Deposition Pattern of Pemphigus Erythematosus Association with the Desmoglein 1 Ectodomain As Revealed by 3 Cases

OBSERVATION

ONLINE FIRST The IgG “Lupus-Band” Deposition Pattern of Pemphigus Erythematosus Association With the Desmoglein 1 Ectodomain as Revealed by 3 Cases

Dyah A. M. Oktarina, MD, PhD; Angelique M. Poot, MD; Duco Kramer, BSc; Gilles F. H. Diercks, MD, PhD; Marcel F. Jonkman, MD, PhD; Hendri H. Pas, PhD

Background: Pemphigus foliaceus is an autoimmune depositions consisted of IgG, complement, and the ectodo- skin disease characterized by subcorneal blistering and main of desmoglein 1 and were located below the lamina IgG antibodies directed against desmoglein 1. In the skin, densa. these antibodies deposit intraepidermally. On rare occa- sions, an additional “lupus band” of granular deposi- Conclusions: High doses of UV light are likely to in- tions of IgG and complement is seen along the epider- duce the cleaving of the desmoglein 1 ectodomain. In pa- mal basement membrane zone. This combined pattern tients with pemphigus foliaceus, the circulating anti– has been connected with a variant of pemphigus folia- desmoglein 1 antibodies precipitate this cleaved-off ceus named pemphigus erythematosus. ectodomain along the basement membrane zone, result- ing in a lupus band–like appearance. In pemphigus ery- Observations: We describe 3 pemphigus foliaceus cases thematosus, a similar mechanism may be active, which in which phototherapy was administered after a misdi- might explain the lupus-band phenomenon. agnosis of psoriasis. This treatment resulted in a flare of skin lesions. Direct immunofluorescence of skin biopsy specimens that were obtained several weeks later dem- Arch Dermatol. 2012;148(10):1173-1178. onstrated intraepidermal and granular basement mem- Published online July 16, 2012. brane zone depositions. The basement membrane zone doi:10.1001/archdermatol.2012.1896

EMPHIGUS FOLIACEUS (PF) IS studies, however, showed less clinicopatho- an autoimmune skin disease logical concurrency with LE because ANAs characterized by subcorneal often appeared to be absent, and the over- blistering and intraepidermal all significance of this finding became dis- deposition of IgG antibodies putedasitemergedthatANAswerealsopres- thatP bind the desmosomal cadherin desmo- ent in a high percentage of the healthy glein 1 (Dsg1). Additional deposition of IgG population.5-9 Although occasional cases of is occasionally present along the epider- LE can present simultaneously with pem- mal basement membrane zone (BMZ), and phigus, the gross findings in patients with this combined pattern has been correlated PE do not meet the criteria for systemic LE with pemphigus erythematosus (PE). Pem- as published by the American College of phigus erythematosus was first described in Rheumatology.10,11 Therefore, what is called 1926 by Senear and Usher1,2 as a condition PE today should be separated from the with a lupuslike butterfly rash or severe seb- sparse cases of actual concurrent LE and orrheic dermatitis, which they suggested was pemphigus/PF. At present, basic dermatol- a combination of pemphigus vulgaris and ogy textbooks consider PE to be a local- lupus erythematosus (LE). When insights ized form of PF.12 The significance of the lu- into the differences between pemphigus vul- pus-band phenomenon in this entity, garis and PF crystallized, PE was not clas- however, remains unexplained, whereas as sified with pemphigus vulgaris but consid- much as 60% of biopsy results reported in ered an early or a nongeneralized form of patients with PE are described as having PF.3 When immunofluorescence (IF) be- coarse granular depositions of IgG and Author Affiliations: Center for came a diagnostic tool, the association with complement along the BMZ in addition to Author Affil Blistering Diseases, Department LE revived. Chorzelski et al4 described a “lu- the pemphigus anti–cell surface (ACS) dep- Blistering Di of Dermatology, University 4,5 of Dermatolo Medical Center Groningen, pus-band” deposition in sun-exposed skin osition. Therefore, this lupus band likely Medical Cen University of Groningen, areas of patients with PE, together with an- reflects a unique immunopathological as- University o Groningen, the Netherlands. tinuclear antibodies (ANAs) as in LE. Later pect of PE.5 In the present study, we inves- Groningen, t

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Figure 1. Representative skin lesions in 2 patients. A, Patient 1. The typical pemphigus erythematosus facial butterfly eruption. B, Patient 2. Extensive lesions 2 months after ending UV-B therapy.

tigated the composition of lupus-band depositions that were bent assay analysis demonstrated anti-Dsg1 antibodies. present in the skin of 3 patients with PF who received ex- Blood tests yielded negative findings for ANA, antiex- tensive UV exposure through phototherapy. tractable nuclear antigen, anti–double-stranded DNA, anti–Sjo¨gren syndrome antigen A, antismooth muscle, and REPORT OF CASES antistriated muscle antibodies.

PATIENT 1 PATIENT 2

An 80-year-old woman was admitted to our hospital with A 76-year-old woman with a 2-month history of general- a 3-year history of generalized progressive erythemato- ized cutaneous blistering was admitted to our hospital. Six squamous skin lesions with pustules and flaccid blis- months earlier, she had developed itching plaques all over ters. This condition had been diagnosed elsewhere as pso- her body and scalp with the exception of her legs. This con- riasis pustulosa complicated by a secondary infection with dition was diagnosed elsewhere as psoriasis vulgaris; 2 Staphylococcus aureus. The patient had received several months later, the patient was treated with UV-B therapy. therapies, including methotrexate sodium, systemic eryth- After 2 more months, she developed painful blisters on the romycin stearate, acitretin, and cyclosporine. Owing to trunk and face, with a burning sensation resembling that methotrexate-related hepatotoxic effects and the insuf- of sunburn. The UV-B therapy was stopped, but the blis- ficient effectiveness of the other therapies, the patient tering progressed. Physical examination at our hospital re- switched to a twice-weekly regimen of psoralen–UV-A vealed multiple crusts on the scalp, face, and lips, without therapy with 40 mg of methoxsalen. During psoralen– involvement of the oral mucosa. In addition, significant ero- UV-A therapy, the skin lesions worsened, and therapy sive lesions were present on the neck, arms, and legs, with was stopped after 3 weeks. Results of a physical exami- crusted erythema on the trunk (Figure 1B). Findings on the nation revealed suberythroderma consisting of conflu- legs and dorsal trunk were positive for the Nikolsky sign. ent and scattered red macules with scales and purulent The overall presentation resembled that of toxic epidermal crusts. A malar distribution was present on her face necrolysis, staphylococcal scalded skin syndrome, or PF. (Figure 1A). Multiple erosions and flaccid blisters were A skin biopsy specimen showed ulcerative and erosive in- seen, and findings were positive for the Nikolsky sign. flammation and secondary impetigo with beginning reepi- The mucous membranes were not involved. Results of thelialization.DirectIFmicroscopyrevealedsmoothintraepi- the histopathological examination revealed subcorneal dermal ACS IgG with weaker C3c depositions. In addition, blisters. Direct IF microscopy of lesional and nonle- granular IgG, IgM, and C3c depositions were present along sional skin specimens (1 biopsy specimen each, taken from the BMZ in nonlesional and perilesional skin (biopsy speci- the upper leg) showed intraepidermal ACS depositions mens were taken from the arm and leg). Indirect IF micros- of IgG and complement factor C3c in the lesional skin copy on monkey esophagus showed circulating anti-ACS and additional coarse granular IgG and C3c depositions antibodies and retrospective enzyme-linked immunosor- along the BMZ in the nonlesional skin. Indirect IF mi- bent assay anti-Dsg1 antibodies. Circulating ANAs were de- croscopy on monkey esophagus revealed ACS IgG anti- tected at titers of 1:20, falling below the cutoff range, and bodies, and retrospective enzyme-linked immunosor- thus findings were evaluated as negative.

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B Pt1 IgG Pt1Dsg1 Pt1 Overlay

C SLE IgG SLEDsg1 SLE Overlay

Figure 2. Immunofluorescence analysis of skin biopsies. A, “Lupus-band” IgG deposition in the skin specimens of the 3 patients with pemphigus foliaceus (PF). B, The deposited IgG (left, green) colocalizes with desmoglein 1 (Dsg1) (middle, red) in the skin of patients with PF. C, The process does not occur in skin from a patient with systemic lupus erythematosus (SLE). All images have the same original magnification ϫ40 µm. Pt indicates patient. Patients are identified by number in the “Report of Cases” section.

PATIENT 3 BMZ. Indirect IF microscopy on monkey esophagus revealed the presence of circulating ACS antibodies, and anti- A 68-year-old man was referred to us with a 2-year his- Dsg1 IgG antibodies were detected by enzyme-linked im- tory of red scaly skin lesions starting in the medial cor- munosorbent assay. Blood tests for ANAs were negative. ner of the right eyelid and progressing to his chest and Despite a malar distribution of skin lesions in 2 of the back. This condition was initially diagnosed elsewhere 3 patients and the relation to UV exposure in all 3, the as psoriasis. The patient was subsequently treated with patients did not otherwise fulfill the American College methotrexate. Five weeks before our examination, the pa- of Rheumatology criteria for LE. Instead, the immuno- tient had been treated with psoralen–UV-A therapy. The pathological findings fit the diagnosis of PF, whereas the next day generalized itching developed, followed by blis- malar involvement and the presence of granular BMZ de- tering on the whole body, including the scalp and ex- positions were as described for PE.4,7 tremities. Results of a physical examination revealed facial malar erythema and erythematous confluent macules RESULTS with central erosions, excoriations, crusts, and flaccid blisters on the scalp, trunk, and extremities. Mucous mem- Nine skin biopsy specimens had been stored from the 3 branes were not involved. Findings were positive for the cases. The specimens were all obtained from UV- Nikolsky sign at the blister margins but were negative exposed sites because the patients had received whole- on nonlesional skin. Skin biopsy specimens from the up- body UV therapy. All 9 biopsy specimens showed in- per leg and back obtained 5 weeks after the start of pso- traepidermal deposition of IgG, and 6 had additional BMZ ralen–UV-A therapy showed a globally intact epidermis deposition of IgG and complement C3c (Figure 2A with what looked like a remainder of a blister in the cor- shows the biopsy findings of all 3 patients). These BMZ neal layer and subepidermal neutrophilic infiltrates sur- deposits were not found in 51 biopsy specimens of 14 rounding the blood vessels. Direct IF microscopy of per- other patients with PF who had not received photo- ilesional skin (taken from the leg) showed intraepidermal therapy (results not shown). intercellular IgG, IgA, and C3c depositions. In addition, Because Dsg1 is the autoantigen in PF, we stained our granular IgG, IgA, and C3c deposits were present along the biopsy specimens with monoclonal Dsg1-P23 that is di-

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C PG Dsg1 ec

D Dsg1 ec ColVII

Dermis

Figure 3. Immunofluorescence analysis of the basement membrane zone (BMZ) deposits. A, The desmoglein 1 endodomain (Dsg1 en; green) is absent in the BMZ deposition. The white bar indicates 40 µm. B, Detail of part A showing that the lower BMZ deposits contain the Dsg1 ectodomain (Dsg1 ec; red) only, whereas the higher deposits in the basal cells contain the endodomain and ectodomain (yellow). The white bar indicates 10 µm. C, In addition, plakoglobin (PG; green) is absent in the BMZ deposition. The white bar indicates 40 µm. D, The Dsg1 ec (green) is found to partly overlap with type VII collagen (ColVII). The white bar indicates 40 µm. E, Immunoelectron microscopy showing Dsg1 ec deposition below the lamina densa. The upper half of the deposition is at the level of ColVII.13 The cryosection was stained with monoclonal Dsg1-P23 and the diaminobenzidine reaction product using the gold-substituted silver-intensified peroxidase reaction.14 The black bar indicates 2 µm; the blue dotted line, the position of the lamina densa. rected to the ectodomain of Dsg1. The staining over- in the BMZ deposits (Figure 2B).We stained 4 biopsy lapped with the IgG and C3c depositions. Thus, Dsg1 was specimens of different patients with LE with the anti- present not only in the intraepidermal deposits but also Dsg1 monoclonal antibody to use as control specimens.

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 Patients with LE also have BMZ depositions of IgG (lu- tinocytes. This apoptotic proteolysis also involves addi- pus band) but ANA instead of anti-Dsg1 antibodies. As tional metalloproteinase-dependent shedding of the 75- expected, Dsg1 was absent from the BMZ depositions in kDa Dsg1 ectodomain fragment. This fragment contains the LE biopsy specimens; thus, the presence of Dsg1 in the extracellular 1 and 2 domains that harbor the epitopes such a band is exclusive to PF (Figure 2C). recognized by the pathogenic autoantibodies in PF.20 There- To confirm our observation, we stained with 3 other anti- fore, when these fragments diffuse into the dermal com- Dsg1 monoclonal antibodies. The Dsg ectodomain– partment, they can form immune complexes with the cir- specific monoclonal antibody Dsg1-P124 colocalized with culating anti-Dsg1 antibodies and deposit along the BMZ. the BMZ IgG, whereas the Dsg endodomain antibodies Although a limiting flaw of our study is that we could (27B2 and DG3.10) did not, demonstrating the absence of not examine biopsy specimens of patients with PE, the data the Dsg1 endomain in the lower BMZ deposits (Figure 3A obtained from our UV irradiation–induced BMZ depositions and B). The somewhat higher clusters contain the Dsg1 en- in the 3 patients with PF may well provide the first clue for domain and ectodomain (Figure 3B, yellow clusters). These unraveling the mechanism behind BMZ deposition in PE clusters are part of the normal intraepidermal granular IgG since its first demonstration by Chorzelski et al4 in 1968. depositions in PF skin that consist of IgG, full-length Dsg1, We hypothesize that a UV-driven mechanism is also active and cytoplasmic protein plakoglobin15 and may look like in PE that releases Dsg1 fragments from the cell membrane, BMZ deposits but are not because they are located in the thus forming deposits along the BMZ. Because this does not basal cells (yellow dots in Figure 3B, right panel). To in- happen in ordinary PF, patients with PE somehow are pre- vestigate whether plakoglobin was also present in the BMZ disposed to develop such pathophysiologic features. In this deposits, we double stained for plakoglobin and the Dsg1 way, PE parallels discoid and subacute cutaneous LE, in ectodomain. Plakoglobin appeared to be present only in which the lupus band is also present in sun-exposed lesional the epidermal deposits (Figure 3C, left) but not in the BMZ skin but not in sun-protected nonlesional skin.21 Pemphi- deposits that contained the Dsg1 ectodomain. Further- gus erythematosus and both LE forms are autoimmune dis- more, the BMZ deposits did not contain other desmo- eases but with different autoantibodies, that is, anti-Dsg1 somal cadherins, Dsg3, or desmocollin 1 or 3 (not shown). and ANA, respectively. In discoid LE and subacute cuta- The absence of the cytoplasmic protein plakoglobin neous LE, characterization of the antigen involved in the and the endodomain of Dsg1 in the BMZ deposits sug- lupus band so far has been unsuccessful, but the favored gested that the deposits were located outside the cells and view is that the IgG reacts with nuclear and cytoplasmic an- were not connected with the cell membrane of the basal tigens that are slowly released from damaged, possibly apop- keratinocytes. To more precisely determine the location totic, keratinocytes.22 Similarly, in PE, the IgG might react of the deposits, we performed double stainings with mono- with the Dsg1 fragments. clonal antibodies to the Dsg1 ectodomain and the adhe- Future studies of the composition of the lupus band sion molecules type XVII collagen, laminin 332, and type deposition in the skin of patients with PE should con- VII collagen that map to different levels of the BMZ. Most firm whether this hypothesis is correct. of the deposits partly colocalized with type VII collagen (Figure 3D). Additional immunoelectron microscopy re- Accepted for Publication: May 6, 2012. vealed that deposits were located at the level of type VII 13,14 Published Online: July 16, 2012. doi:10.1001 collagen and somewhat lower (Figure 3E). /archdermatol.2012.1896 Correspondence: Hendri H. Pas, PhD, Center for Blis- COMMENT tering Diseases, Department of Dermatology, Univer- sity Medical Center Groningen, University of Gronin- gen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands Previous case reports have demonstrated that UV irra- ([email protected]). diation can induce skin lesions in PE and PF.16-18 Al- Author Contributions: Drs Oktarina, Poot, Jonkman, and though BMZ deposition of complement is often seen in Pas had full access to all the data in the study and take re- PF, BMZ deposition of IgG is uncommon. The 3 cases sponsibility for the integrity of the data and the accuracy described herein suggest that UV light therapy can in- of the data analysis. Study concept and design: Oktarina and duce a lupus band in patients with PF. Pas. Acquisition of data: Oktarina, Poot, Kramer, Jonkman, In PE, the BMZ IgG deposition has previously been and Pas. Analysis and interpretation of data: Oktarina, Poot, shown to be related to UV exposure. Giannetti7 demon- Kramer, Diercks, Jonkman, and Pas. Drafting of the manu- strated for patients with PE that BMZ depositions were script: Oktarina, Poot, and Pas. Critical revision of the specific to sun-exposed areas. He investigated biopsy manuscript for important intellectual content: Oktarina, Poot, specimens taken from lesional skin of the face and back Kramer, Diercks, Jonkman, and Pas. Obtained funding: of 5 patients. Where BMZ IgG deposition was present in Oktarina, Jonkman, and Pas. Administrative, technical, and 4 of 5 facial biopsy specimens, no depositions were seen material support: Oktarina, Poot, Kramer, Diercks, and Pas. in any biopsy specimens of the back. Study supervision: Jonkman and Pas. The granular BMZ depositions in the skin of our pa- Financial Disclosure: None reported. tients treated with UV irradiation consisted of the Dsg1 ectodomain, IgG, and complement. The mechanism involved in the shedding of this Dsg1 ectodomain might in- REFERENCES 19 clude apoptosis. One study reports that Dsg1 is a target 1. Senear FE, Usher B. An unusual type of pemphigus combining features of lupus of the effector caspase 3 in UV-induced apoptosis of kera- erythematosus. Arch Derm Syphilol. 1926;13(6):761-781.

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 2. Steffen C, Thomas D. The men behind the eponym: Francis E. Senear, Barney gold studies in two cases of linear IgA dermatosis: are there two distinct types Usher, and the Senear-Usher syndrome. Am J Dermatopathol. 2003;25(5): of this disease? Br J Dermatol. 1992;127(2):112-118. 432-436. 14. Morara S, van der Want JJ, de Weerd H, Provini L, Rosina A. Ultrastructural analy- 3. Perry HO, Brunsting LA. Pemphigus foliaceus: further observations. Arch Dermatol. sis of climbing fiber-Purkinje cell synaptogenesis in the rat cerebellum. 1965;91:10-23. Neuroscience. 2001;108(4):655-671. 4. Chorzelski T, Jablon´ska S, Blaszczyk M. Immunopathological investigations in 15. Oktarina DA, van der Wier G, Diercks GF, Jonkman MF, Pas HH. IgG-induced the Senear-Usher syndrome (coexistence of pemphigus and lupus erythematosus). clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with Br J Dermatol. 1968;80(4):211-217. the desmoglein nonassembly depletion hypothesis. Br J Dermatol. 2011;165 5. Amerian ML, Ahmed AR. Pemphigus erythematosus: Senear-Usher syndrome. (3):552-562. Int J Dermatol. 1985;24(1):16-25. 16. Jacobs SE. Pemphigus erythematosus and ultraviolet light: a case report. Arch 6. Jablon´ska S, Chorzelski T, Blaszczyk M, Maciejewski W. Pathogenesis of pem- Dermatol. 1965;91:139-141. phigus erythematosus. Arch Dermatol Res. 1977;258(2):135-140. 17. Cram DL, Winkelmann RK. Ultraviolet-induced acantholysis in pemphigus. Arch 7. Giannetti A. Immunofluorescence studies in the Senear-Usher syndrome. Arch Dermatol. 1965;92(1):7-13. Dermatol Forsch. 1974;248(4):287-296. 18. Igawa K, Matsunaga T, Nishioka K. Involvement of UV-irradiation in pemphigus 8. Bean SF, Lynch FW. Senear-Usher syndrome (pemphigus erythematosus): im- foliaceus. 2004;18(2):216-217. munofluorescent studies in a patient. Arch Dermatol. 1970;101(6):642-645. 19. Dusek RL, Getsios S, Chen F, et al. The differentiation-dependent desmosomal 9. Tan EM. Special antibodies for the study of systemic lupus erythematosus: an cadherin desmoglein 1 is a novel caspase-3 target that regulates apoptosis in analysis. Arthritis Rheum. 1982;25(7):753-756. keratinocytes. J Biol Chem. 2006;281(6):3614-3624. 10. Hochberg MC. Updating the American College of Rheumatology revised criteria 20. Hacker-Foegen MK, Janson M, Amagai M, Fairley JA, Lin MS. Pathogenicity and epi- for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; topecharacteristicsofanti–desmoglein-1frompemphigusfoliaceuspatientsexpress- 40(9):1725. ing only IgG1 autoantibodies. J Invest Dermatol. 2003;121(6):1373-1378. 11. Malik M, Ahmed AR. Concurrence of systemic lupus erythematosus and pem- 21. Meurer M. Immunopathology of cutaneous lupus erythematosus. In: Kuhn A, phigus: coincidence or correlation? Dermatology. 2007;214(3):231-239. Lehmann P, Ruzicka T, eds. Cutaneous Lupus Erythematosus. Berlin, Germany: 12. Amagai M. Pemphigus. In: Bolognia JL, Jorizzo JL, Rapini PR, eds. Dermatol- Springer; 2005:305-310. ogy. 2nd ed. St Louis, MO: Mosby Elsevier; 2007. 22. Lehmann P, Homey B. Clinic and pathophysiology of photosensitivity in lupus 13. Ka´rpa´ti S, Stolz W, Meurer M, Krieg T, Braun-Falco O. Ultrastructural immuno- erythematosus. Autoimmun Rev. 2009;8(6):456-461.

Notable Notes

The Heliotrope Sign of Dermatomyositis: The Correct Meaning of the Term Heliotrope

A common misconception is that the word heliotrope refers to flower and has received specific color coordinates that are reg- the localization of the cutaneous lesions on sun-exposed areas. istered in A Dictionary of Color.1 The similarity between the hue The terms heliotrope and heliotropic mean “turning towards the of the periorbital rash of dermatomyositis and that of the pet- sun” and derive from Greek helios (ηλιος), meaning “sun,” and als of the flower justifies the use of the term heliotrope. trepein (τρε′πειν), meaning “to turn.” Over the years, the term The flower that turns to the sun in the European coun- heliotrope has been used to indicate things that either reflect tries is the sunflower (Helianthus annuus), which Van Gogh or turn to the sun, including an instrument for land survey, a immortalized with a vivid yellow color (Figure, C). There- mineral, and, above all, a flower. fore, in the absence of knowledge about H peruvianum, the The heliotrope sign (HS) indicates a violaceous to dusky ery- HS associated with dermatomyositis would not make sense thematous skin eruption, with or without edema, symmetri- to European dermatologists, who have their own heliotropic cally involving the periorbital regions and often the forehead flower, but with a different color. The correct etymology of (Figure, A). Sometimes, a milder form appears as a slight dis- the term heliotrope may be found in the Rheumatology Im- coloration of the eyelid border. Although it is rare in lupus ery- age Bank website, which mentions the “association rash- thematosus and scleroderma, the HS is a typical feature of acute flower.”2 Consideration of the etymology of medical terms may dermatomyositis. The HS refers to the flower Heliotropium,a be useful to better understand their significance. genus of flowering plants belonging to the family of Boragina- ceae. The genus Heliotropium includes hundreds of different spe- Terresa Russo, MD cies, among which Heliotropium peruvianum is the most repre- Vincenzo Piccolo, MD sentative and shows small, fragrant, purplish petals (Figure, B). Eleonora Ruocco, MD, PhD The color heliotrope has been defined in relationship to this Adone Baroni, MD, PhD

A B C

Figure. A, Heliotrope sign of dermatomyositis; B, Heliotropium peruvianum; and C, Helianthus annuus.

Author Affiliations: Department of Dermatology and Venereology, Second University of Naples, Naples, Italy. Contact Dr Russo at c/o II Policlinico, Edificio 3, Quarto Piano, Via Pansini 5, 80131 Napoli, Italy ([email protected]). 1. Maerz AJ, Paul RP. A Dictionary of Color. New York, NY: McGraw-Hill; 1930. 2. Dermatomyositis: heliotrope rash. Rheumatology Image Bank website. http://images.rheumatology.org/viewphoto.php?imageId=2862857. Accessed Decem- ber 1, 2011.

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