BP.<sup>6,7</sup> Our study showed a direct positive correlation between TARC levels and disease activity scores in BP patients for the first time. In particular, TARC levels correlated with urticaria/erythema scores of the BPDAI score; this may reflect the inflammatory pathogenic response in BP similar to the Th2 response in atopic dermatitis.<sup>8</sup> Notably, a longitudinal analysis of our cases showed that TARC levels sensitively reflected skin flare-ups and were upregulated before the increase in anti-BP180 Ab levels in some cases. Serum TARC levels sharply reflect disease activity in BP with high sensitivity and across a wide range of changes. In conclusion, these results suggest that in clinical practice, TARC levels could usefully predict disease activity in patients with BP.

**Conflicts of interest**

None to declare.

**Funding source**

None to declare.

M. Suzuki,<sup>1,2</sup> Y. Yamaguchi,<sup>1,*</sup> K. Nakamura,<sup>2</sup> M. Kanaoka,<sup>1</sup> S. Matsukura,<sup>2</sup> K. Takahashi,<sup>1</sup> Y. Takahashi,<sup>3</sup> T. Kambara,<sup>2</sup> M. Aihara<sup>1</sup>

**References**

1 Wang Y, Mao X, Wang Y *et al*. Relapse of bullous pemphigoid: an update on this stubborn clinical problem. *Ann Med* 2018; **50**: 234–239.

2 Bernard P, Reguiai Z, Tancrede-Bohin E *et al*. Risk factors for relapse in patients with bullous pemphigoid in clinical remission: a multicenter, prospective, cohort study. *Arch Dermatol* 2009; **145**: 537–542.

3 Fichel F, Barbe C, Joly P *et al*. Clinical and immunologic factors associated with bullous pemphigoid relapse during the first year of treatment: a multicenter, prospective study. *JAMA* 2014; **150**: 25–33.

4 Lever WF. Pemphigud and pemphigoid: a review of advances made since 1964. *J Am Acad Dermatol* 1979; **1**: 2–31.

5 Murrell DF, Daniel BS, Joly P *et al*. Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts. *J Am Acad Dermatol* 2012; **66**: 479–485.

6 Inaoki M, Takehara K. Increased serum levels of interleukin (IL)-5, IL-6 and IL-8 in bullous pemphigoid. *J Dermatol Sci* 1998; **16**: 152–157.

7 Echigo T, Hasegawa M, Shimada Y, Inaoki M, Takehara K, Sato S. Both Th1 and Th2 chemokines are elevated in sera of patients with autoimmune blistering diseases. *Arch Dermatol Res* 2006; **298**: 38–45.

8 Kakinuma T, Nakamura K, Wakugawa M *et al*. Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity. *J Allergy Clin Immunol* 2001; **107**: 535–541.

DOI: 10.1111/jdv.16851

# Palmoplantar lichen planus-like lupus erythematosus keratoderma: an underrecognized and distinctive cutaneous manifestation of systemic or subacute lupus erythematosus

**Editor**

Palmoplantar keratoderma (PPK) is a rare cutaneous manifestation associated with systemic lupus erythematosus (SLE)<sup>1-3</sup> considered as non-specific and distinct from palmoplantar discoid LE (DLE),<sup>4</sup> chilblain LE<sup>5</sup> or lichen planus (LP)-LE overlap syndrome.<sup>6,7</sup> Herein, we report an underrecognized clinicopathological entity of LP-like/LE PPK associated with SLE or subacute LE subset.

Twelve patients (11 females/1 male; median age: 56.5 years [20–78]) with PPK associated with SLE according to the 2019 European League Against Rheumatism and American College of Rheumatology classification criteria<sup>8</sup> were evaluated in six French Departments of Dermatology, Rheumatology and Internal Medicine over 18 months. PPK occurrence was inaugural of the SLE diagnosis in one-third of the cases after a median delay of 4.5 years (0–40). Cutaneous findings of PPK were characterized by the following: (i) tender or painful symmetrical plantar keratoderma composed of circumscribed yellowish hyperkeratosis overlying the pressure surface of the soles (Fig. 1a, b, e), with associated palmar keratoderma in 50% of cases, mostly arranged in a transversal and linear shape with an elective location in and/or around the palmar interphalangeal fold (Fig. 1f, g); (ii) diffuse livid, red-to-purple, telangiectatic erythema of the soles extending to the periungual area of the toes, with similar erythema on the fingers and/or palms noted in 67% of cases, mostly located on the fingertips including periungual borders and almost extending below the proximal interphalangeal fold; (iii) tender or painful atrophic palmoplantar patches and plaques in 75%, bordered by a minimal marginal collarette of white to yellowish scales (Fig 1c) and associated with erosion and/or haemorrhagic fissures and/or ulceration in 89%; and (iv) scleroatrophy of the tips of the fingers and/or toes in 42% and severe nail dystrophy (Fig 1d) and/or anonychia in 33%. Other relevant cutaneous findings included subacute cutaneous LE lesions (SCLE): 58%, Raynaud's phenomenon: 50%, chronic discoid LE: 42%, chilblain LE: 25%, reticulate livedo: 25% and acute LE: 8%. Oral chronic lesions were present in 58%, characterized by round, well-circumscribed, erythematous and atrophic plaques surrounded by LP-like reticulated leukokeratosis. These were clinically indistinguishable from oral discoid LE or LP. No cutaneous lesions typical of LP were observed.

<footnote n="1"><sup>1</sup>Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan, <sup>2</sup>Department of Dermatology, Yokohama City University Medical Centre, Yokohama, Japan, <sup>3</sup>NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan</footnote>

<footnote>*Correspondence: Y. Yamaguchi. E-mail: yui1783@yokohama-cu.ac.jp</footnote>
<figure><img src="image_1.png" /><figcaption>**Figure 1** Palmoplantar keratoderma and systemic lupus erythematosus (SLE). (a). Circumscribed yellowish plantar hyperkeratosis overlying the pressure surface of the soles (PSS) associated with diffuse livid, purple, telangiectatic erythema of the soles partly sparing the medial plantar area. (b). Association of yellowish keratoderma/livid erythema of the PPS and ulcerated and atrophic linear plaques with a marginal white to yellowish scaling collarette on the anterior lateral eminence of the soles. (c). Atrophic and erosive digital palmar patches bordered by a minimal marginal collarette of white scales. (d). Cutaneous atrophy and erosion of the tip of the two first two toes associated with nail dystrophy (e). Association of yellowish keratoderma, violaceous erythema and ulcerated, atrophic linear plaques of the heel. (f). Distal and well-defined telangiectatic red-violaceous erythema of the fingers associated with hyperkeratosis of the interdigital folds. (g). Association of well-defined purple erythema located below the proximal interphalangeal fold with linear hyperkeratosis of the distal interphalangeal fold and atrophic livid macules of the fingers. (h). Physiological orthokeratotic hyperkeratosis of plantar skin with a dense and continuous lymphocytic infiltrate of the papillary dermis, in direct contact with the epidermal-dermal junction. (i). On higher magnification, vacuolization and necrosis of keratinocytes become visible.</figcaption></figure>

Histological findings of PPK (11/12) were consistent with overlapping features of LP and LE, especially varying degrees of dense band-like infiltrate composed of lymphocytes close to the dermal-epidermal junction, liquefaction degeneration of the basal layer, hyaline thickening of the basement membrane and a number of hyaline bodies (Fig. 1h, i). Presence of antinuclear autoantibodies was constant and associated with, in decreasing order of frequency, anti-Ro/SSA: 83%, anti La/SSB: 42%, anti-DNA: 33%, anti-RNP or anti-centromere: 17% and anti-Sm: 8%. None of the following treatments could be considered

selectively efficient: hydroxychloroquine, oral corticosteroids, thalidomide, lenalidomide, acitretin, dapsone or belimumab.

The occurrence of PPK in patients with LE is rarely mentioned in the literature, partly documented and discussed under such various and confusing designations as ‘ulcerating plantar keratoderma’,<fnref n="1" /> ‘verrucous form of chilblain LE’,³ ‘livedoid palmoplantar keratoderma’,² ‘LE/LP overlap syndrome’ or ‘palmoplantar LP and LE’.⁹,¹⁰ Herein, our large and homogeneous series highlights the distinctive and recognizable pattern of LP-like/LE PPK that could be differentiated from other keratotic and/or inflammatory palmoplantar findings encountered in LE. In particular, it differs from LP/LE overlap syndrome, an umbrella term applied to a rare and heterogeneous disorder characterized by the presence of cutaneous lesions with clinical and histopathological features of both LP and LE, but without unequivocal diagnosis of either disorder.⁹ The uniform clinicopathological pattern of PPK, the absence of other lesions typical of lichen planus and the high frequency of detection of anti-Ro/SSA autoantibodies suggest that LP-like/LE PPK is a specific cutaneous manifestation of SLE and/or the SCLE subset, sometimes inaugural, and associated with a marked risk of distal scleratrophy.

## Acknowledgement

The patients in this manuscript have given written informed consent to the publication of their case details.

## Conflicts of Interest

Drs D. Bessis, J. Gottlieb, L-P. Secco, V. Pallure, Y-M. Pers, J. Gottlieb, C. Girard and D. Lipsker have nothing to disclose; Dr. S.Barete reports personal fees from Novartis, personal fees from Sanofi-Avantis, personal fees from blueprint and personal fees from Janssen, outside the submitted work.

## Funding sources

None.

B. Bergeret,<fnref n="1" /> L.-P. Secco,<fnref n="1" />,² ID V. Pallure,<fnref n="1" />,³ C. Daien,⁴ Y.-M. Pers,⁴ J. Gottlieb,⁵ S. Barete,⁶ C. Girard,<fnref n="1" />,⁷ D. Lipsker,⁸ ID D. Bessis,<fnref n="1" />,⁷,* ID the Study Group of Systemic Diseases in Dermatology (EMSED: Étude des Maladies Systémiques en Dermatologie)

<footnote n="1">¹Department of Dermatology, Saint-Eloi Hospital, University Hospital of Montpellier, Montpellier, France, ²Department of Pathology, Gui de Chauliac Hospital, University Hospital of Montpellier, Montpellier, France, ³Department of Dermatology and Internal Medicine, Perpignan Hospital, Perpignan, France, ⁴Department of Rheumatology, Lapeyronie Hospital, University Hospital of Montpellier, Montpellier, France, ⁵Department of Internal Medicine, Bicêtre University Hospital, AP-HP, Paris, France, ⁶Department of Dermatology, La Pitié Salpétrière University Hospital, AP-HP, Paris, France, ⁷INSERM U1058, Montpellier, France, ⁸Department of Dermatology, Civil Hospital, University Hospital of Strasbourg, Strasbourg, France</footnote>
*Correspondence: D. Bessis. Email: didierbessis@gmail.com
Institutional review board (I.R.B.) Montpellier University Hospital (France)
accreditation number: 198711.

## References

1 Grossberg EB, Scherschun L, Fivenson DP. Ulcerating plantar kerato-derma in association with systemic lupus erythematosus. *Lupus* 2001; **10**: 650-652.

2 Biver-Dalle C, Gil H, Méaux-Ruault N, Mermet-Ginet I *et al*. Acquired ichthyosis and livedoid palmoplantar keratoderma: two unusual skin manifestations of systemic lupus erythematosus. *Rev Med Interne* 2012; **33**: e14-e16.

3 Pock L, Petrovská P, Becvár R *et al*. Verrucous form of chilblain lupus erythematosus. *J Eur Acad Dermatol Venereol* 2001; **15**: 448-451.

4 Rebora A, Bardelli A, Parodi A. Discoid lupus erythematosus of the palms. *J Dermatol* 1985; **12**: 195-197.

5 Millard LG, Rowell NR. Chilblain lupus erythematosus (Hutchinson). A clinical and laboratory study of 17 patients. *Br J Dermatol* 1978; **98**: 497-506.

6 Plotnick H, Burnham TK. Lichen planus and coexisting lupus erythematosus versus lichen planus-like lupus erythematosus. Clinical, histologic, and immunopathologic considerations. *J Am Acad Dermatol* 1986; **14**: 931-938.

7 Braverman. Connective tissue (rheumatic) diseases. In Skin signs of systemic disease. 2nd ed. W.B. Saunders Company, Philadelphia, 1981: 292-295.

8 Dörner T, Furie R. Novel paradigms in systemic lupus erythematosus. *Lancet* 2019; **393**: 2344-2358.

9 Copeman PW, Schroeter AL, Kierland RR. An unusual variant of lupus erythematosus or lichen planus. *Br J Dermatol* 1970; **83**: 269-272.

10 De Jong EM, Van De Kerkhof PC. Coexistence of palmoplantar lichen planus and lupus erythematosus with response to treatment using acitretin. *Br J Dermatol* 1996; **134**: 538-541.

DOI: 10.1111/jdv.16852

# Flag sign: the trichoscopic feature of white hair phenomenon in alopecia areata

## Editor

Trichoscopic features of alopecia areata (AA) are well individualized. Yellow dots, black dots, exclamation mark hairs and tapered hairs are the most common findings.¹ The hair flag sign, referring to the alternating colours of the stripes of a flag, is characterized by horizontal hypo- and hyperpigmented bands in the same hair shaft. Here, we describe trichoscopic hair flag sign in two patients presenting with AA and we emphasize pathophysiological mechanisms of hypopigmented hair phenomenon.

A 10-year-old healthy boy with normal stature and good nutritional status was referred to our outpatient department for patchy hair loss evolving since two months. On physical examination, circular and oval alopecic lesions sized 2-4 cm in diameter were observed all over the scalp, the findings typical for AA (Fig. 1a). The remaining physical examination was unremarkable. Trichoscopy detected black dots and broken hairs (Fig. 1b).

Dermoscopy also demonstrated bands of white and black in the same hair shaft: the hair flag sign (Fig. 1c).

A 21-year-old man with no underlying condition and a good nutritional status presented with a five-year history of hair loss of the scalp and the eyebrows. Clinical examination revealed non-scarring patchy alopecia consisting with AA. The remaining physical examination was normal. Dermoscopy of the scalp and the eyebrows detected black dots, broken hairs and white regrowing hairs. We also observed the hair flag sign in the left eyebrow (Fig. 2a). Microscopic examination showed progressive pigmentation activity from the distal to the proximal part of the hair (Fig. 2b, c, d).

Dermatologists may see the flag sign in hair, skin and nails.² Cutaneous flag sign is an histopathological characteristic of actinic keratosis³ and irritated human papillomavirus-induced keruca.² The nail flag sign has been described in leprosy patients, in individuals with diabetes mellitus,² vitiligo⁴ or diverticulitis.² In the dermatology literature, hair flag sign had been reported in children having the kwashiorkor subtype of protein-calorie malnutrition,⁵ in a child receiving a high-dose methotrexate⁶ and in an alcoholic man.⁷ To the best of our knowledge, the trichoscopic feature of hair flag sign, as observed in our patients, has not been mentioned in AA. It represents the trichoscopic feature of white hair phenomenon in this disease. In fact, it is well known that hypopigmented hair is the first to regrow in AA followed by healthy pigmented hairs after some weeks. In AA, pigment hair is preferentially targeted and the physiopathology of this phenomenon is not completely understood. The most accepted theory considered that AA results of a breakdown of immune-privilege condition and that an autoantigen from melanocytes could be responsible for initiating the immune response against the hair follicle.⁸ This pathogenic mechanism could explain Marie Antoinette syndrome referring to the sudden blanching of the hair like that had experienced Queen Marie Antoinette the night before her execution. It has been postulated that this sudden blanching was caused by a diffuse AA sparing hypopigmented hair.⁹ White hair phenomenon is also noted in white hair regrowth. Analysing regrowing hypopigmented hairs in AA, Messenger et al. found a defective pigment transfer, impairment of pigmentary activity and fewer number of melanocytes.¹⁰ In addition, Fisher et al. investigated the contribution of copy number variants (CNV) to AA. A nominally significant association with AA was found for CNVs spanning the genes MCHR2 and MCHR2-AS1, implicated in melanin aggregation. That is why the hair of AA patients is frequently white when it regrows following an acute episode of AA.¹¹ In our patients, it appears to be two bands with the hypopigmented band being most distal. Probably, the hair is regrowing and progressively resuming the melanocyte activity, as demonstrated by the microscopic examination of the hair shaft. Trichoscopic flag sign, as reported in our observation, is the embodiment of the very complex white hair phenomenon in AA.