Recent progress of Stevens-Johnson syndrome/toxic epidermal necrolysis: Diagnosis criteria, pathogenesis and therapy.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions, primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest through extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advancements in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T cell responses and HLA polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of TNF-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding of the disease and its mechanisms.

Cholecystokinin Downregulates Psoriatic Inflammation by Its Possible Self-Regulatory Effect on Epidermal Keratinocytes.

Cholecystokinin (CCK) is a peptide hormone that functions in digestive organs and the CNS. We previously showed that CCK downregulates peripheral pruritus by suppressing degranulation of mast cells. In this study, we demonstrated that CCK octapeptide (CCK8) was constitutively expressed in the epidermis of normal skin, whereas its expression was lost in acanthotic lesions of psoriasis. In contrast, CCKA receptor (CCKAR), a high-affinity receptor for CCK, was constitutively expressed in the epidermis of psoriatic skin lesions. Expression of CCK was also reduced in skin lesions of an imiquimod (IMQ)-induced psoriatic mouse model. Notably, the expression level of CCK inversely correlated with the severity of epidermal inflammation, raising the possibility that CCK from epidermal keratinocytes suppresses the psoriatic inflammation. To verify this hypothesis, we investigated the effects of sulfated CCK octapeptide (CCK8S) on the development of IMQ-induced psoriatic inflammation. i.p. injection of CCK8S suppressed the IMQ-induced psoriatic inflammation accompanied by reduced mRNA expression of IL-17, IL-22, and IL-6 but not of IL-23. The suppressive effect of CCK8S was completely restored by administration of CCKAR antagonist. In vitro studies showed that exogenous CCK8S suppressed IL-6 production in CCKAR-expressing cultured human keratinocytes, and blocking the endogenous CCK signaling with CCKAR antagonist markedly enhanced IL-6 production. When keratinocytes were stimulated with IL-17, the expression of endogenous CCK was significantly decreased. These findings suggest that CCK physiologically functions as a negative regulator of keratinocyte-based inflammation in an autocrine or paracrine manner, although decreased CCK may pathologically contribute to continuous and aggravated skin lesions such as psoriasis.

Immunological Properties of Atopic Dermatitis-Associated Alopecia Areata.

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.

Plasmacytoid dendritic cells as a possible key player to initiate alopecia areata in the C3H/HeJ mouse.

BACKGROUND: Alopecia areata (AA) is a tissue-specific autoimmune disease, and interferon (IFN)-γ has been regarded as the key cytokine in the pathogenesis of AA. The clinical observation that AA can occur after viral infection or IFN-α administration implies that IFN-α-producing plasmacytoid dendritic cells (pDCs) may be involved in the AA pathogenesis. METHODS: We generated AA in C3H/HeJ mice by intradermal injection of T cells derived from lymph nodes of AA-bearing syngeneic mice and stimulated IL-2, IL-7, and IL-15. Distribution of IFN-γ producing pDCs were immunohistochemically analyzed. Realtime PCR were also demonstrated to detect the expression of IFN-γ mRNA. Hair follicles were cultured with IFN-α in order to calculate the hair elongation. Imiquimod was employed to induce catagen stage. PDCs were injected into C3H/HeJ mice to initiate AA. RESULTS: In this mouse, IFN-α-producing pDCs densely infiltrated around HFs in not only AA lesional but also vicinity of AA lesion. Importantly, intradermal injection of pDCs induced AA lesions. Finally, IFN-α inhibited hair elongation of murine vibrissae and upregulated MHC class I and CXCL10 levels in vitro. CONCLUSIONS: These findings suggest that IFN-α-producing pDCs initiate AA by inducing apoptosis and increasing Th1/Tc1 chemokine production such as CXCL10, that accumulates Th1/Tc1 cells and result in autoimmune reactions against hair follicles.

Palmar hyperlinearity in early childhood atopic dermatitis is associated with filaggrin mutation and sensitization to egg.

BACKGROUND/OBJECTIVES: Palmar hyperlinearity is a typical clinical feature of Filaggrin gene (FLG) null mutations. There are reports of FLG mutations and allergic sensitization; however, reports on the relationship between palmar hyperlinearity to sensitization are limited. This study aimed to examine the association between palmar hyperlinearity and sensitization in atopic dermatitis (AD) children. METHODS: This cross-sectional, case-control study included children ˂ 6 years old with moderate-severe AD whose parents consented for mutation analysis and photographic documentation. Each child underwent genotyping to detect the eight most prevalent FLG mutations in the Japanese population: R501X, 3321delA, S1695X, Q1701X, S2554X, S2889X, S3296X, and K4022X. Clinical features and parameters including egg-specific IgE were examined, and palm photographs were evaluated by 12 trained dermatologists blinded to genotyping results. RESULTS: Of the 57 patients (age range, 2 months to 5 years; median, 22 months), 16 were heterozygotes and three were compound heterozygotes. Palmar hyperlinearity, as recognized by more than two-thirds of dermatologists, was significantly associated with FLG mutation (P = 0.002, OR = 6.98, 95% CI = 2.1-23.7), and this association was observed especially in children over 2 years. Cross-shaped crease of the thenar eminence, as known in previous reports, also demonstrated significant correlation with FLG mutation. When the children were divided according to the presence or absence of palmar hyperlinearity, the egg white-specific IgE was significantly higher in the hyperlinearity group (55.9 vs 18.3 IU/mL, P < 0.05). CONCLUSIONS: Palmar hyperlinearity indicates possible inherited barrier abnormalities of the skin in early childhood. Its identification may help to predict a more accurate prognosis, such as sensitization.

Repeated Amblyomma testudinarium tick bites are associated with increased galactose-α-1,3-galactose carbohydrate IgE antibody levels: A retrospective cohort study in a single institution.

BACKGROUND: Alpha-gal syndrome is a hypersensitivity reaction to red meat mediated by IgE antibody specific to galactose-α-1,3-galactose carbohydrate (alpha-gal). Amblyomma tick bites are associated with this condition, but the pathophysiology is not understood. OBJECTIVE: To clarify the mechanism of development of alpha-gal syndrome after tick bites. METHODS: We compared alpha-gal antibody levels between patients with and without a history of tick bites and examined histologic stainings of tick bite lesions between patients with and without detectable alpha-gal IgE antibody. RESULTS: Patients who had ≥2 tick bites had higher levels of alpha-gal IgE antibody compared with those with only 1 tick bite or healthy individuals. On histologic investigation, greater numbers of basophils and eosinophils, but not mast cells, were observed infiltrating lesions of patients with ≥2 tick bites compared with those with 1 tick bite. Type 2 cytokine-producing T-cell infiltration was predominantly observed in such patients. LIMITATIONS: The study was conducted at a single institution in Japan. CONCLUSION: In Amblyomma tick bite lesions, basophils; eosinophils; and type 2, cytokine-producing T cells infiltrate the skin and alpha-gal IgE antibodies are produced. These findings provide a potential mechanistic connection between Amblyomma bites and red meat hypersensitivity.

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion.

BACKGROUND: Topical combination of a vitamin D3 analogue and corticosteroid is widely used for the treatment of psoriasis, a TH17-mediated disorder, but the underlying mechanism remains unclear. OBJECTIVE: We investigated the effect of this topical applicant, focusing on skin-infiltrating TH17 cells. METHODS: In 10 patients with plaque psoriasis, calcipotriol (Cal), betamethasone dipropionate (Bet), or the calcipotriol and betamethasone dipropionate 2-compound formulation (CB) was applied to 3 different psoriatic plaques with similar severity once a day for 14 days. One nonapplied lesion was used as a control. Four-millimeter biopsy specimens were taken from each site, cut into 2 pieces, and subjected to histologic examination and ex vivo expansion of skin-infiltrating T cells with anti-CD3/CD28 antibodies and IL-2. RESULTS: Clinical, histologic, and IL-17A(+) cell-infiltrate improvement was found in the following order: CB > Cal > Bet > control or CB > Bet > Cal > control. Numbers of ex vivo expanded T cells were decreased by topical application of Bet and CB, and CB exhibited the most suppressive result. Numbers and frequencies of TH17 cells were significantly reduced by CB and Cal, suggesting that Cal has a capacity to preferentially suppress TH17 cells. When the stocked T cells from control samples were stimulated with anti-CD3 antibodies in the presence of Bet, Cal, or both, Cal downmodulated IL-17 and IFN-γ production and tended to upregulate IL-4 and IL-6 without apoptosis, but Bet inhibited production of these cytokines with apoptosis. CONCLUSION: These findings suggest that Cal and Bet have different effects on T cells to normalize psoriatic changes, with decreased TH17 cell expansion in the skin lesions.

Resolution of Molluscum Contagiosum After Discontinuation of Topical Corticosteroids During Dupilumab Therapy for Atopic Dermatitis: A Case Report.

A 35-year-old male patient with atopic dermatitis (AD) was referred to our department for exacerbated AD lesions. His sudden discontinuation of topical corticosteroid had induced erythroderma on his face, extremities, and trunk. Additionally, he presented small multiple whitish papules, mainly on the trunk and thighs, diagnosed as molluscum contagiosum (MC). Dupilumab was initiated in combination with a topical corticosteroid (0.05% betamethasone butyrate propionate). After four weeks, the AD symptoms substantially improved, while MC showed no changes. After 11 weeks of dupilumab therapy, he abruptly stopped topical corticosteroid treatment, and the MC lesions completely resolved in two weeks.

Detection and visualization of intracutaneous allergic type-specific elements using long-wavelength near-infrared hyperspectral imaging.

BACKGROUND/PURPOSE: This study aimed to develop a method for the assessment of allergic dermatitis by using the long-wavelength near-infrared spectrum (more than 1000 nm) to detect intracutaneous allergic type-specific elements. Such a method was realized by establishing a spectral classifier for the spectra of type I and type IV allergic dermatitis reactions. METHODS: Near-infrared spectral images of histamine-induced cutaneous reaction (type I) and contact hypersensitivity erythema elicited by squaric acid dibutylester (SADBE; type IV) were obtained, and the absorption spectra of normal and inflamed skin were extracted from these spectral images. A spectral classifier was established from these training datasets, and it was then applied to two test cases, red flare by methyl nicotinate (normal) and metal allergy (type IV). RESULTS: The spectral classifier established by canonical discriminant analysis (CDA) achieved very accurate detection (normal: 87.67%, type I: 87.00%, type IV: 98.5%). Furthermore, the test cases were also correctly classified: the red flare induced by methyl nicotinate was categorized as normal skin and the metal allergy was categorized as a type IV allergic reaction. CONCLUSIONS: These results suggest a possible application of near-infrared spectral imaging to the assessment of allergic dermatitis.

Successful Treatment of Facial Merkel Cell Carcinoma Using CyberKnife Radiotherapy Alone: A Case Report.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin tumor. Herein, we present a case of MCC which was successfully treated with radiotherapy alone using CyberKnife® (CK) (Accuray Incorporated, Sunnyvale, California, United States). An 86-year-old female patient presented with multiple painless pink rash skin tumors on the left cheek. The patient was diagnosed with MCC based on a lesion biopsy (T2cN2M0, stage IIIB). The patient was referred for CK radiotherapy (CKR) at our institution because of her advanced age and inoperative lesions. The patient underwent CKR alone, with a planning target volume (PTV) of 14.9 ml, a prescribed dose of 30 Gy, a maximum dose of 46.2 Gy, and an isodose line (the minimum dose of 95% of the PTV) of 65% in 10 fractions for 13 days. The lesions had completely regressed on the last day of CKR. Left cervical lymph node metastasis (CLNM) appeared 10 months after CKR. The patient underwent a second CKR for CLNM, the PTV was 4.6 ml, and the prescribed dose was 27 Gy in three fractions for three days. The CLNM had completely regressed one month later after the second CKR. Primary lesions did not recur for 33 months after the initial CKR, and CLNM did not reappear for 23 months after the second CKR with good cosmetic results. No CKR-related adverse event occurred in our follow-up period. Our present case indicates that CKR is an effective treatment option for patients with MCC, particularly elderly patients who may not be suitable candidates for extensive surgical resection.

PD-1 Expression Defines Epidermal CD8+CD103+ T Cells Preferentially Producing IL-17A and Using Skewed TCR Repertoire in Psoriasis.

In psoriasis, CD8+CD103+ memory T cells residing in the epidermis represent an effector population capable of maintaining the condition and driving a recurrence of the disease. Tissue-infiltrating CD8+ T cells expressing PD-1 are regarded as antigen-primed effector cells in others chronic inflammatory diseases. However, the expression and significance of PD-1 on skin-infiltrating CD8+ T cells in human psoriasis is not known. By analyzing skin-infiltrating T cells from human psoriasis, we found that active psoriatic epidermis contained PD-1 expressing CD8+CD103+ T cells that correlated with the disease severity and histopathology. PD-1+CD8+CD103+ T cells possessed a canonical psoriasis-specific resident memory phenotype with IL-23R expression and produced IL-17A, whereas PD-1-CD8+CD103+ T cells preferentially produced IFN-γ. The diversity of skin-infiltrating T cells was dominated by CD4+ T cells, while CD8+ T cells, especially CD8+CD103+T cells, represented an oligoclonal population in active psoriasis. In addition, PD-1+CD8+CD103+T cells used different TCR Vßs from PD-1-CD8+CD103+T cells counterpart. In the early resolved lesion, the composition and functional status of PD-1+CD8+CD103+T cells were markedly altered, while PD-1-CD8+CD103+ T cells population was minimally changed. Collectively, PD-1 expression delineates a putative pathogenic subset of epidermal CD8+CD103+ T cells, which possibly play a role in psoriasis pathogenesis.

Three-dimensional histological explanation of the dermoscopy patterns in acral melanocytic lesions.

Dermoscopic images of pigmented lesions have distinct features on the sole where skin ridges and furrows exist. Pigmentation of benign nevus usually locates on the skin furrow, while the malignant melanoma is pigmented on the skin ridge. Correspondence between dermoscopy and pathology in the pigmented lesions on soles have been studied based on conventional vertical pathological images. However, for the full understanding of the correspondence, observation of horizontal histological images would be required, because the epidermis constructs unique horizontal structures, namely crista profunda limitans, crista profunda intermedia, and transverse ridge. In this study, we analyzed basic dermoscopic images of the representative acral melanocytic lesions (nevus, lentigo, and malignant melanoma) by horizonal histological images. We created serial horizontal pathological images by digital reconstruction of a hundred of serial vertical images. We could show that parallel furrow pattern is created by the pigmentation of crista profunda limitans, parallel ridge pattern by the pigmentation of both of crista profunda limitans and crista profunda intermediate, and lattice-like pattern by the pigmentation of transverse ridge. Our results would be useful for the intuitive histological understanding of dermoscopy.

Pathophysiology of Skin Resident Memory T Cells.

Tissue resident memory T (TRM) cells reside in peripheral, non-lymphoid tissues such as the skin, where they act as alarm-sensor cells or cytotoxic cells. Physiologically, skin TRM cells persist for a long term and can be reactivated upon reinfection with the same antigen, thus serving as peripheral sentinels in the immune surveillance network. CD8+CD69+CD103+ TRM cells are the well-characterized subtype that develops in the epidermis. The local mediators such as interleukin (IL)-15 and transforming growth factor (TGF)-ß are required for the formation of long-lived TRM cell population in skin. Skin TRM cells engage virus-infected cells, proliferate in situ in response to local antigens and do not migrate out of the epidermis. Secondary TRM cell populations are derived from pre-existing TRM cells and newly recruited TRM precursors from the circulation. In addition to microbial pathogens, topical application of chemical allergen to skin causes delayed-type hypersensitivity and amplifies the number of antigen-specific CD8+ TRM cells at challenged site. Skin TRM cells are also involved in the pathological conditions, including vitiligo, psoriasis, fixed drug eruption and cutaneous T-cell lymphoma (CTCL). The functions of these TRM cells seem to be different, depending on each pathology. Psoriasis plaques are seen in a recurrent manner especially at the originally affected sites. Upon stimulation of the skin of psoriasis patients, the CD8+CD103+CD49a- TRM cells in the epidermis seem to be reactivated and initiate IL-17A production. Meanwhile, autoreactive CD8+CD103+CD49a+ TRM cells secreting interferon-γ are present in lesional vitiligo skin. Fixed drug eruption is another disease where skin TRM cells evoke its characteristic clinical appearance upon administration of a causative drug. Intraepidermal CD8+ TRM cells with an effector-memory phenotype resident in the skin lesions of fixed drug eruption play a major contributing role in the development of localized tissue damage. CTCL develops primarily in the skin by a clonal expansion of a transformed TRM cells. CD8+ CTCL with the pagetoid epidermotropic histology is considered to originate from epidermal CD8+ TRM cells. This review will discuss the current understanding of skin TRM biology and their contribution to skin homeostasis and diseases.

Confusion in determination of two types of cutaneous adverse reactions to drugs, maculopapular eruption and erythema multiforme, among the experts: A proposal of standardized terminology.

The clinical classification of cutaneous adverse reactions by drugs should be clearly distinguished to avoid conceptual confusion and inconsistency. Although dermatologists appear to have established a roughly common consensus for cutaneous adverse reactions, some types are more rigorously defined than other, possibly misleading classifications. To assess the consensus on the clinical classifications, we investigated the concordance rate of diagnosis by Japanese experts through a snap visual inspection of various clinical pictures exhibiting erythema multiforme and maculopapular eruption types of cutaneous adverse reactions. The experts were shown images on a screen and were then asked to decide whether to classify cases as maculopapular eruption or erythema multiforme type, and the concordance rates were calculated. Overall, the mean concordance rate was 71.6% (standard deviation, 17.3%), and only 33.8% of cases had a 90% or more concordance rate. Our study shows that the determinations of erythema multiforme and maculopapular eruption types by the existing classification criteria were confusing even among experts, which prompted us to standardize the terminology. We propose clinically defining erythema multiforme type as generalized macules mainly of 1 cm or more with a tendency of elevation and coalescence, and maculopapular eruption type as generalized erythema other than erythema multiforme type. Currently, the clinical definitions of cutaneous adverse reactions are poorly described, which may be problematic upon analyzing large volumes of data. Our proposal for a new terminology will enhance the accuracy and consistency of information for the correct analysis of cutaneous adverse reactions.

Significance of IL-17A-producing CD8+CD103+ skin resident memory T cells in psoriasis lesion and their possible relationship to clinical course.

BACKGROUND: A number of studies have shown the relationship between the pathogenesis of psoriasis and skin resident memory T (TRM) cells. OBJECTIVE: To investigate the cytokine profile of TRM cells from skin lesions of psoriasis and the relationship of skin TRM cells to the future clinical course of psoriasis. METHODS: We used stocked samples of T cells that were ex vivo expanded from skin biopsies of 10 patients with psoriasis vulgaris. A half of 4-mm punch biopsy specimens was subjected to expansion of skin-infiltrating T cells using IL-2 and anti-CD3/CD28 antibody-coated microbeads. More than 106 T cells per specimen were stocked at -80°C. Defrosted cells were subjected to flow cytometric analysis. Another half of skin biopsies were subjected to immmunofluorescence staining for CD103 and other markers. RESULTS: The biopsied skin revealed CD8+CD103+ TRM cells were present in the epidermis of psoriasis and associated with acanthosis. Sorted CD103+ T cells were mostly CD8+ memory T cells expressing CD69 with a skin-homing potential. A part of CD8+CD103+ T cells produced interferon-γ, IL-17A or IL-22. Notably, CD8+CD103+ TRM cells more frequently produced IL-17A than did CD8+CD103- T cells. We retrospectively divided the 10 cases into the non-advanced therapy group, and the advanced therapy group in which systemic biologics or others were initiated within one year. The frequency of CD8+CD103+IL-17A+ TRM cells tended to be higher in the advanced therapy group. CONCLUSION: These results suggest that IL-17A-producing CD8+CD103+ TRM cells are associated with a progressive clinical course of psoriasis.