Hiromasa Matsuda

Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab.

Nivolumab, a blockade of programmed cell death 1, is now administrated for advanced malignant melanomas. Nivolumab‐associated adverse events include organ‐specific autoimmune disorders; autoimmune thyroid disease, vitiligo and insulin‐dependent diabetes. However, predisposed persons are currently unknown. Here, we report serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab: one with Hashimoto disease and another with probable subclinical Hashimoto disease. We should verify if nivolumab‐related hypothyroidism and hyperthyroidism are predisposed to occur in euthyroid individuals with subclinical autoimmune thyroid disease.

IL36RN mutations underlie impetigo herpetiformis.

TO THE EDITOR Impetigo herpetiformis (IH) is a rare pustular dermatosis that typically occurs in pregnant women sporadically with unknown etiology (Sauer and Geha, 1961). Early diagnosis is essential, as IH is life-threatening and is associated with placental insufficiency and electrolyte abnormalities. IH appears to have the same clinical and histologic appearance as generalized pustular psoriasis (GPP), which is also a rare severe episodic pustular dermatosis that occurs repeatedly in both sexes at any age. However, some researchers have regarded IH as an entity distinct from GPP, because some patients are affected by IH only in the gestational period (Lotem et al., 1989). Recently, we reported that the majority of GPP that is not accompanied by psoriasis vulgaris (PV; GPP alone) is caused by homozygous or compound heterozygous mutations of IL36RN, which encodes IL-36 receptor antagonist (IL36RN), although only a small number of cases with GPP preceding or accompanied by PV (GPP with PV) were found to have IL36RN mutations (Sugiura et al., 2013). Very recently, we reported that CARD14 c.526G4C is a significant risk factor for GPP with PV, but not for GPP alone in the Japanese cohort, which further supports the idea that GPP with PV differs genetically from GPP alone (Sugiura et al., 2014a). However, to our knowledge, there have been no reports of IH with IL36RN mutations. Here we report two cases of IH with homozygous and heterozygous IL36RN mutations. Cases 1 and 2 were a 23-year-old woman and a 28-year-old Japanese woman who were admitted to our hospitals for pustular lesions in the 29 week and the 20 week of their first pregnancies, respectively (Figure 1a and b). There was no family history of GPP, no IH, and no consanguinity in their families. Case 1 had no previous history of GPP. Her pustular lesions had begun to develop at the 21 week of pregnancy, and she had been hospitalized in a maternity hospital. Oral prednisolone at a dose of 15 mg per day had been administered, but the eruptions had persisted. A skin biopsy from a pustular eruption on the trunk revealed a spongiform pustule of Kogoj in the epidermis consistent with IH (Figure 1c). Case 2 had suffered from GPP from the age of 8 to 18 years. Skin biopsies from pustular eruptions on the trunk revealed spongiform pustules of Kogoj in the epidermis at the age of 8 and 28 years (Figure 1d). She had been admitted to hospitals four times for GPP flare-ups. She had been treated with cyclosporine or etretinate. In the ten years leading up to her pregnancy, her GPP had been in remission without any treatment. Both cases had erythema with pustules over the whole body and fever of over 38 1C. Blood examinations from Cases 1 and 2, respectively, revealed white blood cell counts of 12,000ml 1 and 21,170ml , and C-reactive protein concentrations of 6.5 and 14.9 mg dl 1 (normal range: o0.3 mg dl ). Bacterial cultures of the pustules were negative. Thus, Cases 1 and 2 were, respectively, diagnosed as having IH and IH with a previous history of GPP. Following ethical approval, written informed consent was obtained in compliance with the Declaration of Helsinki Principles. The entire coding regions of IL36RN including the exon/intron boundaries were sequenced using genomic DNA samples from the patients. Case 1 had the homozygous mutation c.115þ6T4C, which was proven to result in p.Arg10ArgfsX1 in IL36RN by us previously, and Case 2 had the heterozygous mutation c.28C4T (p.Arg10X) in IL36RN. Both of these are GPP-causing founder mutations in the Japanese cohort (Sugiura et al., 2013, 2014b; Figure 1e and f, and Figure 2). A search for a second IL36RN mutation in all intron and putative promoter regions in Case 2 revealed no other IL36RN mutations (Supplementary Figure S1 online and Supplementary Table S1 online). However, there is still the possibility of a second unidentified IL36RN mutation in Case 2. More than 10 cases of GPP with heterozygous IL36RN mutations have been reported (Capon, 2013; Korber et al., 2013; Li et al., 2013; SettaKaffetzi et al., 2013; Sugiura et al., 2013). Moreover, in some patients, heterozygous IL36RN mutations are associated with palmoplantar pustulosis, a type of pustular psoriasis, and acute generalized exanthematous pustulosis, a severe cutaneous drug reaction (Navarini et al., 2013; SettaKaffetzi et al., 2013). IL-36 is absent in normal skin but is induced by inflammatory cytokines such as tumor necrosis factor-a, IL-17A, and IL-22 (Carrier et al., 2011). When functional IL-36RN is absent or underproduced, overexpressed IL-36 can induce neutrophilrich infiltration. Tumor necrosis factor-a is often elevated in the blood of pregnant women, whereby it induces various serious diseases (Mallmann et al., 1991). As for skin diseases, tumor necrosis factor-a sometimes causes exacerbation of PV lesions in pregnant women (Puig et al., 2010). Hence, it is very likely that a pregnant woman who has the IL36RN mutation occasionally cannot produce enough IL-36RN to adequately antagonize IL-36 excessively induced by inflammatory cytokines, and this imbalance results in IH. After longstanding controversy over whether IH is an independent disease Accepted article preview online 9 April 2014; published online 1 May 2014 Abbreviations: GPP, generalized pustular psoriasis; IH, impetigo herpetiformis; IL-36RN, IL-36 receptor antagonist; PV, psoriasis vulgaris K Sugiura et al. IL36RN Mutations and IH

New approach to the evaluation of skin color of pigmentary lesions using Skin Tone Color Scale.

Objective methods of measuring skin color are needed to evaluate pigmentary lesions quantitatively. We have developed a new method of measuring skin color using a plastic bar system called the Skin Tone Color Scale based on Munsells color space system. We have also evaluated the effectiveness of various therapies using this measurement system. Our system was designed to measure skin color in normal skin, pigmentary lesions of solar lentigo, chloasma and ephelides, and postinflammatory pigmentation. Moreover, effectiveness of various therapies for these pigmentary lesions was evaluated. The evaluations made with this system were closely related to physician assessment. This method may be useful in measuring of skin color and evaluating the effectiveness of therapies for pigmentary diseases.

Various colour gradations as a dermatoscopic feature of cutaneous angiosarcoma of the scalp

Cutaneous angiosarcoma is an aggressive malignant vascular tumour that is subdivided into (i) classic angiosarcoma of the scalp, face and neck of the elderly; (ii) angiosarcoma arising as secondary to chronic lymphoedema (Stewart– Treves syndrome); and (iii) angiosarcoma arising in irradiated skin areas. de Giorgi and colleagues reported dermoscopic features in two cases of angiosarcoma arising in irradiated skin areas. We estimated that the significant feature was the various gradations of colour– pink-purplish stream-like areas with a white or skin-coloured central area, and a strengthening of the purple colour at the periphery of the lesions. We herein show dermoscopic figures in an elderly Japanese man with classic angiosarcoma of the scalp.

Paraneoplastic pemphigus associated with Castleman disease: Progression from mucous to mucocutaneous lesions with epitope-spreading phenomena

Paraneoplastic pemphigus (PNP) is a frequently fatal autoimmune blistering disease of the skin and mucous membranes.1 PNP is commonly associated with malignant neoplasms or haematological disorders like Castleman disease (CD). The eruptions may resemble those seen in various other conditions such as lichen planus (LP), graft-versus-host disease, erythema multiforme (EM), bullous pemphigoid and pemphigus vulgaris (PV).2 This article is protected by copyright. All rights reserved.

Bullous pemphigoid associated with psoriasis: A possible example of an inverse intramolecular epitope-spreading phenomenon.

Dear Editor, An 82-year-old Japanese man with a 40-year history of psoriasis was referred to us, because small tense bullae first appeared on the bilateral legs, and then spread over the whole body. Physical examination revealed small tense bullae on the normal skin and the scaly erythematous psoriatic lesions (Fig. 1a,b). Mucous membranes were not involved. Laboratory examinations showed increased leukocytes (10,000/lL; normal, 3900–9300/lL) with normal eosinophils (0.6%; normal, 0.2–4.1%) and normal C-reacted protein (0.042 mg/dL; normal, <0.3 mg/dL). An index in enzyme-linked immunosorbent assay (ELISA) was faintly positive for the recombinant protein (RP) of the BP180-NC16a domain (16.1; normal, <9), whereas indexes were negative for the RP of BP230, desmoglein 3, desmoglein 1 and type VII collagen. A biopsy taken from a bulla on the normal skin showed blister formation, infiltration of eosinophils and neutrophils in the blister, and mononuclear cells in the upper dermis (Fig. 1c), while another biopsy from a psoriatic lesion revealed hyperkeratosis, parakeratosis, acanthosis and Munro’s microabscess in the horny layer (Fig 1d). Direct immunofluorescence (IF) showed linear depositions of immunoglobulin (Ig)G and C3 in the basement membrane zone (BMZ). Indirect IF using normal human skin revealed circulating IgG anti-BMZ autoantibodies at 1:160 dilution (Fig. 1e), which reacted with the epidermal side of 1 mol/L NaCl-split normal human skin at 1:10 dilution (Fig. 1f). In immunoblotting of concentrated culture supernatant of HaCaT cells, IgG antibodies in the patient serum reacted with linear IgA dermatosis antigen-1 (LAD-1) (Fig. 1g). There was no reactivity with the recombinant proteins of NC16a and C-terminal domains of BP180, normal human dermal extract or purified human laminin-332. Intravenous prednisolone 30 mg/day and subsequent 70 mg/day did not suppress progress of blister formation, whereas topical calcipotriol and betamethasone butyrate propionate were moderately effective for psoriasis. Then, the patient was treated with i.v. Ig 400 mg/kg per day for 5 days consecutively from day 19. The treatment suppressed new blister formation. Subsequently, betamethasone 6 mg/day was administrated, and tapered. The ELISA indexes of the BP180NC16a domain RP were 19.5 at day 24 and 3.6 at day 52.

Refractory bullous pemphigoid leaving numerous milia during recovery

Recovery with milia may occur in bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). Scarring commonly occurs in MMP and EBA. Here, we report a 62‐year‐old man patient with BP, who was left with numerous milia during recovery. The patient had immunoglobulin (Ig)G autoantibodies to the recombinant protein of the BP180‐NC16a domain and the soluble 120‐kDa ectodomain of BP180 (linear IgA bullous dermatosis [LAD]‐1). There are cases of BP with IgG autoantibodies to LAD‐1 and/or the recombinant protein of BP180 C‐terminal domain. Extensive milia formation during recovery may be associated with immunological predisposition and/or improper interaction between hemidesmosomes and the extracellular matrix components.

Case of burn‐associated bullous pemphigoid caused by anti‐BP230 immunoglobulin G autoantibodies

glandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet 2008; 40: 789–793. 3 Zhang Z, Xia W, He J et al. Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. Am J Hum Genet 2012; 90: 125–132. 4 Coggins KG, Coffman TM, Koller BH. The Hippocratic finger points the blame at PGE2. Nat Genet 2008; 40: 691–692. 5 Riviere PJ, Farmer SC, Burks TF et al. Prostaglandin E2-induced diarrhea in mice: importance of colonic secretion. J Pharmacol Exp Ther 1991; 256: 547–552.

Efficacy and safety of targeted narrowband ultraviolet B therapy using a flat‐type fluorescent lamp for the treatment of palmoplantar pustulosis

tion caused by a hypersensitivity complex, which affects the skin and the mucous membranes. SJS has a multiple etiologic pattern, drugs being the most frequently implicated usually caused by anti-infective sulfonamides, aromatic anticonvulsants, oxicam non-steroidal anti-inflammatory drugs and allopurinol. Damage to the skin is thought to be mediated by cytotoxic T lymphocytes and mononuclear cells which induce apoptosis in keratinocytes expressing drug-derived antigens at their surfaces. In some groups, drug reaction may be aggravated by genetic factors. Patients who receive sunitinib treatment less commonly develop erythematous eruption and SJS is not a reported sideeffect. Lee et al. reviewed 119 cases and reported adverse events that were related to sunitinib, including hand–foot skin reaction (36%), stomatitis (36%), yellowish-to-grayish discoloration of the face or hair (30%), facial swelling (24%) and erythematous eruption on the trunk (12%). Physicians should be aware of the potential of sunitinib-induced hypersensitivity such as SJS as seen in our case, often leading to fatal outcomes.

Occupational allergic contact dermatitis due to cashew nut oil

A 37-year-old Japanese male, working as a researcher in an industry producing phenol–formaldehyde resins, presented with painful, oedematous erythema with bullae on his right leg (Fig. 1). He had dropped pure cashew nut oil from a bottle onto his right thigh 14 D previously but had taken off his work clothes immediately and thoroughly washed the skin. However, an itchy erythema began to develop 10 D later. Because of the severe swelling, the patient was hospitalized. The dermatitis was treated with systemic and topical steroids and an oral antihistamine. Patch testing was performed with cashew nut oil 3% alcohol (alc.), 0.3% alc., 0.03% alc., urushiol 0.01% pet., ethanol ‘as is’, and pet. ‘as is’. Cashew nut oil was provided by his employer. Urushiol (diluted to 0.01% pet.) was purchased from Torii Pharmaceutical Co., Ltd. (Tokyo, Japan). Reactions were recorded as follows: pet. and ethanol were negative (Fig. 2).