Intrinsic Effects of Exposome in Atopic Dermatitis: Genomics, Epigenomics and Regulatory Layers.

Atopic dermatitis (AD) or atopic eczema is an increasingly manifested inflammatory skin disorder of complex etiology which is modulated by both extrinsic and intrinsic factors. The exposome includes a person's lifetime exposures and their effects. We recently reviewed the extrinsic exposome's environmental risk factors that contribute to AD. The periods of pregnancy, infancy, and teenage years are recognized as crucial stages in the formation of AD, where the exposome leads to enduring impacts on the immune system. However, research is now focusing on the interactions between intrinsic pathways that are modulated by the extrinsic exposome, including genetic variation, epigenetic modifications, and signals, such as diet, stress, and microbiome interactions. As a result, immune dysregulation, barrier dysfunction, hormonal fluctuations, and skin microbiome dysbiosis are important factors contributing to AD development, and their in-depth understanding is crucial not only for AD treatment but also for similar inflammatory disorders.

The Imprint of Exposome on the Development of Atopic Dermatitis across the Lifespan: A Narrative Review.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects more than 200 million people worldwide, including up to 20% of children and 10% of the adult population. Although AD appears frequently in childhood and often continues into adulthood, about 1 in 4 adults develop the adult-onset disease. The prenatal period, early childhood, and adolescence are considered critical timepoints for the development of AD when the exposome results in long-lasting effects on the immune system. The exposome can be defined as the measure of all the exposures of an individual during their lifetime and how these exposures relate to well-being. While genetic factors could partially explain AD onset, multiple external environmental exposures (external exposome) in early life are implicated and are equally important for understanding AD manifestation. In this review, we describe the conceptual framework of the exposome and its relevance to AD from conception and across the lifespan. Through a spatiotemporal lens that focuses on the multi-level phenotyping of the environment, we highlight a framework that embraces the dynamic complex nature of exposome and recognizes the influence of additive and interactive environmental exposures. Moreover, we highlight the need to understand the developmental origins of AD from an age-related perspective when studying the effects of the exposome on AD, shifting the research paradigm away from the per se categorized exposome factors and beyond clinical contexts to explore the trajectory of age-related exposome risks and hence future preventive interventions.

Nipple candidiasis and painful lactation: an updated overview.

Nipple pain and discomfort during or after breastfeeding remains one of the most common reasons for premature cessation of lactation among the affected women. The belief that yeasts, and especially Candida spp., are responsible for such symptoms is highly supported by many physicians, midwives, or lactation specialists, but is also viewed with scepticism by other health care providers. The aim of this paper is to provide an updated report of the evidence against, as well as in favour of, the "Candida hypothesis". Several studies have documented that lactating women with symptoms such as nipple soreness, with or without radiating breast pain, are more likely to test positive for Candida spp. than non-symptomatic women. However, its role as an undisputable aetiopathogenic factor for infection in these cases cannot always be established. Physicians should evaluate thoroughly such patients, because early and correct recognition of the underlying problem can prevent phenomena of early weaning.

Real-world clinical outcomes of treatment with brodalumab in patients with moderate-to-severe psoriasis: a retrospective, 24-month experience from four academic dermatology centers in Greece.

OBJECTIVE: To assess the real-world clinical treatment outcomes with brodalumab in patients with moderate-to-severe plaque psoriasis in Greece. MATERIALS AND METHODS: This was a longitudinal, retrospective, real-world analysis of data from medical records of 106 patients with moderate-to-severe plaque psoriasis, treated with brodalumab for up to 24 months at four University Dermatology Centers in Greece. Efficacy assessments of psoriasis severity [Psoriasis Area and Severity Index (PASI) and Body Surface Area affected (BSA) scores] and its impact on patients' quality of life (QoL) [Dermatology Life Quality Index (DLQI) score] were evaluated at different timepoints up to 24 months. RESULTS: Treatment with brodalumab reduced both mean PASI (14.0-1.5, p < .001) and BSA scores (21.6-2.5, p < .001) across all visits. This effect was accompanied by reduction in mean DLQI score (12.8-2.1, p < .001) across all visits compared with baseline. Moreover, therapeutic efficacy was affected by prior biologic treatment exposure, as biologic naïve patients had greater reductions in all scores from baseline following treatment with brodalumab (numerical for mean PASI, significant for mean BSA and DLQI scores). CONCLUSION: Brodalumab is effective long term, improving disease severity and health-related QoL in patients with moderate-to-severe plaque psoriasis in a real-world setting.

Acremonium nail bed mycetoma masquerading as subungual squamous cell carcinoma.

Acremonium is a large fungal genus that is comprised of approximately 150 species, found ubiquitously in nature. Although the majority are recognized as being saprophytes in soil and pathogens of plants, several species are emerging as causative agents of a variety of human infections, including mycetomas. Herein, we present a young man that was referred to our department with a painful subungual mass that developed following traumatic inoculation of Acremonium spp. In recent years, the role of Acremonium spp. has been increasingly recognized in localized infections, such as mycetoma, in humans. Other locally invasive as well as disseminated infections are also described. Optimal treatment of Acremonium spp. mycetoma is not well defined owing to the rarity of cases, thus posing a therapeutic challenge.

Multiple Primary Melanomas in a Young Patient.

A 45-year-old HIV-negative Caucasian man with no reported past medical history was referred to our Department with a large (7 cm in diameter) oozing nodule on the occipital region of the scalp with spontaneous periodical bloody or purulent discharge. The lesion had appeared over a period of six months, had an irregular color, non-specific dermoscopic features, and resembled squamous cell carcinoma. The physical examination revealed three more atypical melanocytic lesions (on the abdomen, back, and buccal mucosa), and multiple swollen occipital, postauricular, as well as superficial and deep cervical lymph nodes. After clinical evaluation, the patient reported having another in situ melanoma (submammary region) excised 7 years ago. All the lesions were excised and sent for histopathologic examination, which was compatible with primary cutaneous melanoma. Total body computed tomography revealed the presence of multiple visceral metastases, and the patient was referred to an oncologist. He did not consent to proceed to genetic testing. The occurrence of multiple primary melanomas (MPM) is a rare but recognized phenomenon. The estimated incidence of a second primary tumor ranges from 0.2% to 8.7% in large retrospective reviews. While 63% to 88% of patients with MPM are reported to have two primary tumors, the occurrence of more than four primary melanomas is considered exceedingly rare (1-2). Whether the presence of multiple primary melanomas is a function of increased genetic susceptibility of the individual, consistent exposure to a common exogenous promoter of malignancy, or a combination of these two factors remains to be elucidated. These patients should undergo intensive dermatologic screening for the rest of their lives and should consider genetic testing.

Born in the Purple: An Exceptional Case of Cutis Marmorata Telangiectatica Congenita.

A full-term, 2-day-old female neonate with a congenital non-tender reticular patch that did not disappear with local warming was referred to our department for consultation. The family history as well as the antenatal course and delivery were unremarkable. On examination, we evidenced a fixed, marbled, bluish to deep purple lesion with a fishnet appearance extending over the right side of her body, face, and scalp. There was presence of atrophy of the involved skin, along with ulceration above the right lateral malleolus. Upon blanching, the lesions could not be emptied completely. Routine laboratory studies, chest X-rays, and abdominal and cranial ultrasound scan results were nonsignificant. Head and limb circumferences were within normal ranges. The patient was checked by the ophthalmology and neurology department to screen for associated anomalies, which were not detected. Based on the medical history and clinical presentation, the diagnosis of cutis marmorata telangiectatica congenita was established. The infant's parents were reassured about the benign nature of the cutaneous disorder as well as the need for periodic follow-up on an outpatient basis. Cutis marmorata telangiectatica congenita (CMTC), first described by the Dutch pediatrician Van Lohuizen in 1922, is an exceedingly rare congenital sporadic condition with fewer than 300 cases described in the medical literature to date. Affected infants have discolored vascular patches of skin with a blue-violet marbled appearance. The disorder may present with a segmental or generalized persistent reticular mottling but more frequently has localized distribution over the lower limbs (1,2). Skin lesions are reminiscent of cutis marmorata, a common benign response observed in infants, which resolves with warming of the skin surface. In contrast, CMTC lesions do not disappear with rewarming and occasionally present with ulceration and atrophy of the involved skin (aplasia cutis) (1,3). Cutis marmorata telangiectatica congenita is described as occuring in association with a plethora of extracutaneous malformations, including undergrowth or overgrowth of the involved extremity, ocular and neurological abnormalities, growth and developmental delays, as well as additional vascular anomalies. The pathogenesis is not fully elucidated, but a lethal gene hypothesis has been suggested by some authors, while others indicate that the disorder may be inherited as an autosomal dominant trait with low penetrance (1,2,4). Skin biopsy is nonspecific and differential diagnosis is rarely difficult due to the distinctive appearance of cutaneous lesions, and the diagnosis can thus be established on clinical grounds alone. CMTC can be associated with other congenital syndromes including phacomatosis pigmentovascularis and Adams-Oliver syndrome (2,4). Cutaneous lesions carry a good prognosis and show a tendency for fading or spontaneous resolution over the first years of life in most cases, but the extremity discrepancy tends to persist. A thorough screening for associated anomalies as well as annual controls of skin changes and psychomotor development of the patients should be performed (2-3).

Malacoplakia of the skin: overview of a rare clinical entity.

BACKGROUND: Malacoplakia is a rare acquired, infection-related granulomatous disorder, that may affect many systems, but typically occurs in the urinary tract. Cutaneous involvement is less prevalent, and most commonly presents with a perianal or genital region localization. Cutaneous malacoplakia is believed to be caused by an acquired bactericidal defect of macrophages in the setting of chronic infections and immunocompromised states. A diagnosis of cutaneous malacoplakia should be considered when encountering non-specific granulomatous lesions that are refractory to treatment. Histologic findings are marked by the presence of foamy macrophages containing the pathognomonic Michaelis-Gutman bodies. OBJECTIVES: The aim of this review is to discuss the current perspectives on the pathophysiology, clinical features, diagnosis, and treatment of this disease. We would also like to emphasize that the integration of clinical information, microscopic findings, and exclusion of other cutaneous granulomatous processes is necessary to accurately diagnose this exceedingly rare disease and provide opportunity for therapeutic intervention. PATIENTS/METHODS: Data for this work were collected from the published literature and textbooks. RESULTS: Combined surgical excision and protracted antibiotic courses appear to have the highest success rate. Antibiotics should be culture specific, but drugs that easily permeate the macrophages appear to be the best choice.

Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Summarized Overview.

BACKGROUND: The introduction of Immune Checkpoint Inhibitors in the recent years has resulted in high response rates and extended survival in patients with metastatic/advanced malignancies. Their mechanism of action is the indirect activation of cytotoxic T-cells through the blockade of inhibitory receptors of immunomodulatory pathways, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Despite their impressive therapeutic results, they can also induce immune-related toxicity, affecting various organs, including the skin. OBJECTIVE: To provide an updated summarized overview of the most common immune-mediated cutaneous side effects and their management. METHOD: English articles derived from the databases PubMed and SCOPUS and published between 2009 and 2018, were analyzed for this narrative review. RESULTS: The most common adverse cutaneous reactions include maculopapular rash, lichenoid reactions, vitiligo and pruritus, with severity Grade 1 or 2. Less frequent but eventually life-threatening skin side effects, including Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Epidermal necrolysis, have also been reported. CONCLUSION: Basic knowledge of the Immune-Checkpoint-Inhibitors-induced skin toxicity is necessary in order to recognize these treatment-related complications. The most frequent skin side effects, such as maculopapular rash, vitiligo and pruritus, tend to subside under symptomatic treatment so that permanent discontinuation of therapy is not commonly necessary. In the case of life-threatening side effects, apart from the necessary symptomatic treatment, the immunotherapy should be permanently stopped. Information concerning the management of ICIs-mediated skin toxicity can be obtained from the literature as well as from the Summary of Product Characteristics of each agent.

The Association of Various Metabolic Parameters with Multiple Skin Tags.

Background: Skin tags (STs) are benign skin lesions. Their definite etiology remains unknown. We aim to examine the association of obesity, diabetes mellitus, hyperlipidemia, thyroid abnormalities, acanthosis nigricans, and multiple STs in a Greek primary population. Methods: Phototype and body weight were recorded. Fasting serum blood samples were analyzed for cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, and thyroid-stimulating hormone. Univariate ordinal logistic regression multivariate analysis was performed. Results: The univariate analysis showed that patients who were overweight with Fitzpatrick Skin Type III, acanthosis nigricans, and hypothyroidism were more likely to present with multiple skin tags as compared with patients at a normal weight with Skin Type I. Statistically significant associations were also found with the presence of cholesterol and triglycerides. In the multivariate analysis, a significant association between hypercholesterolemia and STs was demonstrated. Those with skin tags were more likely to have hypothyroidism. Conclusion: STs are often associated with obesity. An association between lipid profile and STs has been reported. Multiple STs have been independently associated with acanthosis nigricans. Although a possible relationship between STs and thyroid disease has not yet been proved, our review reveals a possible trend. Future investigations with larger sample sizes might clarify the association between skin tags and hypothyroidism.

Topical application of imiquimod induces alterations in peripheral blood lymphocytes in healthy individuals.

The aim of this study was to determine whether imiquimod, a Toll-like receptor-7/8 agonist, in addition to its well-known topical action on the cutaneous immune response, might also induce alterations in the peripheral blood lymphocytes. A 62.5 mg quantity of imiquimod (5% cream) was applied topically under occlusion once daily every second day for 3 weeks to the skin of 10 healthy volunteers, age range 30-57 years. Ten sex- and age-matched healthy controls applied corresponding quantities of the vehicle under occlusion. Before, and one and 3 weeks after the start of treatment, peripheral blood lymphocyte subpopulations were measured by flow cytometry. Statistically significant alterations in the percentage or absolute numbers of peripheral blood lymphocyte subpopulations were found in the imiquimod-treated group compared with the control group. These alterations indicate for the first time that topical application of imiquimod induces alterations in peripheral blood lymphocyte subsets in healthy individuals, which may be of importance in the immunotherapy of neoplastic and infectious disorders and should be taken into careful consideration in patients who are treated with imiquimod.

Partial purification and characterization of RNase P from human peripheral lymphocytes.

Ribonuclease P (RNase P) is ubiquitous and essential Mg(2+)-dependent endoribonuclease that catalyzes the 5'-maturation of transfer RNAs. RNase P and the ribosome are so far the only ribozymes known to be conserved in all kingdoms of life. Eukaryotic RNase P activity has been detected in nuclei, mitochondria and chloroplasts and demonstrates great variability in sequence and subunit composition. In the last few years we have developed methodologies and pursued projects addressing the occurrence, distribution and the potential physiological role of RNase P in human epidermal keratinocytes. In view of the vital importance of lymphocytes for an effective immune system and their successful application after transfection with RNase P-associated external guide sequences in gene therapy, we concerned ourselves with the isolation and characterization of RNase P of peripheral human lymphocytes. We developed a method described herein, that will enable the study of the possible involvement of this ribozyme in the pathogenetic mechanisms of diverse autoimmune, inflammatory and neoplastic cutaneous disorders and may facilitate the further development of RNase P-based technology for gene therapy of infectious and neoplastic dermatoses.

Epileptic seizures as the sole manifestation of neuro-Behçet's disease: complete control under interferon-alpha treatment.

Behçet's disease (BD) is a multisystemic disease of unknown etiopathogenesis with various clinical features including manifestations from central nervous system involvement. We report the case of a patient presented with a 20-year history of BD and a 10-year history of epileptic seizures refractory to various antiepileptic drugs. Under systemic treatment with interferon-alpha 2a (IFN-alpha) a complete remission of the cutaneous manifestations and a seizure-free state were achieved. The impressive therapeutic response of both the seizures and the non-neurological manifestations to IFN-alpha was also observed upon re-administration of this cytokine subsequent to a severe BD relapse. In view of this response and the lack of any other obvious etiology of the seizures in our patient, it seems reasonable to consider them as being the sole manifestation of neuro-BD. The patient is presently completing a 40-month seizure-free follow-up, despite withdrawal of all antiepileptic drugs for the last 35 months. Further studies on large numbers of patients are now warranted to define the therapeutic efficacy and safety of IFN-alpha in neuro-BD and particularly in neuro-BD-related epileptic seizures.