Association of Clinical Markers With Disease Progression in Patients With Vitiligo From China | Dermatology | JAMA Dermatology | JAMA Network
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Figure 1.  Manifestations of Vitiligo With or Without Clinical Markers Using a Wood Light
Manifestations of Vitiligo With or Without Clinical Markers Using a Wood Light
Figure 2.  Comparison of Disease Progression, Severity, and Prognosis Between Patients With and Without Clinical Markers
Comparison of Disease Progression, Severity, and Prognosis Between Patients With and Without Clinical Markers

VASI improvement is defined as ([baseline VASI–VASI]/baseline VASI).

aP < .001.

Figure 3.  Comparison of Disease Progression, Severity, and Prognosis Between Patients With Single Clinical Markers and With Multiple Clinical Markers
Comparison of Disease Progression, Severity, and Prognosis Between Patients With Single Clinical Markers and With Multiple Clinical Markers

VASI improvement is defined as ([baseline VASI–VASI]/baseline VASI).

aP < .001.

Figure 4.  Disease Progression, Severity, and Prognosis Among Patients With Trichrome Sign (TS), Confetti-like Depigmentation (CD), and Koebner Phenomenon (KP)
Disease Progression, Severity, and Prognosis Among Patients With Trichrome Sign (TS), Confetti-like Depigmentation (CD), and Koebner Phenomenon (KP)

VASI improvement is defined as ([baseline VASI–VASI]/baseline VASI).

aP = .02.

bP = .01.

cP = .03.

Table.  Baseline Characteristics of Participants
Baseline Characteristics of Participants
1.
Ezzedine  K, Eleftheriadou  V, Whitton  M, van Geel  N.  Vitiligo.  Lancet. 2015;386(9988):74-84. doi:10.1016/S0140-6736(14)60763-7PubMedGoogle ScholarCrossref
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Picardo  M, Dell’Anna  ML, Ezzedine  K,  et al.  Vitiligo.  Nat Rev Dis Primers. 2015;1:15011. doi:10.1038/nrdp.2015.11PubMedGoogle ScholarCrossref
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Harris  JE, Harris  TH, Weninger  W, Wherry  EJ, Hunter  CA, Turka  LA.  A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8+ T-cell accumulation in the skin.  J Invest Dermatol. 2012;132(7):1869-1876. doi:10.1038/jid.2011.463PubMedGoogle ScholarCrossref
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Rashighi  M, Agarwal  P, Richmond  JM,  et al.  CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo.  Sci Transl Med. 2014;6(223):223ra23. doi:10.1126/scitranslmed.3007811PubMedGoogle Scholar
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Maouia  A, Sormani  L, Youssef  M, Helal  AN, Kassab  A, Passeron  T.  Differential expression of CXCL9, CXCL10, and IFN-γ in vitiligo and alopecia areata patients.  Pigment Cell Melanoma Res. 2017;30(2):259-261. doi:10.1111/pcmr.12559PubMedGoogle ScholarCrossref
6.
Frisoli  ML, Harris  JE.  Vitiligo: mechanistic insights lead to novel treatments.  J Allergy Clin Immunol. 2017;140(3):654-662. doi:10.1016/j.jaci.2017.07.011PubMedGoogle ScholarCrossref
7.
Speeckaert  R, Speeckaert  M, De Schepper  S, van Geel  N.  Biomarkers of disease activity in vitiligo: a systematic review.  Autoimmun Rev. 2017;16(9):937-945. doi:10.1016/j.autrev.2017.07.005PubMedGoogle ScholarCrossref
8.
Rodrigues  M, Ezzedine  K, Hamzavi  I, Pandya  AG, Harris  JE; Vitiligo Working Group.  New discoveries in the pathogenesis and classification of vitiligo.  J Am Acad Dermatol. 2017;77(1):1-13. doi:10.1016/j.jaad.2016.10.048PubMedGoogle ScholarCrossref
9.
Komen  L, da Graça  V, Wolkerstorfer  A, de Rie  MA, Terwee  CB, van der Veen  JP.  Vitiligo Area Scoring Index and Vitiligo European Task Force assessment: reliable and responsive instruments to measure the degree of depigmentation in vitiligo.  Br J Dermatol. 2015;172(2):437-443. doi:10.1111/bjd.13432PubMedGoogle ScholarCrossref
10.
Strassner  JP, Rashighi  M, Ahmed Refat  M, Richmond  JM, Harris  JE.  Suction blistering the lesional skin of vitiligo patients reveals useful biomarkers of disease activity.  J Am Acad Dermatol. 2017;76(5):847-855.e5. doi:10.1016/j.jaad.2016.12.021PubMedGoogle ScholarCrossref
11.
Naldi  L, Sassi  F.  Vitiligo.  N Engl J Med. 2009;360(17):1788. doi:10.1056/NEJMc090205PubMedGoogle ScholarCrossref
12.
Aboul-Fettouh  N, Hinojosa  J, Tovar-Garza  A, Pandya  AG.  The majority of patients presenting with vitiligo have a clinical sign of activity.  J Am Acad Dermatol. 2017;77(4):774-775. doi:10.1016/j.jaad.2017.05.027PubMedGoogle ScholarCrossref
13.
Wang  XX, Wang  QQ, Wu  JQ,  et al.  Increased expression of CXCR3 and its ligands in patients with vitiligo and CXCL10 as a potential clinical marker for vitiligo.  Br J Dermatol. 2016;174(6):1318-1326. doi:10.1111/bjd.14416PubMedGoogle ScholarCrossref
14.
Goh  BK, Pandya  AG.  Presentations, signs of activity, and differential diagnosis of vitiligo.  Dermatol Clin. 2017;35(2):135-144. doi:10.1016/j.det.2016.11.004PubMedGoogle ScholarCrossref
15.
Hann  SK, Kim  YS, Yoo  JH, Chun  YS.  Clinical and histopathologic characteristics of trichrome vitiligo.  J Am Acad Dermatol. 2000;42(4):589-596. doi:10.1016/S0190-9622(00)90170-1PubMedGoogle ScholarCrossref
16.
Nicolaidou  E, Antoniou  C, Stratigos  AJ, Stefanaki  C, Katsambas  AD.  Efficacy, predictors of response, and long-term follow-up in patients with vitiligo treated with narrowband UVB phototherapy.  J Am Acad Dermatol. 2007;56(2):274-278. doi:10.1016/j.jaad.2006.09.004PubMedGoogle ScholarCrossref
17.
Cavalié  M, Ezzedine  K, Fontas  E,  et al.  Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment: a randomized, double blind, placebo-controlled study.  J Invest Dermatol. 2015;135(4):970-974. doi:10.1038/jid.2014.527PubMedGoogle ScholarCrossref
18.
Richmond  JM, Strassner  JP, Zapata  L  Jr,  et al.  Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo.  Sci Transl Med. 2018;10(450):eaam7710. doi:10.1126/scitranslmed.aam7710PubMedGoogle Scholar
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Riding  RL, Harris  JE.  The role of memory CD8+ T cells in vitiligo.  J Immunol. 2019;203(1):11-19. doi:10.4049/jimmunol.1900027PubMedGoogle ScholarCrossref
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    Original Investigation
    January 22, 2020

    Association of Clinical Markers With Disease Progression in Patients With Vitiligo From China

    Author Affiliations
    • 1Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
    JAMA Dermatol. 2020;156(3):288-295. doi:10.1001/jamadermatol.2019.4483
    Key Points

    Question  Can the clinical markers of vitiligo be used to assess disease progression, severity, and patient prognosis?

    Findings  In this cohort study of 458 patients with vitiligo from China, among 425 patients who completed 12-month follow-up, 224 (52.7%) did not have any clinical marker and 201 (47.3%) had at least 1 clinical marker at the first visit. The proportion of patients in the active stage was significantly higher in the cohort with clinical markers compared with the cohort without any marker at the baseline examination and at 3-month follow-up; presence of clinical markers was also associated with disease progression at 1- and 3-month follow-up

    Meaning  The findings suggest that clinical markers, including trichrome sign, confetti-like depigmentation, and Koebner phenomenon, are associated with vitiligo progression and prognosis and that patients with multiple clinical markers may require more intensive treatment.

    Abstract

    Importance  It is necessary to determine whether established clinical markers of vitiligo are associated with disease progression, severity, and patient prognosis.

    Objective  To evaluate the utility of trichrome sign, confetti-like depigmentation, and Koebner phenomenon in assessing disease progression, severity, and prognosis in patients with vitiligo.

    Design, Setting, and Participants  In this prospective cohort study, 425 patients with vitiligo were recruited from the outpatient department of Huashan Hospital, Fudan University in Shanghai, China, from September 1, 2016, to May 13, 2019.

    Main Outcomes and Measures  Disease progression, severity, and prognosis during a 12-month period. The active stage of vitiligo was defined as Vitiligo European Task Force spreading score of at least 1 or more lesions appearing as hypomelanotic with poorly defined borders using a Wood light. Progression was assessed using the Vitiligo Area Scoring Index (VASI) and serum CXCL10 level measurement.

    Results  Of the 458 enrolled patients, 425 (235 female [55.3%]; mean [SD] age, 30.9 [10.2] years) completed the 12-month follow-up. Of the 425 patients (224 with no clinical marker and 201 with at least 1 clinical marker) included in this analysis, the proportion in the active stage of the disease was significantly higher in the cohort with at least 1 clinical marker compared with the cohort without any clinical marker at the first visit (196 of 201 [97.5%] vs 159 of 224 [71.0%]; P < .001) and at 3-month follow up (91 of 201 [45.3%] vs 52 of 224 [23.2%]; P < .001). The proportion of patients with rapid disease progression was also higher in the group with at least 1 clinical marker at 1-month follow-up (142 of 201 [70.6%] vs 60 of 224 [26.8%]; P < .001) and 3-month follow-up (63 of 201 [31.3%] vs 9 of 224 [4.0%]; P < .001). The improvement in VASI score (SD) was significantly smaller among patients with at least 1 clinical marker compared with those without any clinical marker at 6 months (mean [SD], 0.14 [0.12] vs 0.23 [0.21]; P = .02), at 9 months (mean [SD], 0.29 [0.19] vs 0.44 [0.25]; P = .03), and at 12 months (mean [SD], 0.47 [0.21] vs 0.63 [0.23]; P = .03).

    Conclusions and Relevance  The presence of a clinical marker in patients with vitiligo may be associated with worse prognosis and rapid disease progression. Patients with multiple clinical markers may require more intensive treatment.

    Introduction

    Vitiligo is an acquired depigmentation disorder affecting 0.5% to 2.0% of the global population1 and is often psychologically devastating because the signs usually appear on the face and other visible areas. Disease progression is unpredictable and characterized by periods of disease inactivity interspersed with that of slow or rapid depigmentation, which is frequently indicative of worse prognosis and longer treatment course.2 However, former criteria for defining disease activity was mostly based on small-scale studies.3 Therefore, novel markers for the clinical progression from large-scale prospective studies with long-term follow-up need to be identified to devise early intervention strategies.

    Interferon (IFN)-γ and IFN-γ–induced cytokines and chemokines secreted by the keratinocytes are overexpressed in vitiliginous lesions and are critical for recruiting melanocyte-specific cytotoxic CD8 T cells.3-5 Chemokines CXCL9 and CXCL10 are the predominant chemokines involved in vitiliginous T-cell migration,6 whereas CXCL10 is a potential biomarker that can demarcate between stable and active vitiligo.7 By contrast, reliable phenotypic or clinical markers for vitiligo progression are currently scarce. Trichrome sign, confetti-like depigmentation, and Koebner phenomenon have been reported as clinical features of progressive vitiligo.8 However, the association of these clinical signs with disease activity, severity, and prognosis remains to be elucidated. Therefore, we conducted a study with a large cohort of patients with vitiligo and evaluated the value of trichrome sign, confetti-like depigmentation, and Koebner phenomenon in assessing the stage, progression, severity, and prognosis of vitiligo.

    Methods
    Study Population

    This cohort study was performed during 12 months between September 1, 2016, and May 13, 2019, with the approval of the Huashan Hospital Ethics Committee, Fudan University. Written informed consent was obtained from all patients before the study. The primary inclusion and exclusion criteria for the patients are described in eTable in the Supplement.

    Clinical Grouping and Assessment

    The enrolled patients were classified as positive or negative for the clinical markers; those with markers were further divided by whether they had a single marker (trichrome sign, confetti-like depigmentation, or Koebner phenomenon) or multiple markers. Disease diagnosis was assessed independently by 2 specialists (L.Z., L.X.) using daylight and a Wood light, and the same sites of the lesions were photographed during each follow-up visit using identical background, lighting, and camera settings. Assessment of spreading was based on Wood lamp examination of the same largest macule in each body area (0 indicated similar limits; 1, ongoing subclinical depigmentation; –1, ongoing subclinical repigmentation).9 The disease was defined as active if the lesions appeared as hypomelanotic with poorly defined borders using Wood light or had a Vitiligo European Task Force–spreading score9 of at least 1; otherwise, disease was defined as stable. The disease was defined as progression in terms of the proportion of patients with both higher Vitiligo Area Scoring Index (VASI) scores (compared with the baseline VASI score for each patient) and increased serum CXCL10 levels determined by enzyme-linked immunosorbent assay as previously described.10 Disease severity was assessed in terms of the baseline VASI score and the proportion of patients with baseline VASI score more than 50, and prognosis was assessed as repigmentation at 6, 9, and 12 months. Change in VASI was calculated as ([baseline VASI–VASI]/baseline VASI). If VASI change was more than 0, we used the term of VASI improvement; otherwise, we used the term of VASI aggravation. The length of progression was the period from onset to progression arrest, which was defined once the border of the lesion became well demarcated.

    Treatment

    The patients received narrowband UV-B phototherapy twice a week and applied 0.1% tacrolimus topically twice per day. Short-term administration of systemic corticosteroid therapy was prescribed for patients with progression of disease.

    Statistical Analysis

    Data analysis was conducted using GraphPad Prism (GraphPad Software) and SPSS, version 19 (IBM Corporation). Continuous variables were expressed as means (SDs) and discrete variables as percentage distributions. Fisher exact and χ2 tests were used to compare qualitative data and t test and analysis of variance test for quantitative data. Two-factor repeated measure analysis of variance was used for comparison of the VASI score changes between or within the different groups. In repeated measures analysis, we reported the results of Greenhouse-Geisser correction whenever the result of the Mauchly test of sphericity was significant. To compare the VASI change between groups, pairwise comparisons (with Bonferroni adjustment for multiple comparisons) were used. P < .05 was considered to be statistically significant.

    Results
    Clinical Characteristics of the Patients

    Of all 458 patients with vitiligo, 425 (235 female [55.3%]; mean [SD] age, 30.9 [10.2] years) completed the 12-month follow-up; with 3 patients dropping out at the 3-month follow-up, 12 at the 6-month follow-up, 10 at the 9-month follow-up, and 8 at the 12-month follow-up (Table). The mean (SD) age at disease onset was 25.7 (11.9) years, mean (SD) disease duration was 5.3 (6.4) years, and mean (SD) baseline VASI score in the entire cohort was 15.55 (17.86). In addition, 201 of 425 patients (47.3%) had at least 1 clinical marker, and the 224 remaining patients (52.7%) had no clinical marker. Furthermore, the proportion of patients by type of vitiligo (nonsegmental, segmental, and mixed), the distribution of lesions, and the frequency of halo nevi in the groups were not significantly different.

    Association of Clinical Markers With Progression, Severity, and Prognosis of Vitiligo

    Typical clinical photographs using a Wood light are shown in Figure 1. The proportion of patients in active stage in the clinical marker–positive group was significantly higher than that in the clinical marker–negative group at baseline (196 of 201 [97.5%] vs 159 of 224 [71.0%)]; P < .001]) and at the 3-month follow-up (91 of 201 [45.3%] vs 52 of 224 [23.2%]; P < .001) (Figure 2A). In addition, the presence of clinical markers was associated with the ratio of patients with disease progression at 1 month (142 of 201 [70.6%] vs 60 of 224 [26.8%]; P < .001) and 3 months (63 of 201 [31.3%] vs 9 of 224 [4.0%]; P < .001) of follow-up. The mean (SD) serum CXCL10 levels were consistently significantly higher in patients with clinical markers than in those without clinical markers (1230.0 [311.4] vs 611.6 [118.3] pg/mL; P < .001) (Figure 2B). Although the mean (SD) baseline VASI scores were similar in both groups (16.12 [19.36] in the group with clinical markers vs 15.04 [16.41] in the group without a clinical marker; P = .53), the proportion of patients with a baseline VASI score greater than 50 was significantly higher among those with a clinical marker (26 of 201 [12.9%] vs 15 of 224 [6.7%]; P = .03). The omnibus clinical marker group (with and without clinical markers × time interaction) for VASI change was significant (Greenhouse-Geisser corrected: F = 3.872, P = .02) and was followed by pairwise comparisons, which revealed that the improvement in VASI score was significantly smaller among patients with at least 1 clinical marker compared with those without any clinical marker at 6 months (mean [SD], 0.14 [0.12] vs 0.23 [0.21]; P = .02), at 9 months (mean [SD], 0.29 [0.19] vs 0.44 [0.25]; P = .03), and at 12 months (mean [SD], 0.47 [0.21] vs 0.63 [0.23]; P = .03) (Figure 2C). Moreover, the improvement in VASI score was significantly different from 1 month to 12 months in patients with clinical markers and those without clinical markers. The extent of repigmentation at 12 months was also significantly worse in patients with clinical markers (Figure 2D), which was consistent with the longer length of progression in that cohort (mean [SD], 6.46 [1.48] vs 4.36 [1.05] months; P < .001).

    Of the 201 patients exhibiting at least 1 clinical marker of vitiligo, only 41 presented with 2 or more clinical markers. The proportion of patients in the active stage of the disease at baseline was similar regardless of the presence of a single marker or multiple markers (155 of 160 [96.9%] vs 41 of 41 [100%]; P = .58) (Figure 3A). However, presence of multiple clinical markers at the first visit was associated with a significantly higher proportion of patients in the active stage at 3 months of follow-up (61 of 160 [38.1%] vs 30 of 41 [73.2]; P < .001) (Figure 3A). Furthermore, a significantly higher proportion of patients with multiple markers experienced disease progression at 1 month (106 of 160 [66.3%] vs 36 of 41 [87.8%]; P = .01) and 3 months (34 of 160 [21.3%] vs 23 of 41 [56.1%]; P < .001) of follow-up. Patients with multiple markers also had significantly higher mean (SD) serum CXCL10 levels (1147.0 [251.7] vs 1552.0 [316.0] pg/mL; P < .001) (Figure 3B). In addition, both the mean (SD) baseline VASI score (14.14 [16.65] vs 23.86 [26.35]; P = .004) and the proportion of patients with baseline VASI score greater than 50 (12 of 160 [7.5%] vs 14 of 41 [34.1%]; P < .001) were significantly higher among those with multiple clinical markers than among those with only 1 clinical marker. The omnibus clinical marker group (multiple and single clinical marker × time interaction) for VASI change was significant (Greenhouse-Geisser corrected: F = 3.703, P = .02). Pairwise comparisons revealed that the improvement in VASI score was significantly greater in patients with a single clinical marker compared with those with multiple clinical markers at 6, 9, and 12 months (Figure 3C), which corresponded to higher repigmentation at 12 months (P < .001) (Figure 3D) and shorter mean (SD) length of progression (6.00 [1.14] vs 8.23 [1.31] months; P < .001). Moreover, the improvement in VASI score was significantly different from 1 month to 12 months in patients with multiple clinical markers and in those without a clinical marker (Figure 3C).

    The type of clinical marker (ie, trichrome sign [n = 82], confetti-like depigmentation [n = 68], and Koebner phenomenon [n = 10]) was not associated with the proportion of patients in the active stage at baseline (78 of 82 [95.1%] vs 67 of 68 [98.5%] vs 10 of 10 [100%]; P = .19) or at 3 months (33 of 82 [40.2%] vs 23 of 68 [33.8%] vs 5 of 10 [50.0%]; P = .52) (Figure 4A). In addition, no significant differences were observed in the proportion of patients with disease progression at 1 month (53 of 82 [64.6%] vs 45 of 68 [66.2%] vs 8 of 10 [80.0%]; P = .62) and 3 months (18 of 82 [22.0%] vs 14 of 68 [20.6%] vs 2 of 10 [20.0%]; P = .97) of follow-up, as well as in the mean (SD) serum CXCL10 levels (1147.0 [221.4] vs 1145.0 [275.3] vs 1165.0 [336.9] pg/mL; P = .97) (Figure 4B) across the specific marker groups. However, the mean (SD) length of progression was significantly different among the 3 groups (6.27 [1.00] vs 5.76 [1.15] vs 5.45 [1.60] months; P = .01), with trichrome sign being associated with longer length compared with confetti-like depigmentation (P = .004) and Koebner phenomenon (P = .03). Neither the mean (SD) baseline VASI scores (14.12 [17.47] vs 14.33 [15.74] vs 12.96 [17.44]; P = .97) nor the proportion of patients with mean (SD) baseline VASI scores greater than 50 (7 of 82 [8.5%] vs 4 of 68 [5.9%] vs 1 of 10 [10.0%]; P = .77) was associated with the type of clinical marker. Furthermore, significant differences were observed among patients with trichrome sign, confetti-like depigmentation, and Koebner phenomenon in repigmentation at 12 months (Figure 4C). The omnibus single clinical marker group (trichrome sign, confetti-like depigmentation, and Koebner phenomenon × time interaction) for VASI change was significant (Greenhouse-Geisser corrected: F = 2.482, P = .03). The VASI improvement was significantly greater in patients with trichrome sign compared with those with confetti-like depigmentation at 6 months, at 9 months, and at 12 months (Figure 4C). Moreover, pairwise comparison showed that the improvement in VASI score was significantly different from 1 month to 12 months in the trichrome sign and confetti-like groups. The improvement in VASI score was significantly different from 1 month to 12 months except between month 3 and month 6 in the Koebner phenomenon group.

    Relapse Within Past 2 Years and VASI

    In the cohort with a clinical marker, the VASI aggravation at month 1 and 3 and the VASI improvement at months 6, 9, and 12 were significantly different between patients with a history of relapse in the past 2 years compared with those with no history of relapse in past 2 years. The VASI improvement was significantly different at month 3 in the cohort without a clinical marker (eFigure in the Supplement). In the cohort with multiple clinical markers, the VASI aggravation was greater in patients with a history of relapse compared with those without a history of relapse at month 1. In the cohort with a single clinical marker, the VASI aggravation was greater in patients with a history of relapse compared with those without a history of relapse at month 1; in addition, the VASI improvement was smaller in patients with a history of relapse compared with those without a history of relapse at months 9 and 12 (eFigure in the Supplement). No significant difference was found in patients with confetti-like depigmentation and Koebner phenomenon between month 1 to month 12. In the cohort with trichome sign, the VASI aggravation between those with a history of relapse and those without a history of relapse was not significantly different at months 1 and 3 (eFigure in the Supplement).

    Discussion

    Vitiligo treatment is usually lengthy and challenging.11 Clinical markers, such as trichrome sign, confetti-like depigmentation, and Koebner phenomenon, may be more convenient and noninvasive than serum biomarkers for assessing the prognosis of vitiligo.

    We analyzed a large cohort of patients with vitiligo from China and found a significantly higher frequency of active disease among those with at least 1 of the 3 clinical markers compared with patients without a clinical marker, as well as a greater risk of aggravated symptoms in those with clinical markers 1 and 3 months after initial examination. Similar findings have been reported by Aboul-Fettouh et al.12 Furthermore, presence of clinical markers was associated with significantly higher levels of CXCL10, which is known to recruit cytotoxic CD8 T cells to the epidermis in patients with vitiligo.13 Previous studies14 have shown that the occurrence of confetti-like depigmentation, trichrome lesions, and Koebner phenomenon indicate disease activity. Consistently, the length of progression was longer in patients with clinical markers than in those without clinical markers, which corresponded to a smaller difference in VASI scores and worse repigmentation at the later follow-up time points. We also found that patients with multiple clinical markers had more progressive lesions than did those with a single clinical marker, as well as greater frequency of active disease and severity of symptoms, longer length of progression, and worse repigmentation. Taken together, the presence of clinical markers of vitiligo was associated with unfavorable prognosis, and the risk of disease progression and therapeutic recalcitrance increased further with the presence of additional markers. Of interest, we observed significant differences in long-term (>3 months) disease activity, progression, and prognosis among 3 types of clinical markers. For instance, the length of progression was longer in patients with trichrome sign than in those with confetti-like depigmentation. It has been reported that trichrome lesions naturally progress to typical vitiligo macules with total depigmentation,15 and biopsies of the border of trichrome lesions show inflammatory cell infiltration and degeneration of the basal layer. In line with the abovementioned research studies, we further revealed that more patients with trichrome signs in the present cohort had the progressive stage of disease compared with those with confetti-like depigmentation. Trichrome lesions progressed in the early period of treatment possibly because of loss of functional melanocytes in the hypopigmented portion, and the remaining melanin in keratinocytes may have not yet turned over to exhibit depigmentation. Owing to reduced production of melanin, the hypopigmented portion would then turn to complete depigmentation. This would suggest that trichrome may not be a sign of resistance to treatment but an indication of where the borders will be once stabilized.

    Relapse is also a common problem among patients with vitiligo. As shown in previous studies,16,17 an estimated 40% of patients with vitiligo experience relapse within 1 year after stopping treatment. In our study, we found that a history of relapse within the past 2 years was associated with VASI improvement especially in those with clinical markers. Recent studies have identified that the signals driving CD8 T-cell memory formation and retention in vitiligo were associated with relapse of vitiligo,18,19 which might explain our findings.

    Limitations

    As a single-center study, there was a potential selection bias of the patients in the cohort. Although all patients in active stage were treated with systemic corticosteroids at the onset of this study and underwent identical therapeutic principle to minimize confounding, there was still confounding because not all patients received the same treatment regimen. Moreover, systemic corticosteroids helped prevent progression of vitiligo lesions; thus, the positive rates for the 3 studied clinical markers should have been reduced after systemic corticosteroid treatment. The effects of those clinical markers might be even greater than reported in the study.

    Conclusions

    Clinical markers may be useful for assessing vitiligo progression and prognosis. In this study, prognosis was worse in patients with more than 2 markers. In addition, patients presenting with a trichrome sign may require a more aggressive therapeutic approach.

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    Article Information

    Accepted for Publication: November 23, 2019.

    Corresponding Author: Leihong Xiang, MD, PhD (flora_xiang@vip.163.com) and Chengfeng Zhang, MD, PhD (e3dangdang@hotmail.com), Department of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China.

    Published Online: January 22, 2020. doi:10.1001/jamadermatol.2019.4483

    Author Contributions: Drs L. Zhang and C. Zhang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: L. Zhang, Chen, X. Wang, Yan, Jiang, C. Zhang, Xiang.

    Acquisition, analysis, or interpretation of data: L. Zhang, Chen, Kang, Yan, Jiang, Q. Wang, Liu, C. Zhang, Xiang.

    Drafting of the manuscript: All authors.

    Critical revision of the manuscript for important intellectual content: L. Zhang, C. Zhang, Xiang.

    Statistical analysis: L. Zhang, Chen, Kang, X. Wang, Yan, Jiang, Q. Wang, Xiang.

    Obtained funding: Jiang, C. Zhang, Xiang.

    Administrative, technical, or material support: L. Zhang, Chen, Kang, X. Wang, Jiang, Liu, C. Zhang, Xiang.

    Supervision: L. Zhang, C. Zhang, Xiang.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This research was supported by grants 81872544, 81472901, 81703145, and 81573064 from the National Natural Science Foundation of China.

    Role of the Funder/Sponsor: The funding source had no role in designing the study, the collection, management, analysis, and interpretation of the data, the preparation, review or approval of the manuscript, or the decision to submit the manuscript for publication.

    Additional Contributions: We thank the patient for granting permission to publish this information.

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