CED

Clinical dermatology • Original article

Clinical and Experimental Dermatology

Loss of normal anagen hair in pemphigus vulgaris M. Daneshpazhooh,1 H. R. Mahmoudi,1 S. Rezakhani,1,2 M. Valikhani,1 Z. S. Naraghi,1,3 Y. Mohammadi,1,4 A. Habibi1 and C. Chams-Davatchi1 1 Autoimmune Bullous Diseases Research Center, Department of Dermatology, Tehran University of Medical Sciences, Tehran, Iran; 2Harold Simmons Center, UC Irvine Medical Center, Orange County, CA, USA; 3Department of Dermatopathology, Tehran University of Medical Sciences, Tehran, Iran; and 4 Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

doi:10.1111/ced.12595

Summary

Background. Pemphigus vulgaris (PV) is a known cause of loss of ‘normal’ anagen hair; that is, shedding of intact anagen hairs covered by root sheaths. However, studies on this subject are limited. Aim. To investigate anagen hair shedding in patients with PV, and ascertain its association with disease severity. Methods. In total, 96 consecutive patients with PV (new patients or patients in relapse) who were admitted to the dermatology wards of a tertiary hospital were enrolled in this study. Demographic data, PV phenotype, disease severity and presence of scalp lesions were recorded. A group of 10–20 hairs were pulled gently from different areas of the scalp (lesional and nonlesional skin) in all patients, and anagen hairs were counted. Disease severity was graded according to Harman score. Results. Anagen hair was obtained by pull test in 59 of the 96 patients (61.5%), of whom 2 had normal scalp. The mean  SD anagen hair count was 5.9  7.6 (range 0–31). In univariate analysis, anagen hair loss (P < 0.01) and the presence of scalp lesions (P = 0.01) were associated with severe disease. Mean anagen hair count was significantly higher in the severe (mean 6.83  7.89) than the moderate (mean 1.06  1.94) subgroup (P < 0.001). Multivariate analysis confirmed anagen hair loss (OR = 1.16, 95% CI = 1.05–1.28, P < 0.01), but not scalp lesions (P = 0.69) as an independent predictor of disease severity. Conclusions. According to our study, normal anagen effluvium is a frequent finding in patients with PV, and interestingly, this was observed in nonlesional as well as lesional scalp. In addition, severe anagen hair loss was an independent predictor of the disease severity.

Introduction Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease of the skin and/or mucosa, characterized by antibodies to desmoglein (Dsg)3 and/or Dsg1. Various types of hair loss are described in PV, Correspondence: Dr Maryam Daneshpazhooh, Autoimmune Bullous Diseases Research Center, Department of Dermatology, Razi Hospital, Vahdate-Eslami Sq, 11996 Tehran, Iran E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 21 August 2014

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including telogen hair loss, normal anagen effluvium and tufted hair folliculitis.1–4 This predilection is due to the higher levels of pemphigus antigens in the scalp.5 Histologically, acantholysis and suprabasal cleft may extend down the follicular epithelium; follicular acantholysis has even been reported as the sole pathological manifestation of pemphigus, and considered a subtle clue for early diagnosis of PV.6 Direct immunofluorescence also shows immune deposits of IgG and/ or C3 in the outer root sheath of hair follicles, and plucked anagen hair has been used as a substrate for diagnosis and also for monitoring immunological

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Anagen hair loss in PV  M. Daneshpazhooh et al.

remission in PV.7–9 These immunopathological findings underlie the normal anagen effluvium (hair loss) seen in pemphigus, which refers to the shedding of normal anagen hairs covered by root sheaths, and is considered analogous to the Nikolsky sign.4 The aim of the current study was to investigate anagen hair loss in patients with PV and to assess its association with disease severity.

Methods The study was approved by the local review board and all patients provided informed consent. In total, 96 consecutive patients with PV (new patients or patients in relapse; 50 men and 46 women; mean  SD age 45.8  14.0 years, range 18–90) admitted to the dermatology wards of Razi Hospital (Tehran University of Medical Sciences, Tehran, Iran) were enrolled in this study during the period 2009–2011. Diagnosis was based on clinical (the presence of skin and/or mucosal bullae/erosions), pathological (suprabasal cleft and acantholysis) and immunofluorescence (intercellular epidermal IgG and/or C3 deposits) findings. Demographic data, PV phenotype, disease severity, presence of scalp lesions and symptoms of hair loss were recorded. A group of about 20 hairs was pulled gently from the temporal, occipital and frontal areas of the scalp (nonlesional skin) as well as from lesional skin. The pull test was performed by one of two researchers (HRM or SR), who had been trained at the beginning of the study, and were supervised by a more senior researcher (MD). The obtained anagen and telogen hairs were counted. Telogen hair loss was defined as a telogen count of > 10% of pulled hairs. Anagen hair loss was defined as retrieval of even a single normal anagen hair by gentle pulling. Positive pull test was defined as the presence of telogen hair and/or anagen hair loss. Telogen and anagen hairs were easily differentiated by the morphology of their roots. Telogen hairs have club-shaped depigmented roots, whereas normal anagen hairs have broomshaped pigmented bulbs covered by intact root sheaths. Disease severity was graded according to Harman score.10 Statistical analysis

Data were analysed by IBM SPSS Statistics for Windows (v19.0; IBM Corp., Armonk, NY, USA). Frequency was

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Clinical and Experimental Dermatology

calculated for categorical and mean  SD for continuous variables. Univariate and multivariate analysis were performed to assess the association of different variables with the severity of pemphigus. P < 0.05 was considered statistically significant.

Results The demographic and clinical characteristics of patients are summarized in Table 1. Of the 96 patients, 16 had moderate (16.7%) and 80 had severe disease (83.3%). None of the patients had mild disease, as only admitted patients were studied. The scalp was involved in 57 patients (59.4%). Pull test was positive in 66 patients (68.8%), with anagen hair obtained for 59 (61.5%). Of these, 57 patients had scalp lesions (96.6%) and 2 had normal scalp (3.4%). Of the 57 patients with scalp lesions, 52 had positive lesional anagen pull test (91.2%). Anagen hair was retrieved from lesional scalp only in 32 patients (56.1%), from both lesional and nonlesional scalp 20 patients (35.1%) and from normal scalp only in 5 patients (8.8%). The mean anagen hair count was 5.9  7.6 (0–31). In univariate analysis, anagen hair loss (P < 0.01) and the presence of scalp lesions (P = 0.01) were associated with severe disease. No significant association was found between severity and lesional anagen hair loss (P = 0.08), nonlesional anagen hair loss (P = 0.22), male sex (P = 0.85), age (P = 0.10), disease phenotype (P = 0.07) and telogen hair loss (P = 0.34). The mean anagen hair count was significantly higher in the severe (mean = 6.83  7.89)

Table 1 Demographic and clinical characteristics of patients. Variables Male sex, n (%) Age, years, n (%)* Phenotype Mucosal Cutaneous Mucocutaneous Severity Moderate Severe Scalp lesions, n (%) Hair shedding, n (%)† Positive pull test, n (%) Anagen hair loss, n (%) Anagen hair count‡ Telogen hair loss, n (%)

50 (52.1) 45.8  14.0 17 (17.7) 5 (5.2) 74 (77.1) 16 (16.7) 80 (83.3) 57 (59.4) 47 (49) 66 (68.8) 59 (61.5) 5.86  7.55 (0–31) 23 (29.0)

*Mean  SD; †patient report; ‡mean  SD (range).

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Anagen hair loss in PV  M. Daneshpazhooh et al.

Table 2 Univariate comparison of patients with moderate and severe pemphigus.

Disease severity Variables

Moderate

Severe

P*

Scalp lesion, n (%) Anagen hair loss, n (%) Age, years† Sex, M/F Phenotype, n (%) Mucocutaneous Cutaneous Mucosal Anagen count† Lesional anagen hair loss, n (%) Nonesional anagen hair loss, n (%) Telogen effluvium, n (%)

5 (8.8) 5 (8.5) 44.7  13.5 8/8

52 (91.2) 54 (91.5) 51.0  15.7 42/38

0.01 < 0.01 0.1 0.85

9 (12.2) 1 (20) 6 (35.3) 1.06  1.94 3 (5.9) 2 (7.4) 2 (8.7)

65 (87.8) 4 (80) 11 (64.7) 6.83  7.89 48 (94.1) 25 (92.6) 21 (91.3)

0.07

< 0.001 0.08 0.22 0.34

*Significant (P < 0.05); †mean  SD.

than the moderate (mean = 1.06  1.94) subgroup (P < 0.001) (Table 2). Multivariate analysis confirmed anagen hair loss (OR = 1.16, 95% CI = 1.05–1.28, P < 0.01), but not scalp lesions (P = 0.69) as an independent predictor of disease severity.

Discussion Pemphigus is one of the few diseases showing normal anagen effluvium. This sign is due to acantholysis and cleft formation in the outer root sheath of hair follicles, leading to normal anagen hair loss.4 In other words, intact anagen hairs covered by root sheaths are lost or shed easily; this differs from the broken anagen hairs seen during chemotherapy.4 Normal anagen hairs (characterized by a broom-like hair bulb covered by intact root sheaths) are never removed from normal scalp by gentle pull test, as they are firmly anchored in the skin. Another pattern of anagen hair shedding from normal scalp is observed in loose anagen (LA) syndrome. Unlike normal anagen hair, the hair bulb is misshapen, the cuticle is ruffled and the outer root sheath is missing in LA hair. Interestingly, LA hair may be seen in normal children (61%; average number per hair pull: 1–2) and only rarely in normal postpubescent subjects (2%; maximum of one LA hair out of 6–7 hair pulls).11 Studies evaluating anagen hair loss in pemphigus are limited in the literature. Delmonte et al.4 reported three cases of PV showing normal anagen effluvium. In two of their patients, anagen hairs were also easily pulled out in the perilesional areas from the normal scalp, and in a third patient, hair loss heralded the appearance of skin lesions. The authors suggested normal anagen effluvium as a subclinical involvement

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of the hair follicle and equivalent to Nikolsky sign. In a trichography study, Koslu et al.12 found that in 46% of their 13 patients with pemphigus who had scalp lesions, normal anagen hairs were plucked easily without any resistance. In a recent study, Veraitch et al.13 reported five cases of PV with alopecia and anagen effluvium, and they recommended the pull test in the routine physical examination of PV even in patients with no signs of overt hair loss. They suggested that factors other than anti-Dsg antibodies may be responsible for the alopecia, and proposed bacterial infection as a contributory factor. Pimez14 reported a patient with PV presenting with normal anagen hair loss covered by hair casts, and attributed this dermoscopic feature to acantholysis in the outer root sheath. In the present study, normal anagen effluvium was a frequent finding, seen in 61% of our patients with PV. Interestingly it was observed in nonlesional as well as lesional scalp, and in contrast to the report by Koslu et al.,12 it was also seen in two patients without any scalp lesions. In addition, according to our study, severe anagen hair loss was a positive predictor of the severity of PV. The main limitation of our study was the lack of mild cases in this series, as such cases are usually treated as outpatients in our centre and are not admitted to the wards.

Conclusion Normal anagen effluvium was a frequent finding in our patients with PV, and was observed in both lesional and nonlesional scalp. Further studies on a more representative sample of untreated patients with pemphigus, including the full spectrum of severity, are warranted. Furthermore, we suggest that normal

Clinical and Experimental Dermatology

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Anagen hair loss in PV  M. Daneshpazhooh et al.

anagen effluvium should be ascertained by use of the Pemphigus Disease Activity Index.

What’s already known about this topic?  Normal anagen hair loss may be seen in PV.

What does this study add?  Normal anagen hair shedding is common in

PV.  Such shedding may be seen even in nonlesion-

al scalp.  Severe anagen effluvium is an independent pre-

dictor of disease severity.

References 1 Miteva M, Murrell DF, Tosti A. Hair loss in autoimmune cutaneous bullous disorders. Dermatol Clin 2011; 29: 503–9, xi. 2 Gaitanis G, Patmanidis K, Skandalis K et al. Scarring alopecia in pemphigus vulgaris: a rare or underdiagnosed presentation? Eur J Dermatol 2013; 23: 253–5. 3 Ko DK, Chae IS, Chung KH et al. Persistent pemphigus vulgaris showing features of tufted hair folliculitis. Ann Dermatol 2011; 23: 523–5. 4 Delmonte S, Semino MT, Parodi A, Rebora A. Normal anagen effluvium: a sign of pemphigus vulgaris. Br J Dermatol 2000; 142: 1244–5.

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5 Ioannides D, Hytiroglou P, Phelps RG, Bystryn JC. Regional variation in the expression of pemphigus foliaceus, pemphigus erythematosus, and pemphigus vulgaris antigens in human skin. J Invest Dermatol 1991; 96: 159–61. 6 Mahalingam M. Follicular acantholysis: a subtle clue to the early diagnosis of pemphigus vulgaris. Am J Dermatopathol 2005; 27: 237–9. 7 Schaerer L, Tr€ ueb RM. Direct immunofluorescence of plucked hair in pemphigus. Arch Dermatol 2003; 139: 228–9. 8 Daneshpazhooh M, Asgari M, Naraghi ZS et al. A study on plucked hair as a substrate for direct immunofluorescence in pemphigus vulgaris. J Eur Acad Dermatol Venereol 2009; 23: 129–31. 9 Daneshpazhooh M, Naraghi ZS, Ramezani A et al. Direct immunofluorescence of plucked hair for evaluation of immunologic remission in pemphigus vulgaris. J Am Acad Dermatol 2011; 65: e173–7. 10 Harman KE, Seed PT, Gratian MJ et al. The severity of cutaneous and oral pemphigus is related to desmoglein 1 and 3 antibody levels. Br J Dermatol 2001; 144: 775– 80. 11 Olsen EA, Bettencourt MS, Cote NL. The presence of loose anagen hairs obtained by hair pull in the normal population. J Investig Dermatol Symp Proc 1999; 4: 258– 60. 12 Koslu A, Topal IO, Ekmekci TR. Trichogram findings in pemphigus patients. Indian J Dermatol Venereol Leprol 2009; 75: 303–4. 13 Veraitch O, Ohyama M, Yamagami J, Amagai M. Alopecia as a rare but distinct manifestation of pemphigus vulgaris. J Eur Acad Dermatol Venereol 2013; 27: 86–91. 14 Pirmez R. Acantholytic hair casts: a dermoscopic sign of pemphigus vulgaris of the scalp. Int J Trichology 2012; 4: 172–3.

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Loss of normal anagen hair in pemphigus vulgaris.

Pemphigus vulgaris (PV) is a known cause of loss of 'normal' anagen hair; that is, shedding of intact anagen hairs covered by root sheaths. However, s...
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