Vitiligo and associated disorders including autoimmune diseases: A prospective study of 200 Indian patients

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1 Original Article Vitiligo and associated disorders including autoimmune diseases: A prospective study of 200 Indian patients Swati Garg, Vikram K. Mahajan, Karaninder S. Mehta, Pushpinder S. Chauhan, Mrinal Gupta, R. S. Yadav 1, Satya Bhushan 1 Departments of Dermatology, Venereology and Leprosy and 1 Biochemistry, Dr. R. P. Govt. Medical College, (Tanda), Himachal Pradesh, India Address for correspondence: Dr. Vikram K. Mahajan, Department of Dermatology, Venereology and Leprosy, Dr. R. P. Govt. Medical College, Kangra, Tanda , Himachal Pradesh, India. E mail: vkm1@rediffmail.com Abstract Background: Vitiligo is commonly associated with autoimmune and nonautoimmune disorders. However, there is a paucity of such data in the Indian context. Aims: We studied common disorders including autoimmune diseases associated with vitiligo. Methods: Clinical details and the results of serological studies comprising anti TPO and anti TG antibodies, antiparietal cell antibody, antinuclear antibodies, hepatitis B surface antibody, anti hepatitis C virus immunoglobulin M antibody, rheumatoid factor, and immunoglobulin E (IgE) levels were analyzed in 200 consecutive vitiligo patients. Results: These 200 (male:female 96:104) patients were aged between 3 and 78 (median age 25) years having vitiligo for 15 days to 60 years. Nonsegmental vitiligo in 192 (96%) patients was the commonly reported pattern. Fifty three (26.5%) patients had another affected a family member. Clinically, 37 (18.5%) patients had autoimmune disorders and 121 (60.5%) had serological evidence of autoimmunity. Autoimmune thyroid disorders in 85 (42.5%) patients were the most common. Others were rheumatoid arthritis 9 (4.5%), plaque psoriasis 5 (2.5%), alopecia areata 3 (1.5%), and limited cutaneous scleroderma 1 (0.5%). The presence of antithyroglobulin antibody in 53 (26.5%) and antithyroid peroxidase antibody in 44 (22%) patients, rheumatoid factor in 9 (4.5%) patients, and hyper IgE in 75 (37.5%) patients was significant observation. No patient had antiparietal cell antibodies or pernicious anemia. Conclusion: Clinical presentation of our patients conforms to established patterns of vitiligo. Subclinical autoimmune thyroiditis observed in the most cases is indicative of the potential benefit of screening these patients for concurrent thyroid disorders. The association of atopy remains poorly understood. Pernicious anemia and antiparietal cell antibodies do not appear a significant association in our patients. Key words: Alopecia areata, atopy, autoimmune disorders, autoimmune thyroiditis, pernicious anemia, psoriasis, rheumatoid arthritis Introduction Vitiligo is a common acquired depigmenting disorder having significant psychosocial morbidity. It affects 1% of the world population without any predilection for gender or race but the most studies report female preponderance. Its prevalence varies Quick Response Code: Access this article online Website: DOI: / from 3% to 9% in India. [1] A positive family history in 30 40% cases suggests a genetic predisposition. Emotional stress, sunburn, a major illness or surgical procedure, pregnancy, parturition, and physical trauma are well identified triggers. This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms. For reprints contact: reprints@medknow.com How to cite this article: Garg S, Mahajan VK, Mehta KS, Chauhan PS, Gupta M, Yadav RS, et al. Vitiligo and associated disorders including autoimmune diseases: A prospective study of 200 Indian patients. Pigment Int 2015;2: Pigment International Published by Wolters Kluwer - Medknow 91

2 Different pathogenic mechanisms have been suggested for various clinical types of vitiligo. The autoimmune hypothesis remains the most acceptable and forms the basis of several therapies. An increased frequency of autoimmune disorders in patients or probands and their first degree relatives supports this hypothesis and indicates that individuals can be genetically predisposed to a specific group of autoimmune disorders. [2 4] Many autoimmune or nonautoimmune disorders have been reported associated with vitiligo affecting its overall prognosis. These include both cutaneous (alopecia areata, halo nevi, morphea, scleroderma, lupus erythematosus, lichen planus, psoriasis, poliosis, premature graying of hair, atopy, urticaria, café au lait macules, lichen nitidus, and lichen striatus) and systemic disorders (Addison s disease, diabetes mellitus, thyroid disease, pernicious anemia, rheumatoid arthritis, hypertension, epilepsy, ischemic heart disease, oncological, hematological diseases, and ankylosing spondylitis). [3 10] The overall paucity of data on various disorders associated with vitiligo in the Indian context and especially from this part of the country has prompted this study. Methods Two hundred consecutive vitiligo patients (male:female 96:104) aged between 3 and 78 (median age 25) years were enrolled after informed (personal/guardian s) consent for the study during January to December The demographic profile, duration and evolution of vitiligo, personal and family history, detailed medical history, and associated disorders were recorded. All patients were tested for antibodies against thyroid antigens (antithyroid peroxidase [ATPO] and antithyroglobulin [ATG]), antiparietal cell antibody, antinuclear antibody (ANA), anti hepatitis C virus immunoglobulin M (HCV IgM) antibody, rheumatoid factor, and serum immunoglobulin E (IgE) levels. Quantitative estimation of laboratory parameters was performed by standard chemiluminescent enzyme immunoassay or enzyme linked immunosorbent assay as per manufacturer s instructions using ready to use in vitro kits from Siemens Healthcare Diagnostic Products Ltd., UK. The study was approved by the institutional protocol review board and Institutional Ethics Committee. Results Clinico epidemiological and investigative profile, frequency of vitiligo patterns and associated disorders are shown in Tables 1 and 2. The majority, 101 (50.5%) patients were aged between 21 and 60 years. Eighty six (43%) patients were aged <20 years of which 30 (15%) were children <12 years of age. The duration of vitiligo varied between 15 days and 60 years; it was <5 years in 129 (64.5%) patients and >5 years in others. The majority, 192 (96%) patients had nonsegmental vitiligo involving multiple body sites. Involvement of palms and soles was present additionally in 3 (1.5%) patients. Leukotrichia was present in 108 (54%) patients while 52 (26%) patients had trichrome morphology. Koebnerization was Table 1: Clinicodemographic features of vitiligo patients Features Number of patients (n=200) (%) Age groups years 86 (43) years 65 (32.5) years 36 (18) years 13 (6.5) Children <12 30 (15) Duration of disease <1 month 08 (4) 1-6 months 35 (17.5) 6 month-1 year 23 (11.5) 1-5 years 63 (31.5) 5-10 years 30 (15) >10 years 41 (20.5) Clinical patterns of vitiligo Segmental 8 (4) Nonsegmental 192 (96) Vitiligo vulgaris 83 (41.5) Acrofacial/lip tip 49 (24.5) Acral 28 (14) Facial 02 (1) Localised/focal 24 (12) Vitiligo universalis 05 (2.5) Mucosal 01 (0.5) Body surface area involved (%) <1 88 (44) (47.5) (5) (1) >80 05 (2.5) Sites of onset Lower limbs 64 (32) Scalp, face and neck 46 (23) Trunk 35 (17.5) Upper limbs 22 (11) Eyelids 22 (11) Lips 08 (4) Mucosal 03 (1.5) present in 88 (44%) patients. Body surface area involvement was <50% in 193 (96.5%) patients and only 5 (2.5%) patients had universal vitiligo. The usual sites of onset were lower limbs in 64 (32%), head and neck in 46 (23%), trunk in 35 (17.5%), upper limbs in 22 (11%), eyelids in 22 (11%), and lips in 8 (4%) patients in order of frequency. Physical trauma in 40 (20%) and stress (surgical procedures, marriage, parturition, pregnancy, and psychological) in 30 (15%) patients were the common triggers reported. Family members were affected in 53 (26.5%) patients and included first degree relatives in 27 (13.5%) or second/third degree relatives in 26 (13%) patients. None of the family members had a history of autoimmune disorders. Autoimmune disorders were present clinically in 37 (18.5%) patients and included thyroid disorders (hypo or hyperthyroidism, thyroid swelling) in 10 (5%), halo nevus in 16 (8%), plaque psoriasis in 5 (2.5%), alopecia areata in 3 92 Pigment International Jul-Dec 2015 Vol 2 Issue 2

3 Table 2: Associated disorders and autoantibody profile of vitiligo patients Parameters Number of patients (n=200) (%) Remarks (%) Associated autoimmune disorders 37 (18.5) Thyroid disorders Clinically diagnosed 10 (5) Thyroid swelling 4 (2) Hypothyroidism 5 (2.5) Hyperthyroidism 1 (0.5) Thyroid hormone abnormality 13 (6.5) Altered TSH 11 (5.5) Altered T3, T4 2 (1) Autoimmune thyroid disorder 78 (39) Anti TG Ab+53 (26.5) Anti TPO Ab+44 (22) Both+15 (7.5) Halo nevus 16 (8) Alopecia areata 3 (1.5) Plaque psoriasis 5 (2.5) RA Clinical RA 2 (1) Asymptomatic RA 9 (4.5) RF+9 (4.5) Limited cutaneous scleroderma 1 (0.5) ANA+ Others associated disorders Atopy Clinical atopy 4 (2) Atopic dermatitis 1 (0.5) Nasal allergy 2 (1) Bronchial asthma 1 (0.5) Elevated serum IgE 75 (37.5) Asymptomatic cases 71 Diabetes mellitus 4 (2) Canities 3 (1.5) Poliosis 2 (1) Miscellaneous* 17 Autoantibody profile ANA 1 (0.5) RF 9 (4.5) HbsAg 0 Anti HCV IgM 1 (0.5) Antiparietal cell antibody 0 Anti TPO Ab + IgE 20 (10) Anti TG Ab + IgE 21 (10.5) Anti TPO Ab + Anti TG Ab + IgE 6 (3) Anti TPO Ab + Anti TG Ab 15 (7.5) Anti TPO Ab or Anti TG Ab + IgE 36 (18) *Includes lichen planus, urticaria, melasma granuloma pyogenic, acne keloidalis, chronic uveitis, palmoplantar keratoderma, allergic contact dermatitis, neurofibromatosus, rosacea, and ichthyosis vulgaris. ANA: Antinuclear antibody, RF: Rheumatoid factor, HbsAg: Hepatitis B surface antigen, Anti HCV IgM: Anti hepatitis C virus immunoglobulin M, Anti TPO Ab: Antithyroid peroxidase, Anti TG Ab: Antithyroglobulin antibody, TSH: Thyroid stimulating hormone, RA: Rheumatoid arthritis (1.5%), rheumatoid arthritis in 2 (1%), and limited cutaneous scleroderma in 1 (0.5%) patients, respectively. Diabetes mellitus in 4 (2%), atopy (nasal allergy, atopic dermatitis, and asthma) in 4 (2%) patients, canities in 3 (1.5%), and poliosis in 2 (1.5%) patients were noted. Lichen planus, chronic urticaria, melasma in 3 (1.5%) patients each, and granuloma pyogenicum, acne keloidalis, chronic uveitis, palmoplantar keratoderma, allergic contact dermatitis, neurofibromatosus, rosacea, and ichthyosis vulgaris in one patient each were other miscellaneous disorders. Seventy five (37.5%) patients had elevated serum IgE levels and 13 (6.5%) patients had deranged thyroid hormone (T3, T4 or thyroid stimulating hormone) levels. One hundred and twenty eight (64%) patients were positive for at least one autoantibody; ANA (four patients), rheumatoid factor (nine patients) and various antithyroid antibodies in 78 (39%) patients [Table 2]. Positive ATG antibody (ATG Ab) and ATPO antibody (ATPO Ab) was seen in 53 (26.5%) and 44 (22%) patients respectively; 15 (7.5%) patients had concurrent ATPO Ab and ATG Ab positivity. Twenty (10%) patients had both positive ATPO Ab and elevated serum IgE levels while ATG Ab and elevated serum IgE were noted in 21 (10.5%) patients. Six (3%) patients had positivity for both ATPO Ab and ATG Ab, and elevated serum IgE levels. Only 1 (0.5%) patient had positive anti HCV IgM antibody. Antiparietal cell antibody or pernicious anemia was not detected in any of the patients. Pigment International Jul-Dec 2015 Vol 2 Issue 2 93

4 Discussion The demographic and clinical features of our patients did not differ from those described in the literature. Several cutaneous, ocular, rheumatological, and autoimmune systemic diseases occur in almost two third of vitiligo patients. The presence of other miscellaneous disorders appears fortuitous in our patients. Halo nevus is considered a risk factor for vitiligo and a clinical marker of cell mediated immunity against abnormal melanocytes/nevocytes that might indirectly target normal melanocytes in vitiligo. Halo nevi are seen 1 35% of vitiligo patients, mostly children, and usually herald the onset of vitiligo. [5,6,9] Association between halo nevi and canities or familial premature hair graying observed in vitiligo suggests that premature hair graying perhaps involves, at least partly, an autoimmune pathway. [11] van Geel et al. [12] also found that the first sign of leukoderma, whether vitiligo or halo nevus, was the earlier in patients with halo nevus nonsegmental vitiligo than in those having nonsegmental vitiligo alone. Our 8% patients had halo nevi and 5% had developed them before vitiligo. Canities and scalp vitiligo observed in our three patients also conforms to the views of Gopal et al. [7] and Shajil et al. [8] that canities perhaps represents a form of vitiligo in addition to localized vitiligo manifesting on the scalp. Although the phenomena of co existence and co localization remain poorly explained, it is not uncommon for vitiligo and psoriasis or vitiligo and alopecia areata appearing together, all sharing a prominent immunopathogenetic component. [13,14] Coexistent plaque psoriasis was noted in our 5 (2.5%) patients, 3 of them had generalized vitiligo with co localizing lesions. Dhar et al. [13] suggested structural similarities between antistratum corneum antibodies and antimelanocyte antibodies, and a common neuropeptide being the possible causative factors. Koebner s phenomenon, an immune surveillance paradigm, is a feature observed in both the diseases and is another plausible explanation. Alopecia areata involving scalp or beard was seen in our 3 (1.5%) patients conforming with reported prevalence of 0.49 to 14% in vitiligo patients. [3,4,7,10,15] Co localization of alopecia areata over preexisting vitiligo patches suggest that melanocyte derived antigens released during vitiligo pathogenesis (melanocyte epitopes) could act as auto antigens inducing hair loss. [14] However, we did not observe their co localization. About 30% vitiligo patients have at least one additional autoimmune disorder and circulating antibodies against the thyroid gland, gastric parietal cell, and adrenal gland occur even in the absence of clinical manifestations. [16] Our 37 (18.5%) patients had associated autoimmune disorders while the percentage rose to 121 (60.5%) with positive serology. Autoimmune thyroiditis is the most linked systemic disorder with a reported prevalence of % in vitiligo patients presenting either as clinical thyroid disease or as anti ATPO Ab, thyroid microsomal antibodies, and/or anti ATG Ab. [7,17 19] Subclinical thyroid disorders were more common and overall 57% patients had endocrine, immunological or both abnormalities in an Indian study. [20] About 40% had a biochemical abnormality (hyperthyroidism) and 31.4% were ATPO Ab or ATG Ab positive than 10% of controls. Although 190 (95%) of our patients were euthyroid clinically, immunological thyroid abnormality was seen in 78 (39%) patients, whereas, only 13 of them showed hormonal derangements. Apparently, vitiligo patients perhaps have subclinical thyroid disorder for many years prior to clinical manifestations. It seems prudent to screen all vitiligo patients for autoimmune thyroiditis at first contact itself. Similarly, the concurrent presence of rheumatoid arthritis and vitiligo is possible because of pathogenetic linkages. Melikoglu et al. [21] reported rheumatoid arthritis, autoimmune thyroiditis, and vitiligo in a single patient. Our 2 (1%) patients had associated rheumatoid arthritis diagnosed clinically while the percentage was high 9 (4.5%) when the positive rheumatoid factor was considered. Vitiligo in association with scleroderma, as observed in our 1 (0.5%) patient with localized scleroderma, is reported infrequently and has been suggested to form a part of the multiple autoimmune syndromes. [6,22,23] Although incidental coexistence remains a possibility, it seems that the presence of one autoimmune disorder raises the possibility of another developing concurrently or subsequently. Nearly 1.6% of the patients with pernicious anemia had vitiligo and 4.1% of the vitiligo patients had pernicious anemia in a 1955 study suggesting their strong association. This led to the belief that combined diagnoses of pernicious anemia and vitiligo occurred in a greater number of patients than statistically expected. A recent study [6] demonstrating pernicious anemia in 2 and gastric parietal cell antibodies in 20 vitiligo patients in addition to ATPO Ab, ANA, anti adrenal cortex antibodies, and rheumatoid factor in some of them has renewed interest for this aspect of vitiligo. However, antiparietal cell antibodies or pernicious anemia noted in earlier studies does not appear to be a significant association in our patients. Both diabetes and vitiligo are associated with HLA DR3 and HLA DR4 and a causal relationship has been suggested. Insulin dependent diabetes is seen in 1 7% of vitiligo patients and conversely 4.8% of all diabetic patients may have vitiligo. Noninsulin dependent diabetes in our 4 (2%) cases conforms to the previous Indian studies on its prevalence varying from 2% to 16%. [5,7,8] It has been suggested that longstanding diabetes causes an injury to melanocytes resulting in the release of an antigenic substance, antimelanocyte antibody formation, or inhibition of melanogenesis and occurrence of vitiligo. [4] The products of oxidative stress, free radical generation, and release of various growth factors may also be cytotoxic and affect melanogenesis. Another reason could be that a basic autoimmune disturbance perhaps affects two organ systems as a part of multiple autoimmune syndromes. However, the fortuitous presence of diabetes in these patients remains distinctly possible. 94 Pigment International Jul-Dec 2015 Vol 2 Issue 2

5 Association of atopic co morbidities with vitiligo remains poorly elucidated. Perfetti et al. [24] noted family history, early onset, generalized pattern, and progressive vitiligo more frequently in patients having associated atopy than vitiligo patients without atopy or normal population. They also noted that asthma, hay fever, and positive skin prick test, and radiosorbent allergen testing were more frequent with vitiligo. Our 75 (37.5%) patients had raised serum IgE levels and 4 of them had clinical features of atopy without any difference in clinicoepidemiologic aspects of vitiligo. Chatain et al. [25] also observed no difference in the clinical types, the course, or any other characteristics between pure vitiligo and atopic vitiligo patients. There was no significant difference in IgE serum levels between vitiligo patients and controls in another study. [26] Hence, the relevance of raised IgE in the pathogenesis, severity or progression of vitiligo remains conjectural. Limitations Small sample size, absence of controls, and no follow up for therapeutic outcome or development of disease in seropositive cases are some of the limitations. Conclusion Clinical presentation of our patients conforms to established patterns of vitiligo. Subclinical autoimmune thyroiditis observed in most cases is indicative of the potential benefit of screening these patients for concurrent thyroid disorders. Timely initiation of treatment with corticosteroid/disease modifying drugs will improve therapeutic outcome in such cases. This is particularly true for the occult autoimmune thyroiditis. The relevance of IgE in pathogenesis or clinical presentation of vitiligo in patients with or without atopy needs elucidation. Pernicious anemia or antiparietal cell antibodies noted in earlier studies does not appear to be a significant association in our patients. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. 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