Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2023;13(4)S2:e2023315S 1 Vitiligo: Epidemiology and Economic Impact Luigi Naldi1, Adriano Pagani2, Chiara Alduini2 1 UOC Dermatologia, Ospedale San Bortolo, Vicenza, Centro Studi GISED, Bergamo 2 Kearney, Milan Key words: vitiligo, epidemiology, mental health, social cost Citation: Naldi L, Pagani A, Alduini C. Vitiligo: Epidemiology and Economic Impact. Dermatol Pract Concept.2023;13(4)S2:e2023315S. DOI: https://doi.org/10.5826/dpc.1304S2a315S Accepted: December 11, 2023; Published: December 2023 Copyright: ©2023 Naldi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Chiara Alduini, Kearney, Milan, Italy. Email: chiara.alduini@kearney.com Introduction: Vitiligo is an acquired disorder of pigmentation, characterized by the development of white patches on the skin, often with a typical symmetrical distribution and progressive extension [1,2]. Although vitiligo does not cause direct physical impairment, it can produce a relevant psycho- social burden. Despite this burden, effective treatments are lacking, emphasizing the need for new therapeutic options. Objectives: The aim of this study was to systematically scan the scientific literature for studies dealing with vitiligo epidemiology. Additionally, the study aimed to assess the social costs of vitiligo, ultimately raising awareness about the societal impact of the condition. The focus was on Italian data. Methods: Our research employed a comprehensive methodology. For the epidemiology, we systemati- cally searched PubMed database up to October 2023 and complemented the analysis with Real World Evidence. For social costs, we conducted an in-depth literature review, administered a web-survey to 20 Italian dermatologists and conducted an equivalent number of interviews during the same period in March 2022. Results: The data suggest that in Italy the prevalence of vitiligo increases with age, and it varies from 0.19% (age 18-21) to 0.6% (age >45) [3,4]. We estimated 152,000 patients diagnosed with Non- Segmental Vitiligo (NSV) in Italy; based on Body Surface Area (BSA), 33% are Not Severe, 31% Mild, 27% Moderate/Severe, 9% Very Severe. The yearly social costs of vitiligo amount to €0.5Bln. Conclusions: There is a remarkable association of vitiligo with anxiety and depression [5,6,7,8,9], and Mental Health is associated with 30% of social costs. Moreover, vitiligo social costs distribution highlights inequity, with patients bearing 55% of them. ABSTRACT 2 Review | Dermatol Pract Concept. 2023;13(4)S2:e2023315S Introduction Vitiligo is a chronic autoimmune depigmenting skin disease that results in patchy loss of skin color due to the progressive destruction of melanocytes [1,10]; it is now widely accepted that vitiligo has an autoimmune nature. This condition is characterized by extended periods of stability interspersed with shorter periods of accelerated depigmentation [11]. Treatment remains a challenge in dermatology, as available options produce limited results [12,13]. Vitiligo is a prevalent global skin condition which affects equally both genders, though slightly more prevalent in fe- males, and more than 60% of patients experienced disease onset before the age of 30 [14,15]. There are two main clinical phenotypes [16]: Non- Segmental vitiligo (NSV) and Segmental vitiligo (SV). NSV is the most common form, characterized by symmetrical lesions on both sides of the body, progressing slowly and unpredictably. Vitiligo is frequently associated with various autoim- mune comorbidities such as hypothyroidism and rheumatoid arthritis [17]. The psychological impact is substantial, negatively af- fecting patients’ quality of life (QoL) and Mental Health [5,6,7,8,9,18,19]. Indeed, the stigma associated with vitil- igo impacts personal lives and productivity, leading to poor self-acceptance and psychological distress [20]. Everyday ac- tivities are disrupted, causing considerable time and energy waste for patients and their caregivers. Patients commonly experience depression, anxiety, stigmatization, hopelessness, and loss of self-esteem [20,21]. Despite the substantial burden it places on individuals, there is still a notable unmet need for effective treatments, leaving patients frustrated and hopeful for the development of efficacious options. Objectives The goals of the study were to determine the prevalence of vitiligo in Italy, segment patients to understand treatment adoption and behavior, and assess the social costs associated with the condition. Moreover, the aim was to shed light on the economic and societal burdens of vitiligo in Italy. Methods Our research utilized a comprehensive methodology, en- compassing web-surveys involving 20 Italian dermatologists (i.e., “Medical Survey”) in March 2022, interviews with an additional 20 dermatologists during the same period, and an extensive desk research that scrutinized over 100 publica- tions, articles, and industry reports. In particular, data collec- tion included a broad range of sources, including Real-World Evidence, scientific publications, public entities’ websites (e.g., INPS, GU (Gazzetta Ufficiale)), scientific guidelines, national and regional NHS tariffs, statistics institutes (e.g., ISTAT, EUROSTAT), surveys, interviews, as well as in- formation from company websites and the medical press. Epidemiology We systematically searched PubMed database up to October 4, 2023, with the following key words: epidemiology, prev- alence, incidence, co-morbidities, risk factors. A total of 761 papers were retrieved and, after an eligibility assessment, only 82 were maintained. Out of these papers, 12 were sys- tematic reviews summarising various aspects of the vitiligo epidemiology [5-9,25-28], and another 8 studies presented data on the epidemiology of vitiligo in Italy [3,4,29-35]. To avoid repetition and redundancy, we decided to focus on the above-mentioned studies only, i.e., systematic reviews and Italian data. We then complemented the analysis through a bottom-up approach, using Real-World Evidence [36]. Lastly, we es- tablished patient classes for Non-Segmental vitiligo (NSV) based on clinical and demographic characteristics and vali- dated these classifications through expert interviews. Social Cost We assessed both healthcare and non-healthcare costs asso- ciated with vitiligo. Among healthcare costs, we examined three components: • Vitiligo Treatment: through the Medical Survey, we investi- gated the treatment behavior within distinct patient classes, specifically focusing on topical treatments, phototherapy, depigmentation, and surgery. We further quantified the costs associated with each treatment, using publicly avail- able sources. Both NHS and patient costs were considered. • Autoimmune Comorbidities: our study delved into the prevalence of autoimmune comorbidities among vitiligo patients, including conditions such as hypothyroidism, rheumatoid arthritis, and inflammatory bowel disease. For each of these comorbidities, we examined literature on both direct and indirect associated costs. • Mental Health Conditions Assessment: we explored the prevalence of Mental Health comorbidities, such as de- pression and anxiety, in vitiligo patients and their caregiv- ers, as reported in the literature. On the non-healthcare cost front, we assessed two components: • Non-Drug Products: through Medical Survey, we ex- amined the usage of non-drug products (e.g., make-up/ concealer, self-tanners, sunscreen) within different patient Review | Dermatol Pract Concept. 2023;13(4)S2:e2023315S 3 classes. Other direct costs were also considered (e.g., transportation expenses). • Indirect Social Costs: our study included an estimation of the time allocated for treating vitiligo and Mental Health comorbidities within each patient class. We also evaluated the influence of Mental Health comorbidities on employ- ment status. Results Epidemiology Here we present eight Italian studies with a clear epidemio- logic design [3,4,29-35]. In the Praktis study, conducted between March 1, 2003, and April 30, 2004, a random sample of 12,483 Italian subjects aged 45 or older was collected and interviewed, showing a 0.6% lifetime prevalence of physician-diagnosed vitiligo, with no difference according to gender and an in- creasing prevalence with age [29]. The Epienlist project, carried out by the Department of Dermatology at the Italian Navy Hospital in Taranto, exam- ined 23,468 potential conscripts in southern Italy, aged 18-21. Those with skin lesions were referred to the hospital for diag- nosis. The point prevalence of vitiligo was 0.19% [3]. Qual- ity of life was assessed for 40 vitiligo patients, with a mean Dermatology Life Quality Index (DLQI) score of 1.82 [33]. Analysis revealed that only lesions on the hands (OR:6.32) and face (OR:5.03) significantly influenced the mean DLQI. A survey of quality of life was conducted on 181 consec- utive vitiligo patients at a single institution in Rome, using the Skindex-29 tool [30]. The problems more frequently ex- perienced were worry of the disease getting worse (60%), anger (37%), embarrassment (34%), depression (31%). Another survey of quality of life using DLQI was con- ducted on a sample of 161 vitiligo patients referred to 9 dermatological departments in Italian hospitals [34]. The mean total DLQI score was 4.3 (SD±4.9; range: 0-22). In multivariate analysis, DLQI >5 was associated with female gender, stability of the disease and involvement of the face at disease onset. In a survey conducted during spring 1997, a total of 3,179 schoolchildren attending secondary schools in Italy were assessed through a questionnaire filled in by their par- ents [31]. The reported prevalence of vitiligo was 0.06%. The EDEN Fragrance study enrolled 2,035 randomly sampled individuals aged 18 or older in Italy. Clinical ex- aminations and patch tests were conducted. The lifetime prevalence of vitiligo was 0.4%, with no significant gender difference [35]. The prevalence of vitiligo in Italy, as determined by the studies, falls within the range of 0.19%-0.6%, increasing with age. In addition, an Italian ReS Real-World Evidence study [36] was considered. This study examined the number of patients undergoing phototherapy treatment for vitiligo from 2013 to 2018 and revealed that 0.06% of the patient population received such treatment during that period. Employing a bottom-up methodology, we expanded the study’s scope to incorporate pa- tients who underwent phototherapy prior to 2013 or received alternative treatments, to ensure a complete understanding of the vitiligo-diagnosed population. We then added undiagnosed cases (41%) [35] to derive a lifetime vitiligo prevalence rate of 0.55%, which is in line with that reported by literature. Considering that only 15% of vitiligo cases are Non-Segmental vitiligo (NSV) [37-40], we estimated a to- tal of 279,000 NSV patients in Italy in 2022. Among these, 152,000 received a diagnosis, with 33% classified as having BSA <0.5% (Not Severe at all), 31% with BSA 0.5%-3.5% (Mild), 27% with BSA 3.5%-10% (Moderate/Severe), and 9% with BSA >10% (Very Severe) [41]. Vitiligo Treatment Cost The costs of vitiligo treatment include all direct medical ex- penses, including therapies, examinations, laboratory tests, and supplements. NSV treatment rate varies among patient segments. Treatment rate tends to be higher in more Severe forms of NSV: only 35% of Not Severe NSV patients receive treatment compared to 84% of Very Severe NSV patients. Within the same Moderate-Severe segment, adolescents and females exhibit a relatively higher treatment rate (81% and 80% respectively) compared adult males (70%). For each patient class, treatment preferences were exam- ined through the Medical Survey: preferred options for cases of lower severity included topical corticosteroids and calci- neurin inhibitors, while in Moderate-Severe cases, photother- apy and systemic corticosteroids were preferred (Figure 1). To compute costs, we identified the most used molecules and their average therapeutic regimens, and we distinguished between costs in private and public settings (Table 2). Ac- cording to the Medical Survey, 49.5% of patients are treated in public, and 50.5% in private settings. Then, considering the specific needs of each class of NSV patients, we added costs for dermatologist and nutritionist examinations, blood/ urine tests, and supplements. Total medical costs for NSV patients amount to €80Mln and the large majority (95%) is covered by the patient. Costs consist of treatments (35%) and supplements (38%), fol- lowed by medical examinations (23%) and lab tests (4%). The annual treatment cost per patient ranges from €208 for Not Severe cases to €906 for Moderate/Severe adolescents. Autoimmune Comorbidities In a retrospective study, 15.3% of patients with vitiligo had one or more significant comorbid autoimmune condition, 4 Review | Dermatol Pract Concept. 2023;13(4)S2:e2023315S Table 1. Summarization of data from relevant Italian studies. First Author Publication Focus Study size Results Naldi [29] 2004 Lifetime prevalence Random sample of 12,483 Italian citizens aged >45 Lifetime prevalence 0.06% with no difference based on age and sex Ingordo [3] 2007 Point Prevalence 23,468 conscripts in southern Italy, aged 18-21 Point prevalence 0.19% Sampogna [30] 2008 Quality of life 181 consecutive vitiligo patients at a Roman institution, using Skindex-29 tool, 12-item General Health Questionnaire Problems frequently experienced: worry of getting worse (60%), anger (37%), embarrassment (34%), depression (31%). The prevalence of patients with probable depression or anxiety was 39% Naldi [31] 2009 Risk factors and diseases associated with atopic dermatitis 3,179 schoolchildren aged 12-17 years Lifetime prevalence of vitiligo 0.6% Ingordo [32] 2011 Autoimmunity in vitiligo 40 conscripts with vitiligo systematically assessed for autoantibodies and history of immune-related disease Circulating autoantibodies detected in 42.5% of subjects Ingordo [33] 2012 Quality of life 40 conscripts with vitiligo assessed through DLQI Mean total DLQI score 1.82 (SD± 2.95; min/max: 0-13). The localization on the hands (OR:6.32) and on the face (OR:5.03) influenced significantly the mean DLQI Ingordo [34] 2014 Quality of life 161 vitiligo patients referred to dermatological departments in Italy assessed by DLQI DLQI score 4.3 (SD ±4.9; range: 0-22). In multivariate analysis, DLQI >5 was associated with female gender, stability of the disease over time and involvement of the face at disease onset Svensson [35] 2018 Lifetime Prevalence of vitiligo in a survey on contact dermatitis Random sample of 2,035 people aged >18 in Bergamo Lifetime prevalence of vitiligo 0.4% with no significant difference according to gender Figure 1. NSV Treatment Preference by Patient Class (%) Review | Dermatol Pract Concept. 2023;13(4)S2:e2023315S 5 Major Depressive Disorder (MDD) and anxiety (referred to as Generalized Anxiety Disorder, Social Phobia, Specific Phobia, Post-Traumatic Stress Disorder, Agoraphobia, Ago- raphobia with Panic Disorder and Panic Disorder) were the most reported. Moreover, patients with vitiligo recur to psy- chotherapy more often than the general population. We argue that the cost of mental health issues can be part of the overall cost of vitiligo. This is because the in- creased psychological distress in this group mostly arises from the difficulties caused by the disease itself. Therefore, we collected literature evidence for direct costs of depression (i.e., costs for residential structures, psychiatry-related tests, hospitalizations, antidepressants [55, 56]), costs for anxiety with hypothyroidism and rheumatoid arthritis being the most common [17]. Vitiligo patients incur direct and indirect costs due to autoimmune comorbidities [42-53]. Direct costs include healthcare and non-healthcare costs (e.g., inpatient care, drug costs, tests, transportation). Indirect costs include productivity losses due to morbidity/mortality, borne by the individual, family, society, or the employer (e.g., sick leave, early retirement). Indirect costs were assessed by the human capital approach (HCA) and the friction cost approach (FCA). Mental Health Costs According to a systematic review on psychosocial effects of vitiligo [3,15,23,54,55], disorders including or related to Table 2. NSV treatment options costs (€, yearly). Overall cost Of which on patient Of which on NHS Induction therapy CS systemic (± TCS) 351 192 159 Induction therapy TCS 291 192 99 Induction therapy TCI 461 236 225 Maintenance therapy TCS (lower dose) 84 55 29 Maintenance therapy TCI (lower dose) 200 102 97 UVB phototherapy (e.g., NB-UVB, excimer laser) 4,077 3,947 130 UVB phototherapy + TCS or TCI 4,198 4,014 184 PUVA 4,373 4,247 125 Candidate for surgery (scheduled/operated) 2,488 33 2,454 Depigmentation 800 800 - Table 3. Disease costs for selected autoimmune diseases (€, yearly). Overall cost Of which direct cost Of which indirect cost Hypothyroidism 953 250 702 Rheumatoid arthritis 12,341 5,891 6,450 Inflammatory bowel disease 3,032 2,817 215 Lymphoma 52,992 47,004 5,988 Systemic lupus erythematosus 18,574 2,637 15,937 Seronegative arthritis 12,341 5,891 6,450 Idiopathic thrombocytopenic purpura 8,417 7,294 1,123 Multiple sclerosis 38,000 17,351 20,649 Pernicious anemia 393 103 289 Myasthenia gravis 14,950 12,160 2,790 Table 4. Direct costs associated to Mental Health. Overall cost Of which on patient Of which on NHS Depression treatment 2,879 374 2,504 Overall cost Of which on patient Of which on NHS Anxiety treatment 2,431 615 1,816 Overall cost Of which on patient Of which on NHS Psychotherapy session 76 76 ~0 6 Review | Dermatol Pract Concept. 2023;13(4)S2:e2023315S value of the HC is approximated by the value of an individ- ual’s earning, so that the period of absence from work due to illness/treatment is considered and valued by the achievable gross income [59]. The HC method does not address the is- sue of the categories not receiving any income (typically stay- at-home spouses, unemployed and students) [60] and their inclusion in indirect costs computation is at the researcher’s discretion. To address the limits of HC method, in this study we valued the “unemployed lost time” at the value of gov- ernmental unemployed benefit (NASpI [61]); “Inactive care- givers’ time” at the value of minimum domestic labor wage; “Time lost out of working time for vitiligo treatment” (e.g., ointment application, make-up) at the value of willing- ness to pay for an additional hour of leisure time vs. unpaid work [62], assuming that the burden of treatment is compa- rable to unpaid work. The data for this section comes from scientific publications, public entities’ websites (e.g., INPS), statistics institutes (e.g., INSTAT). Our analysis shows that the indirect costs associated to vitiligo amount to €91Mln/year: 30% of this cost (€31Mln) is associated to Mental Health (for either productivity loss related to treatment time or unemployment). The annual in- direct social cost per diagnosed patient ranges from €288 for Not Severe cases to €1,182 for Moderate-Severe older males. Conclusions In summary, data indicate that vitiligo prevalence increases with age in Italy, ranging from 0.19% at 18-21 years to 0.6% after age 45. Real World Evidence-based prevalence was estimated at 0.55%. These figures align with the find- ings reported in systematic reviews and recent studies. Analyzing five cost components, the annual social cost of vitiligo in Italy is €500 million, with costs per patient rang- ing from €2,200 to €4,600/year. Patients bear 55% of the cost, the NHS covers 18%, and 27% is borne by society. This distribution results in significant inequity, with over half of the social cost being paid directly by patients or caregivers. (drugs, hospitalizations, outpatient care, medical devices [57,58]) and costs for public and private psychotherapy. Factors associated with a higher burden of psychosocial comorbidities include female sex, greater body surface area involvement (i.e., severity), and younger age. Our analysis shows that Moderate-Severe NSV females are the group with the highest spend in Mental Health (1,171€/year), followed by Very Severe NSV (1,157€/year) and Moderate-Severe older males (1,145€/year). Interestingly, another group af- fected by vitiligo-induced Mental Health issues are the care- givers of children and adolescents, spending approximately 1,062€/year. The group spending less on Mental Health is children (642€/year), who are mostly unaware of their phys- ical appearance. Non-Drug Costs Non-drug costs consist in purchases of skin products for vit- iligo (e.g., professional concealers, sunscreen) exceeding the usual expenses associated with standard skincare, and trans- port costs specifically related to vitiligo disease (e.g., trans- port to reach phototherapy center). Research shows that make-up and concealers are mostly used by Moderate/Severe NSV females (65%), followed my Mild NSV cases (55%) and Moderate/Severe NSV adolescents (55%); sunscreen is widely used across patient classes, up to 95% among Very Severe cases. The non-drug annual cost for diagnosed patient ranges from 117€/year for Not Severe cases to 789€/year for Moderate/Severe women. Indirect Costs NSV patients lose time managing their condition, giving up both work and leisure time. Additionally, NSV patients lose time due to mental health comorbidities, either for treat- ment (e.g., psychotherapy) or due to disabling symptoms (e.g., hospitalizations, lost workdays). To assess indirect cost due to productivity loss, we opted for the human capital (HC) approach, which states that the Table 5. NSV non-drug costs (€). Cost of products (€ monthly per patient) Cost of products (€ yearly per patient) Concealers/Make-up 13 150 Self-tanners 12 140 Sunscreen 46 285 Cost of transport (€ for occasion) Cost of transport (€ yearly per patient) Transport for testing/examinations 8 18-38 Transport for phototherapy 6 824 Transport for surgery 12 12 Review | Dermatol Pract Concept. 2023;13(4)S2:e2023315S 7 20. Ezzedine K, Eleftheriadou V, Jones H, Bibeau K, Kuo F, Sturm D, Pandya A EADV 2020. Poster P1239 (Paris, France) Prevalence of Psychosocial Comorbidities in Vitiligo: A Systematic Litera- ture Review 21. Firooz A, Bouzari N, Fallah N, Ghazisaidi B, Firoozabadi MR, Dowlati Y. What patients with vitiligo believe about their con- dition. International journal of dermatology. 2004; 43(11), 811-814. 22. Zhang Y, Cai Y, Shi M, et al. The Prevalence of Vitiligo: A Meta- Analysis. 2016; PLoS ONE 11(9): e0163806. doi:10.1371/ journal.pone.0163806. 23. 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