Ichiro Kurokawa

New developments in our understanding of acne pathogenesis and treatment

Abstract:  Interest in sebaceous gland physiology and its diseases is rapidly increasing. We provide a summarized update of the current knowledge of the pathobiology of acne vulgaris and new treatment concepts that have emerged in the last 3 years (2005–2008). We have tried to answer questions arising from the exploration of sebaceous gland biology, hormonal factors, hyperkeratinization, role of bacteria, sebum, nutrition, cytokines and toll‐like receptors (TLRs). Sebaceous glands play an important role as active participants in the innate immunity of the skin. They produce neuropeptides, excrete antimicrobial peptides and exhibit characteristics of stem cells. Androgens affect sebocytes and infundibular keratinocytes in a complex manner influencing cellular differentiation, proliferation, lipogenesis and comedogenesis. Retention hyperkeratosis in closed comedones and inflammatory papules is attributable to a disorder of terminal keratinocyte differentiation. Propionibacterium acnes, by acting on TLR‐2, may stimulate the secretion of cytokines, such as interleukin (IL)‐6 and IL‐8 by follicular keratinocytes and IL‐8 and ‐12 in macrophages, giving rise to inflammation. Certain P. acnes species may induce an immunological reaction by stimulating the production of sebocyte and keratinocyte antimicrobial peptides, which play an important role in the innate immunity of the follicle. Qualitative changes of sebum lipids induce alteration of keratinocyte differentiation and induce IL‐1 secretion, contributing to the development of follicular hyperkeratosis. High glycemic load food and milk may induce increased tissue levels of 5α‐dihydrotestosterone. These new aspects of acne pathogenesis lead to the considerations of possible customized therapeutic regimens. Current research is expected to lead to innovative treatments in the near future.

What causes hidradenitis suppurativa

Abstract:  Hidradenitis suppurativa (HS) – a rather common, very chronic and debilitating inflammatory skin appendage disorder with a notoriously underestimated burden of disease – has long been a playground for the high priests of nomenclature: Ask a bunch of eminent dermatologists and skin pathologists to publicly share their thoughts on what causes HS, and they will soon get entrenched in a heated debate on whether this historical term is a despicable misnomer. Fortunately, the recently founded Hidradenitis Suppurativa Foundation (HSF; http://www.hs‐foundation.org), to which EXP DERMATOL serves as home journal, has broken with this unproductive tradition and has encouraged publication of the current CONTROVERSIES feature. This is exclusively devoted to discussing the pathobiology of this chronic neutrophilic folliculitis of unknown origin. Although traces of terminological bickering remain visible, it does the HS experts in our virtual debate room credit that they engage in a constructive and comprehensive dissection of potential pathogenesis pathways that may culminate in the clinical picture we know under the competing terms HS or acne inversa. These experts sketch more often complementary than mutually exclusive pathogenesis scenarios, and the outlines of a conceivable consensus on the many open pathobiology questions begin to emerge in these CONTROVERSIES. Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy.

Diagnostic delay in hidradenitis suppurativa is a global problem.

DEAR EDITOR, Hidradenitis suppurativa (HS) is clinically defined with recognized diagnostic criteria and recognizable physical characteristics. Untreated, the disease causes significant morbidity. The prevalence varies between 0 0003% and 4% depending on the study population. Estimates from insurance databases suggest a prevalence of < 0 1%. This variation strongly suggests a significant selection bias or misclassification, and it may be speculated that not all patients present for care. This is reinforced by clinical experience and published evidence indicating a significant delay in diagnosis. This study explores the delay in diagnosis for patients with HS on an international level. The study (survey) was conducted in 2013. Observational data were collected during routine visits or extracted from case records. Because of the simple and obvious symptomatology of recurrent painful lesions present in restricted welldefined areas of the body, patients’ self-reported history was considered valid regarding onset of symptoms. Consecutive patients with HS and psoriasis were included from each participating centre during a period of 4 months or less. The data were anonymized by removing any names, addresses and social security numbers, and included age, sex, age at disease onset, age at diagnosis, delay in diagnosis, time from onset of symptoms to first physician contact, age at first medical contact, number of physicians seen prior to the diagnosis, family history and disease severity. If the diagnosis was made by a primary care physician or by a specialist other than a dermatologist prior to seeing a dermatologist, this was recorded as the date of the diagnosis. Individual centres were responsible for and obtained any locally required permissions and signed informed consent forms, for example ethics committee approval, in accordance with national registry and data protection rules. Patients diagnosed with HS or psoriasis (and confirmed by the investigator) were included. The primary outcome was quantification of the delay in diagnosis. Additionally, documentation was made of both the delay in visiting a physician (and so gaining access to specialist treatment) and the relative delay in diagnosis of HS compared with psoriasis with/without a family history. The severity of HS was determined by Hurley’s staging criteria: stage I, mild; stage II, moderate and stage III, severe. In patients with psoriasis, severity was evaluated by the Psoriasis Area and Severity Index: score < 7, mild; 7–12, moderate and > 12, severe. The t-test, Wilcoxon rank sum test and v-test were used where appropriate. Univariate and multivariate logistic regression analyses were used to identify factors predictive of significant diagnostic delay. Diagnostic delay > 2 years was defined as significant. Diagnosis, sex, age of onset, family history and disease severity were selected as potentially important

Presence of cytokeratins in human eccrine sweat gland epithelia--an immunocytochemical study of the monoclonal antibodies KL1, CK 8.60, PKK2, CK 8.12, CK 8.13, CK 4.62, and RPN 1160 using the APAAP technique.

The distribution of various cytokeratins in human eccrine sweat gland epithelia was studied using the antikeratin monoclonal antibodies KL1, CK 8.12, CK 8.60, PKK2, CK 8.13, CK 4.62 and RPN 1160. Immunocytochemical techniques were performed according to a standard alkaline phosphatase and monoclonal anti‐alkaline phosphatase (APAAP) method.

Beyond acne: Current aspects of sebaceous gland biology and function

The sebaceous gland is most commonly found in association with a hair follicle. Its traditional function is the holocrine production of sebum, a complex mixture of lipids, cell debris, and other rather poorly characterized substances. Due to the gland’s central role in acne pathogenesis, early research had focused on its lipogenic activity. Less studied aspects of the sebaceous gland, such as stem cell biology, the regulation of cellular differentiation by transcription factors, the significance of specific lipid fractions, the endocrine and specially the neuroendocrine role of the sebaceous gland, and its contribution to the innate immunity, the detoxification of the skin, and skin aging have only recently attracted the attention of researchers from different disciplines. Here, we summarize recent multidisciplinary progress in sebaceous gland research and discuss how sebaceous gland research may stimulate the development of novel therapeutic strategies targeting specific molecular pathways of the pathogenesis of skin diseases.

Questionnaire surveillance of hidradenitis suppurativa in Japan.

1 Kalioras V, Thanos L, Mylona S, Pomoni M, Batakis N. Scalp actinomycosis mimicking soft tissue mass. Dentomaxillofac Radiol 2006; 35: 117–118. 2 Valour F, S en echal A, Dupieux C et al. Actinomycosis: etiology, clinical features, diagnosis, treatment, and management. Infect Drug Resist 2014; 7: 183–197. 3 Lee YS, Sim HS, Lee SK. Actinomycosis of the upper lip. Ann Dermatol 2011; 23 (Suppl 1): S131–S134. 4 Appiah-Anane S, Tickle M. Actinomycosis-an unusual presentation. Br J Oral Maxillofac Surg 1995; 33: 248–249. 5 Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff KF. Actinomycosis, nocardiosis, and actinomycetoma, In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K, eds. Fitzpatricks Dermatology in General Medicine, 8th edn. New York: McGraw-Hill, 2011:2241–2244.

Case of generalized eruptive clear cell syringoma with diabetes mellitus

Dear Editor, Headington et al. reported the first case of clear cell syringoma (CCS) in 1972. The disease is frequently associated with diabetes mellitus (DM) (80%). Generalized eruptive clear cell syringoma (GECCS) is an extremely rare variant of CCS. We report a case of GECCS with DM. A 70-year-old-woman consulted our institution for painless, nonpruritic, multiple brown papules on her upper extremities, breast and abdomen. She had type 2 DM without familial history of DM, but no history of hypertension or hyperlipidemia. Nine years prior, she noticed non-pruritic, flat, elevated, yellow to brown papules of 1–3 mm diameter distributed on the upper extremities and abdomen (Fig. 1a). The laboratory data showed high levels of fasting blood sugar (140 mg ⁄ dL) and hemoglobin A1c (6.1%). Other laboratory data were normal. Histological examination revealed nests of clear cells with tadpole appearance and distributed in the upper and middle layers of the dermis. Tumor cells were composed of two to three layers with pale clear cytoplasm and ductal structures (Fig. 1b). Continuity between the epidermis and tumor was not observed. Immunohistochemical staining with keratin (K) showed positive reactivity for K1, K10, K14 and K17, but negative reactivity for K7, K8, K15, K16, K18 and K19. Generalized eruptive syringoma (GES) is a rare variant characterized by eruptions appearing on the trunk and extremities. GECCS is an even rarer GES; only six cases have been reported, and five of these were from Japan. Table 1 summarizes the cases. Among all the cases, there were three women and four men, aged 16–75 years. DM was diagnosed in three of the seven cases. Treatment for GECCS was not effective in all cases and treatment for diabetes was not effective for GECCS. Histopathological features of CCS differ from syringoma. CCS is composed of nests of clear cells. Eighty percent of patients with CCS (13 ⁄ 16) have associated DM or glucose intolerance, and 89.3% of CCS patients over 40 years of age have type 2 DM as well as our case. The mechanism of the comorbid association of CCS and DM is still unclear. Syringoma can differentiate into CCS after the onset of DM, and mixed types of syringoma, and CCS have been reported. Tumor cells of syringoma may differentiate into clear cells due to DM-associated skin glucose disorder. Massive accumulation of glycogen in CCS has been demonstrated by electron microscopy. A previous report has shown positivity for K1, K5, K10 and K19 in syringoma. In the present report, we found positivity for K1, K10, K14 and K17, suggesting that CCS derived from the ductal portion. Immunohistochemical microscopic studies have also demonstrated tumor cells differentiating into eccrine sweat gland ducts. Our results are consistent with this previous report. Further studies should be performed to clarify the origin of GECCS.

Adjuvant alternative treatment with chemical peeling and subsequent iontophoresis for postinflammatory hyperpigmentation, erosion with inflamed red papules and non-inflamed atrophic scars in acne vulgaris

The standard management of acne vulgaris in Japan includes a combination of topical treatment with benzoyl peroxide (BPO) and BPO/clindamycin (CLDM), topical adapalene and systemic antimicrobials. However, the treatment of therapy‐resistant complications such as postinflammatory hyperpigmentation (PIH), erosions with inflamed red papules and atrophic scars has not been established. We performed chemical peeling with glycolic acid and iontophoresis with ascorbyl 2‐phosphate 6‐palmitate and DL‐α‐tocopherol phosphate for the treatment of PIH, erosions with inflamed red papules and non‐inflamed atrophic scars in 31 patients with acne vulgaris (mild to severe severity), and evaluated the efficacy and safety of these interventions. In most of cases, there was remarkable improvement in PIH and erosions with inflamed red papules after treatment. There was also some improvement in non‐inflamed atrophic scars without erythema. Mild redness and irritation was observed in four cases as adverse reactions. Early initial treatment of PIH and erosions with red papules by chemical peeling and iontophoresis is an effective and safe method to prevent the formation of atrophic scars in patients with acne vulgaris.

Porokeratotic Eccrine Ostial and Dermal Duct Naevus and Aberrantly Regulated Keratinization

© 2013 The Authors. doi: 10.2340/00015555-1515 Journal Compilation

Case reports of adjuvant combination therapy in severe acne vulgaris with chemical peeling using glycolic acid and iontophoresis

Dear Editor, In Japan, treatment with topical adapalene and antimicrobials along with systemic antimicrobials has been the mainstay of medical treatment for acne according to guidelines published by the Japanese Dermatological Association (JDA) in 2008. Adjuvant combination therapy with chemical peeling using glycolic acid and subsequent iontophoresis with vitamin A, vitamin C and vitamin E was performed on five patients (age range, 16–27 years; mean age, 19.8 years) with severe acne vulgaris. Chemical peeling with 20% glycolic acid at pH 3.2 (Jorbi Neutralizer 20; Keisei, Tokyo, Japan) and subsequent iontophoresis using either Moisture Gel (Environ; Protea Japan, Tokyo, Japan) or ascorbyl 2-phosphate 6-palmitate (APPS) and DL-a-tocopherol phosphate (TPNa; ITO, Tokyo, Japan) were performed 4–6 times at 2–4-week intervals. Moisture Gel contained vitamin C (ascorbyl acid), vitamin A (retinyl palmitate), vitamin E, vitamin B5 and b-carotene. In all cases, remarkable improvement was observed in acne severity from “severe” to “mild”, and the number of total lesions, inflammatory lesions, and non-inflammatory lesions and postinflammatory pigmentation (PIH). In particular, the number of inflammatory lesions decreased markedly. A representative case is shown in Figure 1. Mild and transient adverse reactions such as redness and stinging after the therapy was noted in two of the five cases. Japanese Dermatological Association guidelines recommend chemical peeling with glycolic acid for treating both non-inflammatory and inflammatory lesions that are unresponsive or unavailable to medical treatment. In the JDA guidelines for chemical peeling, glycolic acid is the agent recommended for one of the methods to treat acne. Chemical peeling promotes remodeling of epithelia, unroofing of red papules and pustules, and improving hypercornification while exerting antibacterial effects against Propionibacterium acnes. Chemical peeling with glycolic acid also inhibits PIH. The mechanisms underlying the action of glycolic acid accelerate the turnover of the epidermis and inhibit melanin formation in melanocytes. The usefulness of iontophoresis for treating acne has been reported. APPS is a vitamin C derivative that has amphipathic (hydrophilic and lipophilic) properties. It is also effective for perifollicular pigmentation. TPNa inhibits the production of lipoperoxide, exerts anti-inflammatory effects and has antimicrobial activity against P. acnes. Combination therapy of chemical peeling and subsequent iontophoresis would be more effective for treating acne than any of these treatments alone. Because chemical peeling breaks through the normal barrier function of the epidermis, effective iontophoresis can be induced. In particular, follicles and the sebaceous gland are not highly resistant areas for permeability; hence, transadnexal absorption is more effective. Based on these results, adjuvant combination therapy with chemical peeling using glycolic acid and subsequent iontophoresis with vitamin A, vitamin C and vitamin E appears to