Clinical features of vitiligo associated with comorbid autoimmune disease: A prospective survey

Abstract

To the Editor: There are several important clinical questions about vitiligo-associated autoimmune diseases (VAAD) that have not yet been resolved. First, which patients with vitiligo should be screened with laboratory testing for VAAD? Second, are there clinical clues that can be used to better identify patients at risk for VAAD? Third, what VAAD should be screened for? We hypothesized that specific VAAD are associated with distinct demographics and vitiligo phenotype.This prospective online questionnaire study was approved by the institutional review board at St Luke's-Roosevelt Hospital Center, New York, NY (www.clinicaltrials.gov registration NCT01401374) for adults and children with vitiligo. Survey validation and distribution were performed as previously described.1Silverberg J.I. Silverberg N.B. Association between vitiligo extent and distribution and quality-of-life impairment.JAMA Dermatol. 2013; 149: 159-164Crossref PubMed Scopus (81) Google ScholarData processing and statistics were done with software (SAS, Version 9.2, SAS Institute Inc, Cary, NC). Logistic regression was used with VAAD as the dependent variables. Independent variables were body surface area (BSA), number of body parts affected, laterality and duration of vitiligo lesions, and itching/burning secondary to vitiligo lesions. Adjusted odds ratios were calculated by including sex, age, and race/ethnicity in multivariate models. No significant linear interaction terms were found. Logistic regression with stepwise selection of predictors was used to determine whether vitiligo distribution (11 sites) is associated with VAAD.Complete case analysis was performed. Correction for multiple dependent tests (k = 107) with the approaches of Benjamini and Hochberg2Benjamini Y. Hochberg Y. Controlling the false discovery rate–a practical and powerful approach to multiple testing.J R Stat Soc Series B Stat Method. 1995; 57: 289-300Google Scholar yielded a critical P value of .03.The survey was completed by 97% (2763); 2644 were given the diagnosis of vitiligo by a physician, including 2273 adults and 371 children/adolescents. In adults, 790 (34.8%) reported VAAD, most commonly hyperthyroidism/hypothyroidism, rheumatoid arthritis (RA), pernicious anemia (PA), type 2 diabetes mellitus (DM), and alopecia areata (Table I). VAAD was associated with female sex (logistic regression, P < .0001) and older age (P ≤ .002), but inversely associated with Indian (P < .0001) and Asian (P = .007) race/ethnicity. BSA, number of body parts affected, bilaterality, prolonged duration of vitiligo, and itching/burning of skin were associated with VAAD, particularly multiple disorders (Table II). Hyperthyroidism/hypothyroidism, RA, PA, and type 2 DM were associated with older age and increased vitiligo extent (BSA, number of body parts, and/or bilaterality). Hyperthyroidism/hypothyroidism and RA were also associated with duration and itching/burning from vitiligo. Sjögren disease was associated with increased BSA. However, type 1 DM, alopecia areata, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and systemic lupus erythematosus (SLE) were not associated with the above-mentioned variables.Table IComorbid autoimmune disorders in adults and children with physician-diagnosed vitiligoVariableAdults (n = 2273)Children (n = 371)No. (%)RankNo. (%)RankComorbid autoimmune disorders790 (34.8)–31 (8.4)– Hyperthyroidism/hypothyroidism540 (23.8)120 (5.4)1 Rheumatoid arthritis82 (3.6)24 (1.1)2 Pernicious anemia80 (3.5)30 (0.0)– Type 2 diabetes mellitus69 (3.0)41 (0.3)7 Alopecia areata61 (2.7)53 (0.8)4 Psoriasis59 (2.6)64 (1.1)2 Chronic urticaria46 (2.0)72 (0.5)5 Type 1 diabetes mellitus27 (1.2)81 (0.3)7 Lichen sclerosus et atrophicus23 (1.0)90 (0.0)– Ulcerative colitis19 (0.8)100 (0.0)– Celiac disease18 (0.8)112 (0.5)5 Sjögren disease18 (0.8)110 (0.0)– Raynaud phenomenon16 (0.7)130 (0.0)– SLE15 (0.7)140 (0.0)– Sarcoid7 (0.3)150 (0.0)– Crohn's disease6 (0.3)160 (0.0)– Dermatitis herpetiformis5 (0.2)170 (0.0)– Addison disease4 (0.2)180 (0.0)– Multiple sclerosis0 (0.0)–0 (0.0)–SLE, Systemic lupus erythematosus. Open table in a new tab Table IIComorbid autoimmune disease is associated with sex, age, race, and vitiligo extent in adultsClinical factorComorbid autoimmune diseaseOneMultipleOR (95% CI)P valueaOR (95% CI)P valueBody surface area (%) 1-25286 (79.4)74 (20.6)1.00 [ref]–1.00 [ref]– 26-50123 (65.4)65 (34.6)2.04 (1.38-3.03).00042.08 (1.38-3.15).0005 51-7578 (65.6)41 (34.5)2.03 (1.29-3.21).0022.18 (1.35-3.51).001 76-10074 (62.2)45 (37.8)2.35 (1.50-3.69).00022.43 (1.51-3.91).0003No. of body parts affected, quartiles 1st104 (77.0)31 (23.0)1.00 [ref]–1.00 [ref]– 2nd131 (75.7)42 (24.3)1.08 (0.63-1.83).791.05 (0.60-1.85).86 3rd176 (73.3)64 (26.7)1.22 (0.75-2.00).431.15 (0.68-1.95).60 4th136 (63.0)80 (37.0)1.97 (1.21-3.21).0062.07 (1.23-3.47).006Laterality of lesions Unilateral/midline19 (63.3)11 (36.7)1.00 [ref]–1.00 [ref]– Bilateral542 (71.9)212 (28.1)0.68 (0.32-1.44).310.57 (0.25-1.29).33Duration of vitiligo (y), quartile 1st121 (79.1)32 (20.9)1.00 [ref]–1.00 [ref]– 2nd162 (74.7)55 (25.4)1.28 (0.78-2.11).321.25 (0.74-2.09).40 3rd121 (69.5)53 (30.5)1.66 (1.00-2.75).051.80 (1.05-2.07).03 4th154 (65.0)83 (35.0)2.04 (1.27-3.27).0031.96 (1.20-3.21).008Itching or burning No324 (75.0)108 (25.0)1.00 [ref]–1.00 [ref]– Yes210 (66.0)108 (34.0)1.54 (1.12-2.12).0081.64 (1.18-2.28).004aOR, Adjusted odds ratio; CI, confidence interval; OR, odds ratio; ref, reference group. Open table in a new tab Hyperthyroidism/hypothyroidism was associated with lesions on the hands, feet, and chest (Table III). PA was associated with gray hair and abdominal lesions. RA, type 2 DM, and Sjögren disease were associated with abdominal lesions. Type 1 DM, inflammatory bowel disease, and SLE were not associated with vitiligo distribution.Table IIIDistribution of vitiligo lesions is a predictor of comorbid autoimmune disease in adults and children with vitiligoVariableAdult (n = 2273)Pediatric (n = 371)aOR (95% CI)∗Binary logistic regression models were constructed with various causes of comorbid autoimmune disease (yes/no) as dependent (outcome) variables. Independent (explanatory) variables included location of vitiliginous lesions, including: (1) face, (2) gray hair, (3) chest, (4) back, (5) abdomen, (6) buttocks, (7) arms, (8) hands, (9) legs, (10) feet, and (11) genitals. All variables were tested in models using forward, backward, and stepwise selection with the same results. Alpha for inclusion was 0.05. Significant explanatory variables included in final models are presented. aOR and 95% CI were determined.P valueaOR (95% CI)∗Binary logistic regression models were constructed with various causes of comorbid autoimmune disease (yes/no) as dependent (outcome) variables. Independent (explanatory) variables included location of vitiliginous lesions, including: (1) face, (2) gray hair, (3) chest, (4) back, (5) abdomen, (6) buttocks, (7) arms, (8) hands, (9) legs, (10) feet, and (11) genitals. All variables were tested in models using forward, backward, and stepwise selection with the same results. Alpha for inclusion was 0.05. Significant explanatory variables included in final models are presented. aOR and 95% CI were determined.P valueHyperthyroid/hypothyroid Hands2.00 (1.33-3.01).0009None Feet1.46 (1.10-1.93).009 Chest1.43 (1.15-1.77).001Rheumatoid arthritis Abdomen1.64 (1.05-2.58).03NonePernicious anemia Gray hair2.23 (1.35-3.67).002None Abdomen2.30 (1.41-3.73).0008Type 2 diabetes mellitus Arms0.37 (0.20-0.70).002None Abdomen2.25 (1.29-3.92).004Type 1 diabetes mellitus NoneNoneIBD (UC + Crohn's disease) NoneNoneSjögren disease Abdomen4.12 (1.34-12.67).01NoneSystemic lupus erythematosus NoneNoneaOR, Adjusted odds ratio; CI, confidence interval; IBD, inflammatory bowel disease; UC, ulcerative colitis.∗ Binary logistic regression models were constructed with various causes of comorbid autoimmune disease (yes/no) as dependent (outcome) variables. Independent (explanatory) variables included location of vitiliginous lesions, including: (1) face, (2) gray hair, (3) chest, (4) back, (5) abdomen, (6) buttocks, (7) arms, (8) hands, (9) legs, (10) feet, and (11) genitals. All variables were tested in models using forward, backward, and stepwise selection with the same results. Alpha for inclusion was 0.05. Significant explanatory variables included in final models are presented. aOR and 95% CI were determined. Open table in a new tab In children, 31 (8.4%) had VAAD, most commonly hyperthyroidism/hypothyroidism, RA, psoriasis, and alopecia areata. There were no associations of demographics, vitiligo extent, duration or distribution and VAAD.The prevalence of VAAD, except for type 2 DM, are considerably higher than the general adult population (hyperthyroidism = 1.15%, hypothyroidism = 0.79%, RA = 0.86%, PA = 0.15%, type 2 DM = 11.3%, SLE = 0.024%, Sjögren disease = 0.014%3Jacobson D.L. Gange S.J. Rose N.R. Graham N.M. Epidemiology and estimated population burden of selected autoimmune diseases in the United States.Clin Immunol Immunopathol. 1997; 84: 223-243Crossref PubMed Scopus (1241) Google Scholar, 4Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States 2011. Available at: http://www.cdc.gov/diabetes/pubs/estimates11.htm. Accessed March 1, 2013.Google Scholar).Based on these results, we recommend screening for thyroid disease in all patients with vitiligo, especially with extensive disease. Patients with increased extent and duration of vitiligo, itching/burning of skin, and older age should be evaluated for RA, PA, and type 2 DM. Based on the low prevalences and lack of consistent association with vitiligo extent, routine screening for Sjögren disease, inflammatory bowel disease, celiac disease, Addison disease, and dermatitis herpetiformis are not indicated unless suggestive symptomatology is present. Although SLE is uncommon in vitiligo, it may flare with phototherapy. Therefore, screening antinuclear antibody testing may be needed in patients requiring phototherapy. To the Editor: There are several important clinical questions about vitiligo-associated autoimmune diseases (VAAD) that have not yet been resolved. First, which patients with vitiligo should be screened with laboratory testing for VAAD? Second, are there clinical clues that can be used to better identify patients at risk for VAAD? Third, what VAAD should be screened for? We hypothesized that specific VAAD are associated with distinct demographics and vitiligo phenotype. This prospective online questionnaire study was approved by the institutional review board at St Luke's-Roosevelt Hospital Center, New York, NY (www.clinicaltrials.gov registration NCT01401374) for adults and children with vitiligo. Survey validation and distribution were performed as previously described.1Silverberg J.I. Silverberg N.B. Association between vitiligo extent and distribution and quality-of-life impairment.JAMA Dermatol. 2013; 149: 159-164Crossref PubMed Scopus (81) Google Scholar Data processing and statistics were done with software (SAS, Version 9.2, SAS Institute Inc, Cary, NC). Logistic regression was used with VAAD as the dependent variables. Independent variables were body surface area (BSA), number of body parts affected, laterality and duration of vitiligo lesions, and itching/burning secondary to vitiligo lesions. Adjusted odds ratios were calculated by including sex, age, and race/ethnicity in multivariate models. No significant linear interaction terms were found. Logistic regression with stepwise selection of predictors was used to determine whether vitiligo distribution (11 sites) is associated with VAAD. Complete case analysis was performed. Correction for multiple dependent tests (k = 107) with the approaches of Benjamini and Hochberg2Benjamini Y. Hochberg Y. Controlling the false discovery rate–a practical and powerful approach to multiple testing.J R Stat Soc Series B Stat Method. 1995; 57: 289-300Google Scholar yielded a critical P value of .03. The survey was completed by 97% (2763); 2644 were given the diagnosis of vitiligo by a physician, including 2273 adults and 371 children/adolescents. In adults, 790 (34.8%) reported VAAD, most commonly hyperthyroidism/hypothyroidism, rheumatoid arthritis (RA), pernicious anemia (PA), type 2 diabetes mellitus (DM), and alopecia areata (Table I). VAAD was associated with female sex (logistic regression, P < .0001) and older age (P ≤ .002), but inversely associated with Indian (P < .0001) and Asian (P = .007) race/ethnicity. BSA, number of body parts affected, bilaterality, prolonged duration of vitiligo, and itching/burning of skin were associated with VAAD, particularly multiple disorders (Table II). Hyperthyroidism/hypothyroidism, RA, PA, and type 2 DM were associated with older age and increased vitiligo extent (BSA, number of body parts, and/or bilaterality). Hyperthyroidism/hypothyroidism and RA were also associated with duration and itching/burning from vitiligo. Sjögren disease was associated with increased BSA. However, type 1 DM, alopecia areata, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and systemic lupus erythematosus (SLE) were not associated with the above-mentioned variables. SLE, Systemic lupus erythematosus. aOR, Adjusted odds ratio; CI, confidence interval; OR, odds ratio; ref, reference group. Hyperthyroidism/hypothyroidism was associated with lesions on the hands, feet, and chest (Table III). PA was associated with gray hair and abdominal lesions. RA, type 2 DM, and Sjögren disease were associated with abdominal lesions. Type 1 DM, inflammatory bowel disease, and SLE were not associated with vitiligo distribution. aOR, Adjusted odds ratio; CI, confidence interval; IBD, inflammatory bowel disease; UC, ulcerative colitis. In children, 31 (8.4%) had VAAD, most commonly hyperthyroidism/hypothyroidism, RA, psoriasis, and alopecia areata. There were no associations of demographics, vitiligo extent, duration or distribution and VAAD. The prevalence of VAAD, except for type 2 DM, are considerably higher than the general adult population (hyperthyroidism = 1.15%, hypothyroidism = 0.79%, RA = 0.86%, PA = 0.15%, type 2 DM = 11.3%, SLE = 0.024%, Sjögren disease = 0.014%3Jacobson D.L. Gange S.J. Rose N.R. Graham N.M. Epidemiology and estimated population burden of selected autoimmune diseases in the United States.Clin Immunol Immunopathol. 1997; 84: 223-243Crossref PubMed Scopus (1241) Google Scholar, 4Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States 2011. Available at: http://www.cdc.gov/diabetes/pubs/estimates11.htm. Accessed March 1, 2013.Google Scholar). Based on these results, we recommend screening for thyroid disease in all patients with vitiligo, especially with extensive disease. Patients with increased extent and duration of vitiligo, itching/burning of skin, and older age should be evaluated for RA, PA, and type 2 DM. Based on the low prevalences and lack of consistent association with vitiligo extent, routine screening for Sjögren disease, inflammatory bowel disease, celiac disease, Addison disease, and dermatitis herpetiformis are not indicated unless suggestive symptomatology is present. Although SLE is uncommon in vitiligo, it may flare with phototherapy. Therefore, screening antinuclear antibody testing may be needed in patients requiring phototherapy.