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Table 1 Patch test results and number of relevant reactions Allergens

Relevant positives, Total

Positive reactions, Total

Positive reaction, Males

Positive reactions, Females

Source of the allergen

Fragrance mix 8%

2

2

0

2

Lip balm- lipstick-toothpaste

Eugenol 5%

2

2

1

1

Lip balm

MCI/MI 0.01% (aq.)

2

2

0

2

Cosmetic

Propolis 20%

2

2

1

1

Lip balm

Lyral 5%

1

1

1

0

Lip balm

Paraphenylenediamine 1%

1

1

1

0

Mustache dye

Nichel sulfate 5%

1

9

3

6

Metal tool

Para- tertiary butylphenol-formaldehyde resin 1%

1

1

0

1

Glue leather

Anethole 5%

1

1

0

1

Toothpaste

Spearmint oil 2%

1

1

0

1

Toothpaste

Epoxy resin 1%

1

1

0

1

Artificial nail

Bisphenol A-Glycidyl Methacrylate 2%

1

1

0

1

Artificial nail

Urethane dimethacrylate 2%

1

1

0

1

Artificial nail Artificial nail

Triethylene glycol dimethacrylate 2%

1

1

0

1

Dibromodicyanobutane 0.3%

0

1

0

1

Thiuram mix 1%

0

2

0

2

Neomycin 20%

0

1

1

0

Dermatophagoides mix 30%

0

4

1

3

Toothpaste as is

0

1

0

1

Cobalt chloride 1%

0

1

1

0

Table 2 Relation between eczematous cheilitis and anatomical involvement Localization

Atopic cheilitis

ACC

ICC

Cutaneous side (c)

9

3

2

Vermilion (v)

0

2

2

c+v

3

5

5

c + v + lip mucosa (m)

0

3

1

v+m

0

1

2

interest in the subject matter or materials discussed in the manuscript on this page. N. Milanesi,* M. Gola, A. Verdelli, S. Francalanci Allergological and Occupational Dermatology Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy *Correspondence: N. Milanesi. E-mail: [email protected]

References 1 Schena D, Fantuzzi F, Girolomoni G. Contact allergy in chronic eczematous lip dermatitis. Eur J Dermatol 2008; 18: 688–692. 2 Francalanci S, Sertoli A, Giorgini S, Pigatto P, Santucci B, Valsecchi R. Multicentre study of allergic contact cheilitis from toothpastes. Contact Dermatitis 2000; 43: 216–222. 3 Lim SW, Goh CL. Epidemiology of eczematous cheilitis at a tertiary dermatological referral centre in Singapore. Contact Dermatitis 2000; 43: 322–326. 4 Freeman S, Stephens R. Cheilitis: analysis of 75 cases referred to a contact dermatitis clinic. Am J Contact Dermat 1999; 10: 198–200.

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5 Strauss RM, Orton DI. Allergic contact cheilitis in the United Kingdom: a retrospective study. Am J Contact Dermat 2003; 14: 75–77. 6 Zug KA, Kornik R, Belsito DV et al. Patch-testing North American lip dermatitis patients: data from the North American Contact Dermatitis Group, 2001 to 2004. Dermatitis 2008; 19: 202–208. 7 Zoli V, Silvani S, Vincenzi C, Tosti A. Allergic contact cheilitis. Contact Dermatitis 2006; 54: 296–297. 8 Katsarou A, Armenaka M, Vosynioti V, Lagogianni E, Stavropoulos PG, Kalogeromitros D. Allergic contact cheilitis in Athens. Contact Dermatitis 2008; 59: 123–125. 9 Collet E, Jeudy G, Dalac S. Cheilitis, perioral dermatitis and contact allergy. Eur J Dermatol 2013; 23: 303–307. 10 Conti R, Bassi A, Difonzo EM, Moretti S, Francalanci S. A case of photoallergic contact dermatitis caused by unusual exposure to ketoprofen. Dermatitis 2012; 23: 295–296. DOI: 10.1111/jdv.13104

Vemurafenib mucosal side-effect Editor BRAF mutations have been described in a variety of tumours such as thyroid, colon and melanoma1 becoming a suitable therapeutic target. After promising clinical trials,2 BRAF V600E inhibitor Vemurafenib has been approved for metastatic or unresectable melanoma treatment. Furthermore, the same mutation has been described in Langerhans cell histiocy-

© 2015 European Academy of Dermatology and Venereology

Letters to the Editor

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tosis (LCH).3 Recently, Haroche and co-workers3 have described two LCH cases characterized by a ‘dramatic’ response after Vemurafenib administration. Although BRAF inhibitors are well tolerated, cutaneous toxicity has been observed in all clinical studies.4,5 We report a mucosal toxicity case in an LCH patient. A 54-year-old woman had been affected by LCH since 1998. She had been previously treated with radiotherapy and thereafter with different chemotherapeutic regiments such as MACOP-B, VNCOP-B, IEV, the latter being followed by an aborted autologous stem cell transplantation attempt. In March 2013 the disease showed skeletal, nodal and hepatic involvement as well. Six Bendamustine cycles were administered with no improvement. BRAF V600E mutation was detected from a nodal lesion. In November 2013 Vemurafenib was started at 960 mg twice a day. A month later, the patient presented a painful erythematous hyperkeratotic area set on the lower left gingival arch, and on the hard palate (Fig. 1a,b). A biopsy from the latter area showed hyperkeratosis, verrucous proliferation, thickened granular zone, the presence of koilocytes, as well as dilated vessels in the corium (Fig. 2a,b). Both direct and indirect immunofluorescence were negative, as well as ANA and ENA title. Due to the fact that koilocytosis is a typical feature of papillomavirus (HPV) replication, we performed PCR assays targeting the E6 gene of 16 mucosal HPV types belonging to the alpha genus (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68 and 73). HPV DNA was assessed in three consecutive 10 lm thick sections, from formalin-fixed paraffin-embedded oral biopsy. HPV 52 high-risk mucosal genotype was detected. A daily oral lenitive mouthwash was administered. Four weeks later, local treatment was cut to three times per week, due to the fact that the two lesions improved, including the complete regression of the hard palate lesion. At 3 months from first Vemurafenib administration, a mucosal relapse was observed. According to the literature, BRAF V600 E inhibitors side-effects can spontaneously regress over time with no therapy changes or discontinuation for few days.6 Thus, we decided to stop for 4 days and re-start the therapy at 720 mg twice a day, with an improvement in the oral situation after 2 weeks. However, gum hyperkeratosis completely regressed only after complete Vemurafenib discontinuation, 4 months later. No other skin toxicity signs were observed until the end of the therapy. Vemurafenib effectiveness has been reported in melanoma treatment as well as in haematological disorders like hairy cell leukaemia2,4–6 and LCH.3 Moreover, adverse cutaneous events can commonly be observed, such as skin rash (either perifollicular hyperkeratotic, or photo-induced) as well as cutaneous neoplasm growth (keratoacanthoma or squamous cell carcinoma),4,5 the latter being due to a paradoxical MitogenActivated Protein Kinase (MAPK) pathway activation.4

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(a)

(b)

Figure 1 (a) painful erythematous hyperkerototic area set on the hard palate and (b) the lower gingiva.

(b)

(a) Figure 2 (a) hyperkeratotic verrucous proliferation, thickened granular zone, presence of koilocytes as well as dilated vessels in the corium (Haematoxylin and Eosin 9 10), (b) koilocytes detail at higher scanning magnification (Haematoxylin and Eosin 9 40).

Furthermore, second primary melanoma has also been observed after Vemurafenib administration.7 Sinha et al.8 have developed an algorithm for Vemurafenib side-effect identification and management. However, no algorithm was provided for an exclusive mucosal side-effect appearance. Only Boussermart et al.4 have described a patient with a condition similar to our case. Differently from our case, neither histology nor HPV PCR detection was shown. Differential diagnosis should encompass erosive lichen planus and mucous membrane pemphigoid as well. However, neither histology nor direct immunofluorescence fit for those diseases. The patient experienced an initial improvement after biopsy and local mouthwash administration. However, Vemurafenib discontinuation was warranted to observe a complete regression. High-risk HPV types are commonly found in non-malignant and malignant oral cancer.9 Indeed, p16/HPVs are also found in oral squamous cell carcinoma as secondary malignancies in post-allogenic stem cell

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Letters to the Editor

transplant patients.10 Accordingly, we found the presence of HPV 52 in our patient’s oral lesions. Hence, Vemurafenib administration in an immunosuppressed patient may have triggered the onset of HPV associated lesions that completely regressed after drug discontinuation. A. Pileri,1,2,* M. Cricca,3 L. Gandolfi,4 C. Misciali,1 B. Casadei,4 P.L. Zinzani,4 A. Patrizi1 1

Dermatology Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 2Division Dermatology, Departement of Surgery and Translational Medicine, University of Florence, Florence, 3Microbiology Unit, Department Of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 4Haematogy Unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy *Correspondence: A. Pileri. E-mail: [email protected] The content of this manuscript has never been published or presented elsewhere.

References 1 Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol 2013; 27: 11–18. 2 Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809–819. 3 Haroche J, Cohen-Aubart F, Emile JF et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013; 121: 1495–1500. 4 Boussemart L, Routier E, Mateus C et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: a study of 42 patients. Ann Oncol 2013; 24: 1691–1697. 5 Fava P, Marra E, Astrua C et al. Dermatological approach to vemurafenib skin toxicity: a single centre experience. G Ital Dermatol Venereol 2014; [Epub ahead of print]. 6 Samuel J, Macip S, Dyer MJ. Efficacy of vemurafenib in hairy-cell leukemia. N Engl J Med 2014; 370: 286–288. 7 Dalle S, Poulalhon N, Debarbieux S et al. Tracking of second primary melanomas in vemurafenib-treated patients. JAMA Dermatol 2013; 149: 488–490. 8 Sinha R, Edmonds K, Newton-Bishop JA, Gore ME, Larkin J, Fearfield L. Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br J Dermatol 2012; 167: 987–994. 9 Bouda M, Gorgoulis VG, Kastrinakis NG et al. High risk HPV types are frequently detected in potentially malignant and malignant oral lesions, but not in normal oral mucosa. Mod Pathol 2000; 13: 644–653. 10 Katz J, Islam MN, Bhattacharyya I, Sandow P, Moreb JS. Oral squamous cell carcinoma positive for p16/human papilloma virus in post allogeneic stem cell transplantation: 2 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 118: e74–e78. DOI: 10.1111/jdv.13105

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Successful treatment of Wilson disease-associated IgA pemphigus with IVIG IgA pemphigus (IgAP) is a rarely seen autoimmune bullous disease. Corticosteroids (CS) are the mainstays for the treatment of IgAP, owing to the inflammatory nature of the disease.1 Due to its neutrophilic nature, dapson and colchicine also are an effective treatment option in IgAP.2 Oral retinoids like isotretinoin and acitretin were found to be effective in the treatment of IgAP.3,4 Mycophenolate mofetil and adalimumab are also reported to be useful in treating IgAP.5 Azathioprine, a commonly used immunosuppressant in pemphigus, does not seem to be effective in treating IgAP.2 Aggressive therapy with prednisone, cyclophosphamide and plasmapheresis has also been used for a recurrence after initial treatment with dapsone and prednisone.6 To our knowledge, up to now intravenous immunoglobulin (IVIG) never used against IgAP. Furthermore, there are no reports regarding Wilson disease (WD)-associated IgAP in the literature. Here we report a recalcitrant WD-associated IgAP case, which was successfully treated with IVIG. A twenty-year-old male patient was hospitalized in the dermatology department due to a massive vesiculopustular skin lesion on the scalp and axilla. On dermatologic evaluation, diffuse, superinfected, purulent, vesiculopustular skin lesions were found on the scalp and the unilateral axillar region which were secondarily vegetated (Fig. 1). Lesions were very itchy and painfull. Oral mucosa involvement was absent. A skin sample was taken from the vesiculopustular lesion that revealed intraepidermal fishnet like deposition of IgA autoantibodies in IF examination. On microscopic evaluation, perifollicular neutrophil accumulation and significant acantholysis was found (Fig. 1). Two-time desmoglein (DSGL) levels were measured in the blood sample and a negative result was obtained. Liver enzymes were highly elevated in this patient so possible liver pathologies were considered. Copper level in blood and 24 h urine was higly elevated. The Kayser–Fleischer ring was positive on eye examination. Liver biopsy revealed cirrhosis. In conclusion WD was diagnosed in this patient. CS treatment at the dosage 0.5–1 mg/ kg was initiated and patient responded to it very quickly. However, disease relapsed following the CS tapering. Due to increase of relapse frequencies, IVIG administration was started. As a result, long-term remission was obtained and frequency of relapses decreased during 1 year of follow-up. IgAP shows a moderate clinical course compared to IgG pemphigus.7 WD is an autosomal recessive liver disease due to abnormal deposition of copper in hepatocytes. This patient was diagnosed with IgAP and WD simultaneously in the dermatology department. Development of autosomal recessive

© 2015 European Academy of Dermatology and Venereology