Yo Kaku

Bullous pemphigoid suggestive of complement-independent blister formation with anti-BP180 IgG4 autoantibodies

DEAR EDITOR, Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies against structural proteins of the dermoepidermal junction, such as BP180. Approximately 10% of patients with BP are C3-negative at the basement membrane zone (BMZ) by direct immunofluorescence (DIF) microscopy. However, anti-BP180 pathogenic IgG antibodies failed to induce disease under the conditions where complement activation was defective in animals. Thus, complement activation in situ is considered essential in blister formation in BP, and a clinical hallmark of the diagnosis. In both pemphigus and pemphigoid diseases, tissue-bound and circulating autoantibodies mainly belong to the IgG4 and IgG1 subclasses. In pemphigus diseases, acantholysis is considered to be complement-independent and IgG4 antibodies seem to mediate acantholysis. However, tissue damage in pemphigoid diseases is thought to be mainly mediated by IgG1, because IgG4 has a very limited ability to activate complement. Complement-independent, subepidermal autoimmune blister formation has been implicated in vitro and in animal models. However, it remains unclear whether complement activation is essential in pemphigoid diseases. Here, we report two cases of pemphigoid, without complement activation at the BMZ, which may partly explain the clinical diversity in pemphigoid diseases. In case 1, a 78-year-old woman presented with eczematous lesions on the trunk and limbs. Topical clobetasol propionate and oral prednisolone (5 mg daily for 4 months) was effective and tapered off. After 1 month, the eczematous lesions relapsed and tense blisters developed on the lower legs (Fig. 1a). Serum anti-BP180 NC16a IgG was 83 4 U mL 1 (normal range 0–9) and BP230 IgG was 87 2 U mL 1 (normal range 0–9). Histology skin specimens showed detached epidermis and infiltration of eosinophils and neutrophils in the dermis (Fig. 1b). Indirect immunofluorescence (IIF) showed that IgG antibodies were reactive to the epidermal sides of 1 mol L 1 NaCl-split human skin (Fig. 1c). DIF of the skin specimens showed linear deposition of IgG, but no C3, at the BMZ of the epidermis (Fig. 2a). Our diagnosis for this patient was BP. Treatment with oral prednisolone 15 mg daily was quite effective and was tapered. There was no recurrence for more than 6 months. In case 2, an 80-year-old man presented with small, itchy erythemas and blisters on the trunk and legs (Fig. 1a). Histology skin specimens showed subepidermal blister formation and infiltration of eosinophils and neutrophils in the dermis (Fig. 1b). Although serum anti-BP180 NC16a or BP230 IgG was not detectable, IIF of NaCl-split skin showed that IgG antibodies were reactive to the epidermal sides (Fig. 1c). DIF of the skin specimens showed linear deposition of IgG and a faint, nonspecific, granular deposition of C3 at the BMZ (not shown). Our diagnosis for this patient was BP. Topical clobetasol propionate was not effective and pustules developed. However, treatment with prednisolone 20 mg daily was effective. Unfortunately, computed tomography detected a pancreatic mass, with multiple masses in neighbouring organs and lungs, suggestive of pancreatic carcinoma with multiple metastases. The patient died 4 months later. The DIF of the skin specimens for IgG subclasses showed that IgG4 was the major subclass of the anti-BMZ IgG antibodies in both case 1 (Fig. 1d) and case 2 (not shown). IIF of healthy skin specimens for IgG subclasses demonstrated that IgG4 antibodies from the patients’ sera bound linearly to the BMZ (not shown). Immunoblotting of plasmin-digested recombinant BP180 detected anti-LAD-1/p120 antibodies in both cases, and anti-p97 antibodies in case 2 only (not shown). Immunoblotting of BP180-transfected 293T cell lysates detected the anti-BP180 IgG4 antibodies in both cases (Fig. 1e). To investigate the mechanism, we tested the patients’ sera for the ability to fix complement in situ by using complement IIF techniques. Neither serum samples from these patients nor healthy control serum fixed complement at the BMZ, whereas BP serum did (Fig. 2a). Furthermore, we carried out the complement fixation (CF) test using human full-length BP180 and found that circulating autoantibodies against BP180 from either case did not fix complement, whereas sera from common BP cases did (Fig. 2b). These results suggest that autoantibodies may lack the ability to fix complement, and that there is a complement-independent mechanism in blister formation in these cases. Serum IgG4 and complement were within normal range, and there was no sign in either case that suggested any IgG4related diseases, such as plasma cell infiltration. Histology of skin specimens from both cases was similar to those from common BP. This was not unexpected as anti-BP180 antibodies can directly induce keratinocytes to produce proinflammatory cytokines and chemokines.

Eosinophilic annular erythema limited on the palms and the soles and possibly associated with thymoma

HPV 18 (high-risk genotype) cause cervical cancer and squamous cell carcinoma (tonsils, larynx, anus, vulva and penis) whereas HPV 6 and HPV 11 (low-risk genotype) cause warts and condylomas. Conventional treatments for HPV infection involve topical drugs (podophyllotoxin, imiquimod, retinoid acid derivatives) and, in case of failure, CO2 laser ablation. The two HPV vaccines, the bivalent vaccine (Cervarix, Glaxo Smith Kline) and the quadrivalent vaccine (Gardasil, Sanofi Aventis MerckSharp&Dome) remain the only preventive measure against most HPV-related diseases. Several immunodeficiencies (epidermodysplasia verruciformis, WHIM syndrome, SCID, CVID, HIV, etc.) result in severe HPV. In the immunocompromised, treatment and cure of HPV may represent a complex and challenging task. The identification of a high-risk HPV genotype in our patient prompted us to investigate the potential effect of the quadrivalent vaccine (HPV 6/11/16/18 subtypes). Our observation of a complete remission of plantar warts after the second dose with absence of genital response is intriguing. To our knowledge, the treatment with HPV vaccine of a few anecdotal cases with recalcitrant warts and condylomas has produced ambiguous results. Although spontaneous regression of warts may occur, a role for HPV vaccination in the immunocompromised is undefined. A thorough analysis of HPV innate and adaptive immune response will help guide a prudent answer to this unexpected dual response. Yet, prospective randomized multicentre clinical trials are warranted to investigate whether HPV vaccines can treat common warts and/or prolong their progression time with significant advances on the immune mechanisms that control HPV infection and potential impact on the quality of life of our patients.

Three-dimensional evaluation of subclinical extension of extramammary Paget’s disease: Visualization of histological border and its comparison to clinical border

In extramammary Paget disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). However, the spreading pattern of Paget cells in subclinical extension remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown.

Sebaceous carcinoma arising at a chronic candidiasis skin lesion of a patient with keratitis–ichthyosis–deafness (KID) syndrome

therapy is required in a 46XX true hermaphrodite to ensure the development of secondary sexual characteristics, which renders patients susceptible to the development of iatrogenic AGA. Therefore, physicians should be aware of this potential complication and advise patients on the possibility of unwanted alopecia through the management process. To treat iatrogenic AGA in our patient, we referred to a case of iatrogenic AGA in a woman receiving exogenous androgen supplementation who responded well to finasteride. Because our patient with 46XX true hermaphroditism was genetically female, the iatrogenic AGA in our patient appeared to be similar to that in a female. Therefore, we treated our patient with finasteride and observed an improvement in hair coverage, despite continuing testosterone replacement therapy. Finasteride is highly effective in men with AGA, but its efficacy is less clear in women. Indeed, many conflicting reports have been issued regarding its efficacy in women with AGA. These disagreements have raised doubts about the androgenic aetiology in women with AGA. Furthermore, some reports failing to prove the evidence of elevated androgens in women with AGA also supported that mechanisms other than androgens contribute to AGA in women. However, there have been several reports about women with AGA responding well to finasteride, providing evidence of androgen dependence in female pattern hair loss. Our case provides more direct evidence that androgens can induce hair loss in a genetically female individual and supports an androgenic aetiology in women with AGA. As a certain subgroup of women with AGA responds to finasteride, it is important that a positive predictive marker of finasteride therapy be identified. AGA in women has been described as showing three different clinical patterns, namely, the Ludwig pattern, the Christmas tree pattern, and the Hamilton pattern. Hamilton type or male pattern hair loss with frontotemporal recession is usually observed in men with AGA, and the condition responds well to finasteride. In addition, women with AGA showing Hamilton type hair loss (as occurred in our patient) have also been reported to respond well to finasteride. These observations suggest that Hamilton type hair loss in women may be a positive predictive marker of finasteride therapy. However, further study is needed to confirm this hypothesis. In summary, we describe a case of iatrogenic AGA in a patient with 46XX true hermaphroditism. This case serves as a reminder that iatrogenic AGA should be considered in patients on testosterone replacement therapy and supports an androgenic aetiology in women with AGA. Furthermore, we suggest that Hamilton type alopecia could be a positive predictive marker of finasteride therapy in female patients.

Oral erosive lichen planus and alopecia areata with Good's syndrome (thymoma with hypogammaglobulinemia)

Auteur(s) : Yo KAKU1,2, Noriko SHIMAMOTO3, Hiromi MATSUNAGA2, Munehiko MAKIURA2, Akihiro FUJISAWA3, Kazumasa MORITA2 montreux77@live.jp 1 Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan 2 Department of Dermatology, Tenri Hosptal, Tenri 632-8552, Japan 3 Department of Dermatology, Yamatotakada Municipal Hospital, Yamatotakada 635-8501, Japan In May 2007, a 71-year-old female was referred to our department from the odontology unit in our hospital for [...]

Oral lichen planus associated with candidiasis during secukinumab treatment.

Dear Editor, Oral lichen planus (OLP) is a chronic T-cell-mediated inflammatory disease of the oral mucosa. Although the pathogenesis of OLP remains unknown, some reports note the involvement of drug intake, virus infection and candidiasis in its development. Secukinumab is a monoclonal human immunoglobulin G1 antibody that can fully neutralize interleukin (IL)-17A and exhibits great efficacy in the treatment of psoriasis. Because IL-17A plays pivotal roles in host protection against fungal infections, patients treated with secukinumab sometimes develop oral candidiasis. Herein, we report a case of OLP accompanied by candidiasis during secukinumab treatment. A 74-year-old woman diagnosed with rheumatoid arthritis (RA) and psoriasis vulgaris had presented with persistent painful erosion of the oral mucosa for several months. She had received various systemic medications including cyclosporin, etretinate, adalimumab (an anti-tumor necrosis factor [TNF]-a antibody) and ustekinumab (an anti-IL-12/23p40 antibody) for psoriasis. Her skin symptoms gradually worsened, however, and secukinumab was thus prescribed. After secukinumab administration, her skin symptoms improved significantly, but 5 months after the administration, she developed painful whitish plaque on the left oral mucosa (Fig. 1a). The lesion repeatedly deteriorated with secukinumab administration. We suspected the lesion to be candidiasis or lichen planus, and performed a microscopic analysis of Candida and an oral mucosa biopsy. We detected abundant pseudohyphae of Candida by microscopy. Histological examination showed bandlike lymphocyte infiltration just beneath the mucosal epithelium with liquefaction and colloid body formation (Fig. 1b). In addition, aggregates of Candida, which was confirmed by periodic acid-Schiff staining, were observed on the epithelial surface (Fig. 1c,d). We diagnosed the lesion as OLP with candidiasis. Because secukinumab was suspected as the causal factor for the oral lesion, and as the psoriasis lesion had almost completely disappeared at this point, we discontinued secukinumab treatment. We also started oral amphotericin B (360 mg/day) syrup treatment after every meal for oral candidiasis for 2 months. The OLP and candidiasis diminished in 2 months, and have not relapsed since then. In this case, the development and exacerbation of OLP was closely related to the administration of secukinumab. Although the actual pathological relationship between OLP and secukinumab remains unknown, secukinumab might have contributed to the development of OLP by inducing oral candidiasis, a common side-effect of secukinumab.

Pyoderma gangrenosum of the penis possibly associated with pazopanib treatment.

chemical characterization of a thaumatin-like kiwi allergen. J Allergy Clin Immunol 2002; 110: 805–810. 3 Grozdanovic M, Popovic M, Polovic N et al. Evaluation of IgE reactivity of active and thermally inactivated actinidin, a biomarker of kiwifruit allergy. Food Chem Toxicol 2012; 50: 1013–1018. 4 Palacin A, Quirce S, Sanchez-Monge R et al. Sensitization profiles to purified plant food allergens among pediatric patients with allergy to banana. Pediatr Allergy Immunol 2011; 22: 186–195. 5 Aleksic I, Popovic M, Dimitrijevic R et al. Molecular and immunological characterization of Mus a 5 allergen from banana fruit. Mol Nutr Food Res 2012; 56: 446–453. 6 Nikolic J, Mrkic I, Grozdanovic M et al. Isolation protocol for three important banana allergens. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 962C: 30–36. 7 Clendennen SK, May GD. Differential gene expression in ripening banana fruit. Plant Physiol 1997; 115: 463–469.

Methotrexate‐associated EBV‐positive vasculitis in the skin: a report of two cases simulating rheumatoid vasculitis

Rheumatoid vasculitis (RV) is one of the most serious extra‐articular complications of rheumatoid arthritis (RA), generally treated with a high dose of immunosuppressive drugs. Recently, we encountered two cases of ulcerative vasculitis in methotrexate (MTX)‐prescribed RA patients, which simulated RV; however, Epstein–Barr virus (EBV)‐encoded RNA in situ hybridization on their skin biopsies revealed many EBV‐positive lymphocytes (over 50 cells/high‐power field) within the vessel walls and perivascular stroma, which led us to the diagnosis of EBV‐related vasculitis instead of RV. Subsequently, both ulcers regressed after the discontinuation of MTX and no recurrence was noted during the follow‐up period. To prevent unnecessary treatment, EBV‐positive vasculitis should be added in the differential diagnosis of lymphocytic vasculitis observed in MTX‐administered RA patients.

Case of pityriasis rubra pilaris with annular pattern as an early manifestation.

Figure 1. Clinical manifestations and histology of the patient. (a) Initial cutaneous manifestation: annular erythematous plaques on the left neck and right cheek. (b) Histological examination of the annular lesion: although focal and subtle, lamellar hyperkeratosis with parakeratosis in both vertical and horizontal directions (so-called “checkerboard pattern”) and follicular plugging were present (hematoxylin–eosin [HE], original magnification 9 200). (c–e) Despite topical and oral corticosteroid treatment, the patient developed the typical manifestation of classic pityriasis rubra pilaris, (c) keratotic follicular papules, (d) generalized erythroderma with spared clear islands of normal skin, and (e) his palm showing the keratoderma (e). (f,g) Histological findings of the second biopsy revealed a more prominent checkerboard pattern of the corneal layer and follicular plugging. Higher magnification view of the boxed area is shown in (g) (HE, original magnifications: [f] 9 100; [g] 9400).

Low-grade Neuroendocrine Carcinoma of the Skin (primary Cutaneous Carcinoid Tumor) as a Distinctive Entity of Cutaneous Neuroendocrine Tumors: A Clinicopathologic Study of 3 Cases With Literature Review.

Abstract: There is scarcity of information on primary cutaneous low-grade neoplasms commonly known as carcinoid tumors, owing to their rarity. The authors present 3 cases that were named “low-grade neuroendocrine carcinoma of the skin” (LGNECS). These occurred in the dermis and subcutis of the anterior chest or the inguinal region in the elderly. Histologically, the tumors showed infiltrating proliferation of nests of various sizes, with low-grade neuroendocrine cytologic features but without mucin production. All cases exhibited varying degrees of intraductal tumor components. On immunohistochemical examination, these tumors expressed estrogen receptor alpha, progesterone receptor, androgen receptor, gross cystic disease fluid protein 15, mammaglobin, and GATA3 as well as neuroendocrine markers. Although a literature review revealed 8 additional possible cases with no evidence of other diseases, it was difficult to determine if these were true cases of LGNECS, because of the limited information available. Based on its characteristic histologic features and immunoprofile, it can be proposed designating LGNECS as a distinct entity among cutaneous neuroendocrine tumors. Otherwise, such tumors could be misdiagnosed as mammary carcinomas (particularly when involving the skin of the breast) or as metastatic visceral neuroendocrine tumors of the skin.