The Prevalence and Treatment Options of Melasma as Well as its Association with Quality of Life in Darker Skin Types: A Scoping Review Protocol

Melasma is one of the most encountered dermatoses in dermatology and skin care clinics. It is a challenging chronic, recurrent condition associated with hyperpigmentation. Its etiology is poorly understood. Melasma affects all races and gender but is more prevalent in women with darker skin types. Being a facial lesion, melasma has a severe impact on quality of life due to its disgurement. While many modalities of treatment for melasma exists, unfortunately, effectiveness and safety remain a huge concern. Treatment modalities are variable and often unsatisfactory. The objective of this scoping review is to systemically map available evidence from literature regarding melasma, garner insight as to how melasma affects the quality of life and begin to investigate and gain understanding on effectiveness of different treatments used for melasma.


Background
Melasma remains a huge medical burden. Melasma is one of the most common hyperpigmentation skin disorders seen more frequently in pigmented skin individuals (Black, mixed ancestry, Indians, Hispanics and African Americans) (1)(2)(3). In a study conducted in South Africa in the public sector by Dlova et al, 2019 pigmentation disorders are in the top 5 skin conditions seen, with melasma accounting for most of the cases (4). While this skin disorder is common among women, men also get affected (5, 6). There is no known cure for melasma and currently, available treatment is meant to either halt, stabilize or improve the appearance and progression of the condition (7)(8)(9). The current standard treatment for melasma includes the use of hydroquinone which is the standard benchmark and other depigmenting agents like arbutin, kojic acid and retinoids (6, [10][11][12][13]. Some of these therapeutic modalities have side effects like contact dermatitis and ochronosis, especially if used for long periods at higher concentrations without proper monitoring by dermatologists. Due to its complex pathogenesis, melasma is challenging to treat and can be quite dis guring. There is a convincing body of knowledge showing evidence of a negative impact on the quality of life of those affected (14)(15)(16)(17)(18).
Concerns about side effects and the long-term safety of current melasma interventions have spurred efforts to develop alternative treatment options. In rural arrears, black African women use, among others, indigenous plants, for example, Cassipourea anaganii in an attempt to treat hyperpigmentation disorders (19)(20)(21)(22). However, C. anaganii is rapidly becoming extinct as it is highly sought after by the communities (19,20,(22)(23)(24). It is known that prolonged use of skin lightening products, has been proven to be a signi cant problem for public health as such use can lead to therapeutic failure and drug resistance which could result in death (25,26). Most of these ingredients are harmful and pose a health risk considering the frequency of application, the duration of practice, the area of the body involved, their use during pregnancy and lactation put their developing foetus or infants at high risk (27,28). Likewise, prolonged use of C. anaganii may pose health risks similar to skin lightening products.
The aim of this scoping review is to map evidence from literature on effects of melasma and glean available information on e cacy of various interventions used to treat melasma on darker skin types.
Insights gained from this study will help identify and guide the development of an alternative, safe and cost-effective treatment for melasma, which can be locally manufactured in South Africa. Most therapeutic interventions for melasma are imported, making the costs exorbitant and not accessible to the poor of the poorest, resulting in abuse of unsolicited over the counter banned skin bleaching creams.
In addition to commercialisation through cultivation, it is anticipated that knowledge gained will contribute toward the creation of bene ciation for rural communities through the biodiversity act for the indigenous communities, particularly during recent times where unemployment rates are skyrocketing in SA.

Methodology
The purpose of this scoping review is to systemically map available evidence from literature regarding the prevalence of melasma, garner insight as to how melasma affects the quality of life and begin to investigate and gain an understanding of the treatments used for hypermelanosis. Furthermore, insights gained from this scoping review will enable and generate a deep scienti c understanding when dealing with melasma and may help enhance the current melasma treatment armamentarium.
The research question that guides this scoping review is: What effect does melasma have on darker skin types and what information is available on e cacy of various treatment interventions?
To answer the question, a scoping review will be conducted. Guided by Arksey and O'Malley's framework (29) enhanced by Levac et al., 2010 (30) and the 2015 Joanna Briggs Institute's guidelines (31), evidence in the literature regarding melasma will be mapped. In accordance with this methodological framework, the systematic search will include the six-stage framework as follows: 1. identifying the research question, 2. identifying relevant studies, 3. study selection, 4. charting the data, 5. collating, summarizing, and reporting the articles, and 6. consultation (knowledge translation). To ensure no steps are omitted, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis: Extension for Scoping Review guidelines (PRISMA-ScR) will guide the process (32) (Figure 1). Furthermore, the results will be summarized and presented using the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 checklist to ensure a rigorous process (33).
A systematic search to synthesise literature for published and unpublished records and articles will be undertaken. The Preferred Reporting Items for systematic Reviews and Meta-analyses (PRISMA) guidelines and the Population, Exposure, and Outcome (PEO) framework for determining the eligibility of the research question (Table 1) will be followed. Since the study will utilise a secondary synthesis of data, ethical approval and consent to participate in the study are not necessary as evidence is already available in the public domain. 4. Are there any acceptable, safety systematic pro le after a long-term use of these treatments?
A Population, Exposure, Outcome (PEO) framework will be applied to adequately address the research question and eligibility of selected and included literature (Table 1). For population, we will include studies done on all people, both male and female, who are classi ed as darker skin types who suffer from facial melasma. For exposure, we will include studies of treatments used for melasma and for outcome we will look at e cacy of treatment, reported toxicity and a possible improvement in quality of life. Types of treatment interventions used for melasma include medical and non-medical interventions. Studies could be published in any language and will not be limited by time frame to ensure that we cover the breadth and comprehensiveness of the available literature. Studies with no evidence of melasma treatment interventions will be excluded as well as studies that investigated extra-facial melasma. The range of evidence will include different methodologies from qualitative to quantitative in nature. Sources such as grey literature and unpublished theses and dissertations will be included. Cochrane, CINAHL Complete, ScienceDirect, and Web of Science Core Collection will be conducted to attain published peer-reviewed articles of all study designs excluding reviews. This literature search will not be restricted by language or date of publication. All studies included in the review will be amalgamated and stored using the Endnote x 20 library to avoid duplicates in the database (34). We will work closely with the librarians from University of Pretoria and Durban University of Technology during database searching and retrieval of articles. A search strategy using Boolean terms 'AND' and 'OR' to separate search words and terms as well as MeSH terms and keywords will be used. The search results with keywords, search string, Boolean terms, databases and the number of articles retrieved will be recorded on an electronic database search recording table (Table 2). To obtain additional literature, a hand search of included articles reference lists will be conducted.

Framework stage 3: study selection
Articles and records will be regarded as either eligible for inclusion or exclusion if they meet the following criteria:  Table 2. To reduce any selection bias, screening of study titles and abstracts from the databases listed above will be conducted by two investigators independently. The principal investigator will screen titles of all records retrieved from database search and export all eligible records to the endnote library. Using google forms, the two reviewers (primary and secondary authors) will review in parallel all abstracts applying the inclusion criteria to determine eligibility of the selected and identi ed records. Google forms will also be piloted to ensure all screeners understand how to utilize the tool. Both reviewers will subsequently conduct full-text screening of all eligible records. Discrepancies between the two reviewers will be resolved through discussion and by inviting a third reviewer. To determine the level of agreement between the two reviewers, the kappa statistics will be used (35). A kappa statistic of >0.21 will be considered acceptable agreement while >0.61 will be considered as an adequate agreement and 0.81-0.99 will be considered as almost perfect agreement. Framework stage 4: charting the data Data charting form, will be designed using google forms (Table 3). Data chart form will be independently populated electronically by the screeners with all literature that possesses characteristics and the key information relevant to the review question. The data chart form will be piloted by the two independent reviewers using a random sample of 5 included articles for consistency. The results will be presented as a 'map' of the data in a logical table form that aligns to the research question and scope of the review. During this iterative process the data charting form will be kept current by regularly updating it to ensure accuracy and rigour. This process comprises of three stages 1. descriptive, thematic, and quantitative analysis 2. reporting the results, and 3. identifying literature gaps for future research. The themes from the extracted data will be examined in relation to the aim of the study which is to map evidence from literature on effects of melasma and glean available information on e cacy of various interventions used to treat melasma on darker skin types. A narrative report will be produced to summarize the extracted data around the following outcomes: interventions used to treat melasma; prevalence of melasma; effects of melasma on quality of life and e cacy. These results will be described in relation to the research question and the context of the overall study purpose. The review results will be published in a peer-reviewed journal and presented at relevant conferences.

Quality appraisal
To determine the quality of the selected studies, this review will utilize the Mixed Method Appraisal tool (MMAT) version 2018 to appraise all included evidence. This will help avoid any risk of bias and also ensure that all evidence included in the study is appropriate (36). The MMAT is a critical appraisal tool designed for the appraisal stage of systematic mixed studies reviews, for example, reviews that include both quantitative and qualitative as well and mixed methods studies (36). According to Hong et al (2018), the MMAT tool permits appraisal of the methodological quality of ve categories of studies as follows: 1. qualitative research, 2. randomized controlled trials, 3. non-randomized studies, 4. quantitative descriptive studies, and lastly 5. mixed methods studies. The two screeners will be responsible for assigning ratings such as 100% for high average articles, 75% for above-average articles, 50% average and 25% for lowquality articles.

Discussion
This scoping review aims to identify and describe the effects of melasma on those who suffer from it by systematically mapping the evidence available in literature, garner insight on its prevalence and how melasma affects the quality of life and to investigate and gain an understanding of the e cacy of different interventions used for hypermelanosis on darker skin types. Numerous treatment interventions such as hydroquinone (HQ), kojic acid, arbutin, chemical peels, micro-needling, lasers and lights are used to manage melasma, however the effectiveness of these treatment interventions is limited due to their adverse effects (6, [10][11][12][13]. Currently, there is no cure for melasma and treatment is meant to be chronic to try and minimize progression. Being a facial dis guring lesion, many authors have published data showing evidence of a negative impact on the quality of life of those affected by the condition (7)(8)(9). In rural areas women use plants including c. anaganii in an attempt to resolve hypermelanosis, however the plant is becoming extinct due to over harvesting (19,20,(22)(23)(24), also long-term systematic effects due to prolonged use of this plant are not yet known.
Melasma is reported to be a huge medical burden. It has been highly reported in patients of Hispanic, African American, Arab, South East Asian, East Asian and African descents (1)(2)(3). Despite numerous attempts to resolve the problem, it is evident that the problem still exists. While many modalities of treatment for melasma exist, unfortunately effectiveness and safety remain a huge concern. Treatment modalities are variable and often unsatisfactory. This portrays a lack of ideas when optimal relief cannot be offered.
The insights gained from this proposed scoping review could help enhance the scienti c understanding on how to address melasma. Insights gained from the study could assist in commercialisation and in addition create bene ciation for rural communities. Possible outcomes for this study may include the identi cation of a holistic, safe and cost effective alternative and desirable treatment plan for melasma which can be locally manufactured in South Africa, therefore adding to the current treatment melasma armamentarium and in turn improving the quality of life. We plan to disseminate the study's ndings in peer-reviewed journals and at conferences that focus on dealing with hypermelanosis and present at both international and national seminars. This study could assist in mapping out literature gaps pertaining to treatment of melasma in darker skin types. The results will help offer recommendations on how further research can address and close these gaps.

Limitations
The study results will be limited by skin types as it only focuses on darker skin types. Strict time lines will be adhered to. Availability of data and materials All data generated or analysed during this study will be included in the published scoping review article and will be available upon request.
Ethics approval and consent to participate Not applicable Consent for publication

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