, Gadag, Karnataka, India
14 Shifa Clinic, Gadag, Karnataka, India
15 Haribhakti Skin Clinic, Ahmedabad, Gujarat, India
16 Amrut Skin Clinic, Rajkot, Gujarat, India
17 Sikar Hospital and Research Centre, Sikar, Rajasthan, India
18 Mittal Skin Clinic, Jaipur, Rajasthan, India
19 Dr. P N Behl Skin Institute, New Delhi, Delhi, India
20 KJ Somaiya Medical College, Mumbai, Maharashtra, India
Correspondence Address:
Sanjeev Kandhari
Kandhari's Skin and Dental Clinic, F Block, 11, Munirka Mark, Vasant Vihar, New Delhi – 110 057, Delhi
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ijd.ijd_461_23
Abstract
Background: Treatment of vitiligo is still a challenge in dermatology. Literature is sparse on the definitive clinical role of basic fibroblast growth factor (bFGF) in vitiligo patients. Aims: We decided to generate a consensus in an attempt to answer some critical questions related to the management of vitiligo and the role of bFGF. Materials and Methods: A Delphi method among 21 experts across India was conducted. A consensus (agreement was 75% or greater) was taken on 27 statements on the prevalence, epidemiology, and treatment of vitiligo and the role of bFGF in the management of vitiligo. The consensus process was completed after two rounds. Results: Topical corticosteroid therapy is the first-line therapy for vitiligo; however, its adverse effects are widely known, especially in sensitive areas. Topical calcineurin inhibitors are preferred in stable vitiligo of the face, neck, genitals, or intertriginous regions as an alternative to topical corticosteroids. Topical bFGF is a relatively newer therapy with a promising role in stable vitiligo. bFGF is safe and effective in inducing repigmentation of vitiligo lesions. Combination therapy of bFGF with other topical therapies, phototherapy, and surgical procedures can be beneficial in patients of vitiligo. Conclusion: This consensus would complement the currently available literature on bFGF and help the practitioner to recognize the unmet need in the treatment of vitiligo.
Keywords: bFGF, consensus, Delphi method, recommendations, vitiligo
Background 
Vitiligo is a multifactorial common depigmenting skin disorder with a worldwide prevalence of 0.5–2%. The disease is characterized by the absence of pigment in the skin due to selective loss of melanocytes.[1] Though vitiligo is an autoimmune condition, multiple factors are responsible for its pathogenesis. The most accepted etiology of vitiligo is the autoimmune hypothesis. However, the deficiency of basic fibroblast growth factor (bFGF) also has established a significant role in melanocyte homeostasis.[2]
Based on the available literature, bFGF may be involved in repigmentation in patients with vitiligo.[3] However, the clinical evidence which can define the role of bFGF is limited. Against this background, we decided to generate a consensus to answer some critical questions related to the management of vitiligo and the role of bFGF by using the Delphi method. This consensus includes statements on the prevalence, epidemiology, and treatment of vitiligo and the role of bFGF in the management of vitiligo.
Materials and Methods We included two core committee members and 21 experts (all of whom were dermatologists) for the generation of consensus by the Delphi method. A total of 27 statements were finalized for the generation of consensus with the help of core committee members. A first round of a Delphi voting process was conducted by sending these 27 statements to all the experts over an email. Responses of the first round were collected in the form of “'agree' or 'disagree.” The agreement was defined when statements received a response of “agree.” Statements were included wherein the agreement was 75% or greater. After the first round of voting, statements were redrafted with the help of core committee members, if 75% agreement was not achieved. The second round was conducted individually, with each member using an online survey tool to assess the level of agreement. After the completion of this process, results were analyzed, and recommendations were proposed with a corresponding expert agreement and grading of the level of relevant evidence [Table 1]. This methodology did not need the ethics committee approval.
Table 1: Levels of evidence based on Oxford Center for Evidence-Based Medicine[4] Results Vitiligo Prevalence and Epidemiology
Vitiligo is the most common depigmenting disorder, with a prevalence of 0.5– 2% worldwide.[1] In this consensus, 90% of the experts agreed that vitiligo is most commonly seen in the age group of 10–30 years. A review by Sehgal and Srivastava[5]. showed that almost 50% of the patients reported vitiligo before the age of 20 years and about 70–80% of patients before the age of 30 years. A study by Hann and Lee[6] stated that vitiligo usually occurs at a younger age with the onset at 10–30 years. In this consensus, 90% of the experts agreed that the prevalence of vitiligo is equal in both males and females. A study conducted by Das et al.[7] in India also reported the same in their study. An epidemiological study of 2624 vitiligo patients also stated that vitiligo equally affects both males and females. However, in some studies prevalence of vitiligo is more in females, which can be due to concerns or a higher tendency of autoimmune diseases in the female population.[8]
About 81% of the experts in this consensus opined that nonsegmental vitiligo is the most common form of vitiligo, among which generalized vitiligo is the most common. In the literature, it is mentioned that the nonsegmental type of vitiligo is the most common type. In addition, generalized vitiligo is the most common subtype of nonsegmental vitiligo.[1],[9],[10] This consensus showed 95% of agreement on the incidence of segmental vitiligo at a younger age than nonsegmental vitiligo. A cross-sectional study by Ezzedine et al.[10] has described similar outcomes. Vitiligo European Taskforce (VETF) formed a consensus on vitiligo, reporting similar agreement about the early age of onset of segmental vitiligo than nonsegmental vitiligo.
In this consensus, 86% of the experts agreed with the role of genetic factors in the predisposition of vitiligo and the association of vitiligo with thyroid disorders and other autoimmune diseases (Refer [Table 2]). Epidemiological studies have established the strong family predisposition of vitiligo.[11],[12],[13] A meta-analysis also showed a significant association of human leukocyte antigen A2 (HLA-A2) with vitiligo and its associations with other class I and II genes of major histocompatibility complexes, for example, and human leukocyte antigen-DR4 (HLA-DR4).[14],[15] A meta-analysis highlighted the association of thyroid disorders with vitiligo. Subclinical hyperthyroidism, overt hyperthyroidism, Graves' disease, subclinical hypothyroidism, overt hypothyroidism, and Hashimoto's thyroiditis were the main thyroid disorders. The highest prevalence of vitiligo was seen in subclinical hypothyroidism.[16] Another meta-analysis of 14 observational studies has established an association between atopic dermatitis and vitiligo.[17] Many studies also have demonstrated the association of vitiligo with other autoimmune diseases, like alopecia areata, rheumatoid arthritis, type 2 diabetes mellitus, Addison's disease, pernicious anemia, and systemic lupus erythematosus and psoriasis.[8],[18],[19]
Table 2: Consensus recommendations for vitiligo prevalence and epidemiologyDiagnosis and Treatment of Vitiligo
Vitiligo can be easily diagnosed based on clinical findings like chalky-white patches with distinct margins.[1] According to the established literature, the presence of characteristic clinical features is sufficient for the diagnosis of vitiligo and does not require any confirmatory laboratory tests.[20],[21],[22],[23] Concordantly, in our consensus, 81% of the experts agreed that clinical findings are sufficient to diagnose a patient of vitiligo, other lab investigations are not needed, and 76% of experts agreed that Wood's lamp examination has limited role in clinical practice, especially in the Indian setting.
Treating vitiligo is still a challenge, despite the availability of vast management options. These treatment modalities include topical therapy, systemic therapy, phototherapy, and surgical techniques. All these options may conjointly help to limit the progression of disease and stimulation of repigmentation.[1] In this consensus, 76.2% of the experts agreed that topical corticosteroids (TCS) are the first-line therapy for stable vitiligo. According to guidelines available on vitiligo, TCS are recommended first-line therapy for vitiligo.[24],[25] In a meta-analysis, Njoo et al.[26] evaluated the effectiveness of TCS in localized vitiligo. They have reported that TCS as a monotherapy achieved ≥75% repigmentation and is preferred as a first-line option for the treatment of vitiligo. However, the known adverse effect profile of TCS includes atrophy, striae, telangiectasias, hypertrichosis, and acneiform reactions. In addition, a few areas of skin, viz. face, neck, genitals, and intertriginous skin are more sensitive to TCS and susceptible to more side effects due to higher dermal absorption. In this consensus, 100% of the experts agreed that topical calcineurin inhibitors (TCI) should be preferred in patients with stable vitiligo of the face, neck, genitals, or intertriginous regions, as an alternative to TCS. Available literature also recommends TCI as a preferred agent for vitiligo in these areas.[27],[28],[29] In a meta-analysis, Lee et al.[30] reported that usage of TCI in patients of vitiligo, with lesions on the face and neck, resulted in a favorable therapeutic response and recommended TCI monotherapy for these patients.
Phototherapy is a traditional treatment option for vitiligo and the treatment of choice for progressive or stable vitiligo.[25],[31] Studies state, phototherapy, in combination with topical monotherapies, is superior to using topical therapy alone. Similarly, in this consensus, 100% agreed on this recommendation. In a meta-analysis performed by Lee et al.[30] the responses to treatment with TCI plus phototherapy were higher than TCI monotherapy. A study by Khullar et al.[32] reported the synergistic action of topical vitamin D analog and phototherapy. According to the British Association of Dermatologists guidelines for the management of vitiligo 2021, phototherapy can be combined with TCI or potent TCS for localized vitiligo.[25] In our consensus, 95% of the experts also agreed that combination therapies (e.g. TCS + bFGF or TCI + vitamin D analogs or TCS + excimer laser) should be preferred when vitiligo is extensive or not responding to the monotherapies. According to published guidelines, systemic corticosteroids (SCS) are administered in cases of rapidly progressive active vitiligo.[25],[27] About 95% of the experts in this consensus agreed that systemic corticosteroids alone or in combination with phototherapy should be administered to treat rapidly progressive vitiligo (Refer [Table 3]). The main objective of SCS use is to suppress the immune response, stabilize, and arrest the disease activity.[33],[34],[35]
Table 3: Consensus recommendations for diagnosis and treatment of vitiligoRole of basic fibroblast growth factor (bFGF) in Vitiligo
Statement 1: bFGF can be prescribed as a monotherapy in patients of stable vitiligo with limited involvement
There is a scarcity of literature on the usage of bFGF as monotherapy for vitiligo. A prospective, comparative, and interventional study by Subhashini et al. compared the efficacy and safety of 0.1% bFGF solution against the betamethasone valerate (BV; 0.1%) ointment, in 62 patients of vitiligo. The authors reported that at the end of 16 weeks, the percentage of repigmentation was significantly greater in the bFGF group than in the betamethasone group (P < 0.05).[36] In this study, topical bFGF was found to be more efficacious than topical BV 0.1% ointment, without any major side effects.
Conclusion: bFGF can be prescribed as a monotherapy in patients of stable vitiligo with limited involvement. (Level of evidence: 2b, Agreement: 95%).
Statement 2: bFGF should be prescribed as an adjuvant therapy for patients of stable vitiligo
According to the available published literature, bFGF can be given as an adjuvant therapy along with tacrolimus and narrowband ultraviolet light (NBUVB). A phase IV randomized study by Parsad et al.[2] compared the topical combination of bFGF and tacrolimus, to tacrolimus monotherapy in stable vitiligo. The authors reported that after 12 months of treatment, the combination of bFGF and tacrolimus showed significantly greater repigmentation and response rate in stable vitiligo patients than tacrolimus monotherapy. A multicenter randomized study conducted by Ramaiah et al.[3] compared the combination of bFGF and NBUVB to NBUVB alone. The study reported that NBUVB plus bFGF, was superior to NBUVB alone, with respect to the achievement of a greater percentage of repigmentation in vitiligo macules after 3 months of treatment.
Conclusion: bFGF can be prescribed as an adjuvant therapy for patients of stable vitiligo. (Level of evidence: 1b, Agreement: 90%).
Statement 3: bFGF can be a better option as an adjuvant to steroids, as it reduces potential long-term side effects of steroid therapy and leads to a higher response rate with a faster onset of repigmentation
Vitiligo management requires long-term treatment. However, long-term therapy with potent topical steroids can cause potential side effects like skin atrophy, striae, telangiectasias, acneiform eruptions, etc.[37] No substantial literature is available for the combination therapy of steroids and bFGF. However, a study by Subhashini et al.[36] states that faster repigmentation is achieved with bFGF treatment compared to Betamethasone Valerate.
Conclusion: No study evaluating the role of bFGF as an add-on therapy to steroids in vitiligo treatment. However, based on the consensus achieved, bFGF can be given as an adjuvant therapy with topical steroids. (Level of evidence: Not graded, Agreement: 95%).
Statement 4: bFGF gives better results as an adjuvant therapy when used with tacrolimus in patients of vitiligo
A phase IV, randomized, open-label, prospective study by Parsad et al. compared the topical combination of bFGF and tacrolimus to tacrolimus monotherapy in stable vitiligo, after 12 months of the treatment. They carried out an interim analysis after 6 months of treatment.
The study concluded that the combination of bFGF and tacrolimus showed significant improvement in the extent of repigmentation (achieving more than 50% of repigmentation) as compared to tacrolimus alone. Also, a significantly higher mean response rate was observed in the combination group than in tacrolimus monotherapy.[2],[38]
Conclusion: bFGF gives better results as an adjuvant therapy when used with tacrolimus in patients of vitiligo. (Level of evidence: 1b, Agreement: 95%).
Statement 5: Tacrolimus should be applied in the morning and bFGF in the night when prescribed together as a combination therapy
In a study where a combination of bFGF and tacrolimus was given to the patients of stable vitiligo, suggested that bFGF solution should be applied at bedtime daily, followed by morning exposure to sunlight for 5–10 min. In the study, patients applied tacrolimus twice daily; however, the details of the diurnal frequency are not mentioned.[2],[38]
Conclusion: Tacrolimus can be applied in the morning and bFGF at night when prescribed together as a combination therapy. (Level of evidence: Not graded, Agreement: 90%).
Statement 6: Phototherapy shows faster repigmentation when used with bFGF in patients of vitiligo
A multicenter randomized, double blind phase IV clinical trial by Ramaiah et al. concluded that NBUVB in combination with bFGF was effective, and the repigmentation of vitiligo macules was achieved faster than NBUVB alone. The authors also further add that both drugs act synergistically when given as a topical therapy. The effect of bFGF on sun exposed vitiligo macules may be considerably greater than non sun exposed vitiligo macules.[3],[39]
Conclusion: Phototherapy shows faster repigmentation when used with bFGF in patients of vitiligo. (Level of evidence: 1b, Agreement: 100%).
Statement 7: Using bFGF along with surgical procedures gives better results in patients of vitiligo
The study by Esmat et al.[40] reported that the addition of bFGF to the medium used in the autologous melanocyte keratinocyte transplantation procedure (MKTP) improved the results of the procedure. No other study reported that the addition of bFGF with surgical procedures gives better results. However, in our consensus, 90% of the experts agreed that the usage of bFGF in surgical procedures would give better results.
Conclusion: Using bFGF along with surgical procedures can give better results in patients of vitiligo. (Level of evidence: 2b, Agreement: 90%).
Statement 8: bFGF should be applied once daily (OD) at night, followed by sun exposure for 10 minutes the next morning
Studies on bFGF mentioned the treatment schedule of bFGF use should be at bedtime daily on the vitiligo lesions, followed by exposure to sunlight the next morning for 10–20 min.[2],[41] Published studies found that sun exposure after bFGF application would lead to greater repigmentation than nonexposed vitiligo macules.[3]
Conclusion: bFGF should be applied (OD) at night, followed by sun exposure for 10 minutes the next morning. (Level of evidence: 1b, Agreement: 95%).
Statement 9: bFGF should be prescribed at least for 3 months or more for the visible results in the treatment of stable vitiligo
Randomized phase IV studies by Ramaiah et al.[3],[39] used bFGF for a period of 3 months in patients of vitiligo. Subsequently, patients showed effective repigmentation of vitiligo patches. Overall, vitiligo treatment takes a longer duration to show effective repigmentation. Some studies of bFGF were carried out for different duration of treatment, like 4 –12 months.[2],[36],[41]
Conclusion: bFGF should be prescribed at least for 3 months or more for the visible results in the treatment of stable vitiligo. (Level of evidence: 1b, Agreement: 100%).
Statement 10: bFGF therapy may take time for initial improvement of vitiligo, however, long-term therapy results are satisfactory
Two studies on bFGF therapy observed its long-term effects in patients of vitiligo. Parsad et al. studied the effects of the topical combination of bFGF and tacrolimus for 12 months. Significant improvement was noted in terms of the extent of repigmentation with combination therapy. Waheed et al.[2],[41] studied bFGF therapy in patients of stable vitiligo for 9 months, along with 6 months of posttreatment follow-up. bFGF had shown effective regimentation, both at the end of the 9-month treatment and after 6 months of the follow-up period.
Conclusion: bFGF therapy may take time for the initial improvement of vitiligo, however, long-term therapy results are satisfactory. (Level of evidence: 4, Agreement: 100%).
Statement 11: bFGF is effective in inducing repigmentation and safe for treating vitiligo in children
All the available studies of bFGF included patients of above 18 years of age. A single study by Subhashini et al.[36] included patients of age 12 years and above. In this study, bFGF was given as a monotherapy for 12 weeks and found to be efficacious and safe without any major side effects. No studies of bFGF therapy in children below the age of 12 years are available.
Conclusion: According to consensus, bFGF can be considered as a potential option for treating vitiligo in children. (Level of evidence: Not graded, Agreement: 95%).
Statement 12: bFGF is a safe therapy option for the treatment of vitiligo
Studies describe topical bFGF to be safe in vitiligo patients aged 18–60 years. bFGF has shown a favorable safety profile and was well tolerated without any major side effects.[2],[36]
Conclusion: bFGF is a safe therapy option for the treatment of vitiligo. (Level of evidence: 1b, Agreement: 100%).
Statement 13: bFGF can be used in treating cosmetically important areas like the face, neck, and periorbital area
Face, neck, and periorbital areas are cosmetically important, as well as the sensitive regions owing to higher absorption of the drug. According to many authors, TCI are preferred for these areas.[28],[29],[42] study of topical bFGF in facial, neck, and periorbital vitiligo is not available. However, Waheed et al.[41] included 19 out of 75 vitiligo patients of focal vitiligo, with the face being the most common site. bFGF had shown effective repigmentation in these patients. A review by Razmi et al.[43] mentioned that bFGF can be used as first-line agents for facial vitiligo along with TCI.
Conclusion: According to consensus, bFGF can be used in treating cosmetically important areas like the face, neck, and periorbital area. (Level of evidence: Not graded, Agreement: 90%).
Statement 14: bFGF is considered as a potential therapy option for the treatment of mucosal vitiligo, like lip vitiligo
Waheed et al.[41] compared the repigmenting effects of two drugs; Unani herbal drug and bFGF on stable (segmental, mucosal, and focal) vitiligo. Results showed that bFGF was effective on mucosal vitiligo. Mucosal vitiligo (lip being the commonest site) is considered the most resistant vitiligo, however, it had excellently repigmented with bFGF. No other studies showed the effects of bFGF on mucosal vitiligo.
Conclusion: bFGF can be considered as a potential therapy option for the treatment of mucosal vitiligo, like lip vitiligo. (Level of evidence: 4, Agreement: 90%). The Consensus recommendations for the role of basic fibroblast growth factor have been summarized in [Table 4].
Table 4: Consensus recommendations for role of basic fibroblast like growth factor (bFGF) in Vitiligo Conclusion The management of vitiligo is complex due to inconsistency in clinical improvement and high relapsing rates. Therapy should be patient-oriented according to vitiligo type, its progression, and side effects of the drugs. No known conventional treatment can consistently produce repigmentation in all patients of vitiligo. To address this, we have generated evidence-based statements on the role of bFGF in the management of vitiligo, with the aim of adding the clinical experience of dermatologists. This consensus concludes that bFGF can be used as a monotherapy in patients of stable vitiligo with limited involvement as well as can be effective as an adjuvant therapy in the management of vitiligo. It is a safe option for the treatment of vitiligo and can be considered as a potential therapy in the treatment of mucosal vitiligo, like lip vitiligo. However, further clinical studies are required to strengthen the recommendations.
Acknowledgements
We acknowledge the contribution of Zydus Healthcare Ltd. for its scientific and logistic support. The views expressed and stated in this consensus article are the views of the authors and not of Zydus Healthcare Ltd.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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