Clinical patterns and associated comorbidities of vitiligo in Kandahar, Afghanistan. A case-control study

Vitiligo is an acquired, idiopathic depigmentation disorder of skin and hair with characteristic white macules and patches. Vitiligo affects 0.1–2% of global population [1]. Highest incidence of this disorder is observed in India and Mexico [2]. In India, its prevalence is nearly 3–4% of patients visiting skin clinics of different hospitals [3]. Its prevalence is nearly equal between males and females [4]. Vitiligo causes decreased self-esteem, poor body images, problems in sexual relations, as well as cosmetically and psychologically devastating. Most of its impact on quality of life is observed in individuals with darker skin phototype [5].


INTRODUCTION
Vitiligo is an acquired, idiopathic depigmentation disorder of skin and hair with characteristic white macules and patches. Vitiligo affects 0.1-2% of global population [1]. Highest incidence of this disorder is observed in India and Mexico [2]. In India, its prevalence is nearly 3-4% of patients visiting skin clinics of different hospitals [3]. Its prevalence is nearly equal between males and females [4]. Vitiligo causes decreased self-esteem, poor body images, problems in sexual relations, as well as cosmetically and psychologically devastating. Most of its impact on quality of life is observed in individuals with darker skin phototype [5].
Vitiligo is a refractory skin disorder for which the risk factors and treatment modalities have not yet been established [6]. Vitiligo has three clinical types, i.e., generalized vitiligo (spreads widely over the body), segmental vitiligo (dermatomal spread along the course of a nerve), and localized vitiligo (it is unclassifiable and can develop into either generalized or segmental type in the future) [7]. Pathogenesis of vitiligo has not yet been explained fully. Some of the proposed theories are autoimmune [8], neurogenic [9], self-destruct [10], genetic factors [11], biochemical defects [12], and recently transepidermal malanocytorrhagy [13]. Its onset is gradual and asymptomatic. The initial lesion usually has depigmented macules different in size, shape, number, and location with unpredictable course. However, it is progressive in >80% of patients [14]. Patients with a positive family history, mucosal involvement, isomorphic Koebner's phenomenon, and nonsegmental vitiligo are usually associated with progressive vitiligo. Presence of positive family history can be observed in 20-30% of cases [2] with polygenic or autosomal dominant gene inheritance. Vitiligo seems to be related with autoimmune disorders like thyroid disorders (especially hypothyroidism) [15], alopecia areata, type 1 diabetes mellitus [16,17], SLE (systemic lupus erythematosus), psoriasis, rheumatoid arthritis, Addison's diseases, and pernicious anemia [18,19]. The most commonly occurring autoimmune disorder is hypothyroidism.
Afghans are suffering from vitiligo too. This disorder is creating problems for all age groups, especially causing cosmetic problems and stigma in female and male adolescents before their marriages. Currently there is no published data showing the situation of vitiligo in Afghanistan. Null-hypothesis of our study was there is no difference in demographic data and associated factors between cases and controls. Main objectives of this study were to find out the epidemiology of vitiligo by observing the demographic data, clinical patterns of vitiligo, as well as common possible risk factors associated with vitiligo in Kandahar, Afghanistan.

Study Design and Period
This was a case-control study. Data was collected from the patients who fulfilled the eligible criteria of the study during 1-year-period (July 2017-June 2018).

Study Population
The study population was comprised of cases (patients having clinically diagnosed vitiligo) and controls (patients not having vitiligo) attending skin OPD clinic of Kandahar University Teaching Hospital, Kandahar, Afghanistan. Controls were sex-and age-matched randomly selected patients.

Research Question
What are the demographic data, clinical patterns, and possible risk factors of vitiligo in Kandahar, Afghanistan?

Primary Objective
To find out the epidemiology of vitiligo by observing the demographic data and clinical patterns of vitiligo.

Secondary Objective
To assess the common possible risk factors associated with vitiligo in Kandahar, Afghanistan.

Inclusion Criteria
• Patients having clinically diagnosed vitiligo • All age and sex groups • Patient consenting to the study • Permanent residents of Kandahar.

Exclusion Criteria
• Patients who do not want to take part in the study • Patients with depigmentation of skin due to causes other than vitiligo • Control group patient with autoimmune or altered immune disorders. • Control group patient with family member in case group.

Sample Size Calculations
Sample size was determined using the formula: n = Z2pq/d 2 . Our sample size was 200 patients. As it was a case-control study, 200 more subjects were added as controls.

Ethical Considerations
Written informed consents were taken from all the patients prior to the study. Names and other identification information of all the patients will not be disclosed. Ethical approval was taken from Kandahar University Ethics Committee.

Data Analysis
Data was analyzed using SPSS statistical software (version 22). For the analysis of data; descriptive statistics, Chi-square test, and logistic regression were used. P-value of <0.05 was assumed as statistically significant.

Operational Defi nitions
1. Clinical patterns of vitiligo [20] • Focal vitiligo: lesions confined to one or a few patches localized in a particular area. • Segmental vitiligo: lesions distributed in a segmental/dermatomal pattern. • Acrofacial vitiligo: lesions noted over both face and acral regions. • Vitiligo vulgaris: lesions affecting many parts of the body. • Mucosal vitiligo: lesions confined only to mucous membranes. • Universal vitiligo: when more than 80% of the skin is depigmented. 2. Signs and symptoms of vitamin D deficiency [21] • Getting sick or infected often, fatigue and tiredness, bone and back pain, depression, impaired wound healing, bone loss, hair loss, muscle pain. 3. Signs and symptoms of B12 deficiency [22] • Pale or jaundiced skin, weakness and fatigue, sensation of pins and needles, changes to mobility, glossitis and mouth ulcers, breathlessness and dizziness, blurred vision, mood changes, high temperature. 4. Signs and symptoms of folate deficiency [23] • Persistent fatigue, Weakness, Lethargy, Pale skin, Shortness of breath, Irritability.

RESULTS
A total of 400 patients were recruited for this study, with 200 patients as cases and 200 as controls. The age and gender distribution were same in cases and controls with no statistically significant dif ference. Mean age ± standard deviation (SD) of the patients were 21 (Table 3).
Accompanying disorders with no altered or autoimmunity present among cases and controls are summarized in Table 4 (Table 7).

DISCUSSION
In this case-control study 400 patients were recruited with 200 cases and 200 controls. In our study, more than half of the patients were females (107/200 [53.5%]). Similar results have been reported from studies in Turkey (62.5%) [24] and Saudi Arabia (53.5% [19] 56% [25]). Increased number of females among vitiligo patients is may be due to the fact that females are usually more concerned about pigmentation changes of their skin. So social stigma and marital concerns prompt females to seek early medical consultation.
Vitiligo can occur in all age groups with highest prevalence among young adults [26]. In our study, mean age of the patients was 21.7 years, with majority (38.5%) of patients in 11-20 years' age group. A study in Tunisia showed that most (66%) of the patients  developed vitiligo in their adulthood [27], mean age of occurrence of vitiligo was 18.8 years among Chinese patients [28], while a Turkish study reported that vitiligo occurred early in life with mean age of 10 years [ (24)]. Some studies have reported mean age ranging from 24.5-34 years [29][30][31][32][33][34].
In our study family history was present in 30% of cases as compared to 1.5% controls (p-value <0.001).
Most of the patient (63%) in our study were living in urban areas, where there are many environmental pollutants. A study in India also reported that majority of the patients (78%) were living in urban areas [35]. Contrary, a study in China showed that there is no significant difference between rural and urban residents [36]. In the etiology of vitiligo, Slominki et al. pointed out several environmental factors; including sunlight, stress, and extreme exposure to pesticides [37].
There is association of vitiligo with autoimmune disorders [25]. In our study 13.3% of the cases while 1% of the controls were having accompanying altered immunity and autoimmunity disorders which was statistically significant (p-value <0.001). Our main observed accompanying altered immunity and autoimmunity disorders were alopecia areata and atopic dermatitis. Other studies have also reported association of autoimmune disorders in Canada (19%) [43], North America and UK (23%) [44], and China (8%) [44].
For finding the possible risk factors of vitiligo, we conducted logistic regression of our data. It showed that family history, accompanying altered immune or autoimmune disorders, premature graying of hair, halo nevus, and atopic diathesis were the risk factors of vitiligo with odds ratios of 37.1, 9.0, 6.0, 13.9, and 3.9 respectively. In a large retrospective Japanese study with 713 vitiligo patients, younger age of onset and higher antinuclear antibodies (ANA) were the main risk factors [6]. A retrospective Chinese study on 101 vitiligo-associate halo nevus patients showed that personal history of thyroid diseases, Koebner phenomenon, multiple halo nevus, and familial history of vitiligo were risk factors associated with halo nevus vitiligo [45].
There were limitations in our study. Data was collected among patients attending one hospital. It would be better if data was collected randomly from different hospitals and clinics of the city and surrounding di stricts. Deficiencies of vitamin D, vitamin B12, and folate were detected using clinical signs and symptoms, not by laboratory examinations. Also, we could not work on all the possible risk factors of vitiligo (especially thyroid disorders). All these were due to limited funds, facilities, and personnel. Further more detailed studies are needed (in Kandahar and other regions of Afghanistan) to describe the demographic features, clinical patterns, and possible risk factors of vitiligo in details.
In conclusion, vitiligo affects women slightly more than men. Mean age of vitiligo patients is 21.7 years, observed mostly in second decade of life. Vitiligo vulgaris is the most prevalent type, affecting 74% of the patients. Common risk factors of vitiligo are family history, accompanying altered immunity/autoimmunity disorders, premature graying of hair, halo nevus, and atopic diathesis.

Statement of Human and Animal Rights
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Statement of Informed Consent
Informed consent was obtained from all patients for being included in the study.