Safety assessment for nail cosmetics: Framework for the estimation of systemic exposure through the nail plate.

All cosmetics products, including nail care products, must be evaluated for their safety. The assessment of systemic exposure is a key component of the safety assessment. However, data on the exposure, especially via ungual route (nail plate) are limited. Based on the physicochemical properties of human nails and permeability data of topical onychomycosis drugs, the nail plate is considered a good barrier to chemicals. We examine factors impacting penetration of nail care ingredients through the nail plate, including properties of the nails of the ingredients and formulations. The molecular weight, vapor pressure, logP, water solubility, and keratin binding, as well as formulations properties e.g., polymerization of acrylate monomers are considered important factors affecting penetration. To estimate systemic exposure of nail care ingredients through the nail plate, a standardized framework is applied that quantifies the impacts of these properties on penetration with an adjustment factor for each of these influencing properties. All the adjustment factors are then consolidated to derive an integrated adjustment factor which can be used for calculation of the systemic exposure dose for the ingredient. Several case studies are presented to reflect how this framework can be used in the exposure assessment for nail cosmetic products.

Skin sensitization quantitative risk assessment for occupational exposure of hairdressers to hair dye ingredients.

Occupational exposure of hairdressers to hair dyes has been associated with the development of allergic contact dermatitis (ACD) involving the hands. p-Phenylenediamine (PPD) and toluene-2,5-diamine (PTD) have been implicated as important occupational contact allergens. To conduct a quantitative risk assessment for the induction of contact sensitization to hair dyes in hairdressers, available data from hand rinsing studies following typical occupational exposure conditions to PPD, PTD and resorcinol were assessed. By accounting for wet work, uneven exposure and inter-individual variability for professionals, daily hand exposure concentrations were derived. Secondly, daily hand exposure was compared with the sensitization induction potency of the individual hair dye defined as the No Expected Sensitization Induction Levels (NESIL). For PPD and PTD hairdresser hand exposure levels were 2.7 and 5.9 fold below the individual NESIL. In contrast, hand exposure to resorcinol was 50 fold below the NESIL. Correspondingly, the risk assessment for PPD and PTD indicates that contact sensitization may occur, when skin protection and skin care are not rigorously applied. We conclude that awareness of health risks associated with occupational exposure to hair dyes, and of the importance of adequate protective measures, should be emphasized more fully during hairdresser education and training.

Ultraviolet radiation signaling through TLR4/MyD88 constrains DNA repair and plays a role in cutaneous immunosuppression.

UV radiation (UVR) induces DNA damage, leading to the accumulation of mutations in epidermal keratinocytes and immunosuppression, which contribute to the development of nonmelanoma skin cancer. We reported previously that the TLR4-MyD88 signaling axis is necessary for UV-induced apoptosis. In the dinitrofluorobenzene contact hypersensitivity model, UV-irradiated MyD88-deficient (MyD88(-/-)) C57BL/6 mice had intact ear swelling, exaggerated inflammation, and higher levels of dinitrofluorobenzene-specific IgG2a compared with wild-type (WT) mice. Even with normal UV-induced, dendritic cell migration, DNA damage in the local lymph nodes was less pronounced in MyD88(-/-) mice compared with WT mice. Cultured, UV-irradiated WT APCs showed cleavage (inactivation) of the DNA damage-recognition molecule PARP, whereas PARP persisted in MyD88(-/-) and TLR4(-/-) APCs. Epidermal DNA from in vivo UV-irradiated MyD88(-/-) mice had an increased resolution rate of cyclobutane pyrimidine dimers. Both in vitro treatment of MyD88(-/-) APCs with and intradermal in vivo injections of PARP inhibitor, PJ-34, caused WT-level cyclobutane pyrimidine dimer repair. Lymphoblasts deficient in DNA repair (derived from a xeroderma pigmentosum group A patient) failed to augment DNA repair after MyD88 knockdown after UVR, in contrast to lymphoblasts from a healthy control. These data suggest that interference with the TLR4/MyD88 pathway may be a useful tool in promoting DNA repair and maintaining immune responses following UVR-induced damage.

Immunologic Studies of Progesterone-Induced Neutrophilic Urticaria.

A 33-year-old woman presented with recurring pruritic, erythematous papules around the mouth and on the hands, of 1.5 years' duration. These flares typically began several days before her menstrual cycle and persisted for approximately 1 week. Physical examination revealed urticarial plaques on the neck. Due to the nature of the eruption, which corresponded with her menstrual cycle, a diagnosis of autoimmune progesterone urticaria was considered and workup pursued.

TLR4 acts as a death receptor for ultraviolet radiation (UVR) through IRAK-independent and FADD-dependent pathway in macrophages.

UVR-induced apoptosis in cutaneous antigen presenting cells (APC) causes systemic immune suppression and is dependent on TLR4/MyD88 signalling, but the apoptotic signalling pathways have not been defined. Macrophages pretreated with lipopolysaccharide (LPS) were unresponsive to subsequent LPS treatment, however, but were susceptible to UVR-induced apoptosis. Macrophage survival and apoptotic events after UVR were also unaffected by treatment with TLR4 antagonists, a blocking IgG or a TLR4 analog antagonist, suggesting that UVR cell death is independent of a soluble ligand. After UVR, IRAK4KDKI (catalytically inactive IRAK4) and wild-type (WT) macrophages show equivalent levels of survival, as measured by MTT assay, and apoptosis, as measured by cleaved caspase-3. Furthermore, in macrophages from both mice, UVR activated caspase-8 and PARP, while inactivating Rip3. This finding is supported by a lack of IRAK1 degradation after UVR, compared to treatment with TLR2 or TLR4 agonists. UVR induced association of MyD88 with FADD, an extrinsic apoptotic pathway protein, but not IRAK4. UVR-induced migration of FADD to the cell membrane of WT macrophages, but not MyD88-/- macrophages, was observed (confocal microscopy). Co-immunoprecipitation using an epitope-tagged MyD88 revealed that FADD, but not TRADD, was recruited to MyD88 within 30 minutes of UVR exposure. UVR engages TLR4/MyD88 as a death signalling complex, rather than the classical inflammatory signalling pathway triggered by PAMP recognition of TLR4. These studies provide the rationale for the future development of topical TLR4 modulating therapies to interfere with this UVB-mediated apoptosis and the associated negative consequences of immune suppression.

New and emerging biologic therapies for moderate-to-severe plaque psoriasis: mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors.

The development of effective and well-tolerated biologic therapies has advanced the management of psoriasis by enabling clinicians to treat underlying disease mechanisms. Biologics approved for the treatment of moderate-to-severe psoriasis include three tumor necrosis factor alpha inhibitors and an interleukin-12/interleukin-23 inhibitor. The establishment of the immunological basis of psoriasis has led to the development of biologic agents targeting specific downstream mediators in the psoriatic cascade. These drugs inhibit cytokines and cytokine signaling/transcription mediators like interleukin-17, which plays an important role in immunopathogenesis. Several interleukin-17 inhibitors are undergoing phase 3 clinical studies. In addition, biologics that selectively inhibit interleukin-23 have been assessed in phase 2 studies. This review describes how the dissection of pathways in the immunopathogenesis of psoriasis has led to the development of therapeutic agents and highlights the latest clinical efficacy, safety and tolerability data on new and emerging biologic therapies that selectively target interleukin-17 or interleukin-23.

Hidradenitis suppurativa and concomitant pyoderma gangrenosum treated With infliximab.

Pyoderma gangrenosum (PG) and hidradenitis suppurativa (HS) are rare chronic inflammatory dermatoses of unknown etiologies that often are refractory to conventional treatments. The therapeutic benefits of tumor necrosis factor a (TNF-α) inhibitors have been reported in patients with refractory PG or HS. The copresentation of these 2 diseases has previously been described in several cases in the literature and may present a therapeutic challenge. We present the case of a 51-year-old man who developed widespread inflammatory ulcers affecting approximately 50% of the body surface area and subsequent chronic debilitation from severe pain. He was ultimately diagnosed with concurrent PG and HS. Both diseases remitted in response to treatment with infliximab, which resulted in complete restoration of skin integrity and resolution of his chronic severe pain.

Toll-Like Receptors and Contact Dermatitis.

Contact dermatitis (CD) is a common cutaneous inflammatory condition that affects millions of people worldwide. Xenobiotic agents are frequently encountered in substances used in everyday life, making it difficult to avoid personal and occupational exposure. Toll-like receptors (TLRs) are transmembrane receptors that modulate the innate immune system in response to tissue injury or infection. TLRs play a key role in the pathophysiology of contact dermatitis. TLR signaling is involved in three major forms of CD: protein CD, allergic contact dermatitis (ACD), and irritant CD. Of the 10 TLRs found in humans, three play an important role in ACD. This makes TLRs a useful potential therapeutic target to consider against CD. In this review, we discuss the role of TLRs in CD and summarize current and emerging treatments for CD that target TLRs.

Imiquimod-induced TLR7 signaling enhances repair of DNA damage induced by ultraviolet light in bone marrow-derived cells.

Imiquimod is a TLR7/8 agonist that has anticancer therapeutic efficacy in the treatment of precancerous skin lesions and certain nonmelanoma skin cancers. To test our hypothesis that imiquimod enhances DNA repair as a mechanism for its anticancer activity, the nucleotide excision repair genes were studied in bone marrow-derived cells. Imiquimod enhanced the expression of xeroderma pigmentosum (XP) A and other DNA repair genes (quantitative real-time PCR analysis) and resulted in an increased nuclear localization of the DNA repair enzyme XPA. This was dependent on MyD88, as bone marrow-derived cells from MyD88(-/-) mice did not increase XPA gene expression and did not enhance the survival of MyD88(-/-)-derived bone marrow-derived cells after UV B exposure as was observed in bone marrow-derived cells from MyD88(+/+) mice. Imiquimod also enhanced DNA repair of UV light (UVL)-irradiated gene expression constructs and accelerated the resolution of cyclobutane pyrimidine dimers after UVL exposures in P388 and XS52. Lastly, topical treatment of mouse skin with 5% imiquimod cream prior to UVL irradiation resulted in a decrease in the number of cyclobutane pyridimine dimer-positive APC that were found in local lymph nodes 24 h after UVL irradiation in both wild-type and IL-12 gene-targeted mice. In total, these data support the idea that TLR7 agonists such as imiquimod enhance DNA repair in bone marrow-derived cells. This property is likely to be an important mechanism for its anticancer effects because it protects cutaneous APC from the deleterious effects of UVL.

Use of lenalidomide in treating refractory prurigo nodularis.

Prurigo nodularis is a chronic, relapsing neurodermatitis that is often resistant to standard therapies with topical corticosteroids and oral antihistamines. Thalidomide, while efficacious in treating recalcitrant cases of prurigo nodularis, causes significant toxicity. Thalidomide-induced peripheral neuropathy frequently results in drug discontinuation. Lenalidomide (Revlimid; Celgene Corporation, Summit, NJ) is a derivative of thalidomide with less neurotoxicity approved for the treatment of multiple myeloma and myelodysplastic syndromes that has not been widely studied in dermatologic disorders. Here, we report a case of refractory prurigo nodularis effectively treated with lenalidomide. Given its favorable side-effect profile, lenalidomide may offer a superior alternative to thalidomide in the treatment of this condition.

Merkel cell polyomavirus detection in a patient with familial epidermodysplasia verruciformis.

We report a case of Merkel cell polyomavirus detection in the skin of a patient with epidermodysplasia verruciformis (EDV) and a family history remarkable for an unusual inheritance pattern for EDV.

Editors and Journals: Part I-Responsibilities And Expectations Of Editors: Who Is the Editor and Why an Editor?

Important components of a medical journal include its readers, authors, editor, and owner. Editor is the individual to whom the journal is branded. The editor determines the journal's published content and establishes its caliber. The success of a journal depends on the general and specific responsibilities of the editor toward its readers, authors, and owner. For a journal to maintain its stature of excellence, the expectations of the editor-including editorial independence-must be preserved; therefore, in the best interest of the journal, the owner must provide unequivocal support to the editor.

Editors and Journals: Part II-Relationship between the Editor-in-Chief and the Owner of the Journal: The Consequences When Editorial Independence Dissolves.

A symbiotic relationship between the editor and the owner of a medical journal is important for the journal to fulfill successfully the expectations of its readers and authors. Editorial freedom and transparency by owner of the journal are important qualities that enable the editor to provide valid scientific information in an unbiased manner. Unresolved impedance of editorial freedom or the persistent lack of transparency or both frequently results in untenable consequences for editor and often a substantial defamation of the journal's credibility. Unfortunately, misguided and inappropriate behavior by a medical society or the publication owner repeatedly occurs with the same devastating effect for the editor: prompt, unanticipated, and unjustified termination of the position at the journal. Alternatively, conditions imposed by a journal's owner may lead to the resignation of the editor because of untenable conditions. Because the owner does not have to account for its actions and there is no recourse for the editor, currently there seems to be no effective measures to prevent this tragic sequence of events in the future.

CD1d-dependent, iNKT-cell cytotoxicity against keratinocytes in allergic contact dermatitis.

Conventional CD8+ T-lymphocytes are thought to be major effector cells in allergic contact dermatitis (ACD). However, previous work has demonstrated a significant population of invariant natural killer T-cells (iNKT-cells) in the elicitation phase of ACD. In this study, we investigate whether iNKT-cells have the capacity to serve as effector lymphocytes in ACD. Using in situ staining of skin biopsy specimens from ACD lesions, we observed intra-epidermal iNKT-cells. Presence of these cells provides the possibility of interactions with keratinocytes (KC), Langerhans cells (LC) and CD1d-bearing antigen-presenting cells (APC). Investigation into gene expression profiles of cytotoxic effector molecules in seven different cases of ACD found that the expression of perforin and granzymes A, B and K were significantly elevated in ACD relative to paired clinically normal skin. Immunostaining of ACD skin biopsy specimens revealed that these cytotoxic granules indeed localized to iNKT-cells. Studies of antigen presentation of KC to iNKT-cells show that these epithelial cells do not activate the expression of cytotoxicity effector genes in resting iNKT-cells, but had the capacity to serve as targets for activated iNKT-cells, which was dependent on CD1d expression. Mature LC were not able to present glycolipids to iNKT-cells and did not up-regulate CD1d in vitro to a variety of maturational stimuli or in vivo during ACD. These data suggest that iNKT-cells can serve as effector cells during human ACD and provide the rationale for developing inhibitory glycolipids as therapeutic agents for ACD.

Generalized verrucosis: a review of the associated diseases, evaluation, and treatments.

Generalized verrucosis has been described in the past as synonymous with epidermodysplasia verruciformis. It has been shown, however, that epidermodysplasia verruciformis and other genetic or immunodeficiency diseases are just a subset of diffuse infections with human papillomavirus termed "generalized verrucosis." This article defines generalized verrucosis and distinct diseases associated with generalized warts. The indications for histopathologic testing, human papillomavirus typing, and other laboratory analyses and potential treatment options are discussed.

The 2-Methoxymethyl Modification of p -Phenylenediamine Reduces the Sensitization Risk for Hairdressers to Hair Dyes-An Occupational Hand Exposure-Based Risk Assessment.

BACKGROUND: Allergic contact dermatitis involving the hands is a common occupational skin disease for hairdressers and the potent sensitizers p -phenylenediamine (PPD) and toluene-2,5-diamine (PTD) are associated with the development of occupational allergic contact dermatitis. OBJECTIVE: The aim of the study was to analyze whether the use of the moderate sensitizer 2-methoxymethyl-PPD (ME-PPD) in professional hair dyes is a suitable tool to reduce the occupational contact allergy risk for hairdressers. METHODS: Hand exposure of hairdressers (N = 11) to ME-PPD was analyzed under routine hair coloring conditions in commercial salons. By accounting for wet work and uneven hand exposure, the daily hand exposure was derived and compared with the occupational acceptable exposure level (AEL), that is, the sensitization induction threshold of ME-PPD adjusted for interindividual variability among workers. RESULTS: The daily hand exposure to ME-PPD was 1.6 µg/cm 2 , and the occupational AEL was 215 µg/cm 2 . The ratio of hand exposure to AEL was calculated as the margin of safety (MOS) against occupational sensitization. For ME-PPD, the MOS of 134 indicates a low likelihood of sensitization versus PPD and PTD with MOS values of 2.7 and 5.9, respectively. CONCLUSIONS: Our data predict that the use of ME-PPD in professional hair color products improves the protection of hairdressers against hair dye-related contact allergy versus the use of PPD and PTD.

Patterns of Allergic Contact Dermatitis in African Americans in a Major Metropolitan Area Over a 10-Year Period.

BACKGROUND: Differences in patterns of allergic contact dermatitis (ACD) among underrepresented minority populations are not well studied. OBJECTIVE: The aim of the study was to investigate patterns of ACD in African American and White patch-tested patients in a distinct metropolitan area over a 10-year period. METHODS: We conducted a retrospective review of 297 ACD patients patch tested from 2009 to 2019. Differences in allergen frequency, relevance, and sources of exposure were evaluated. Fisher exact test analyses were performed to examine these differences. RESULTS: Among 297 patients, 215 were White and 47 were African American. The most common sensitizers differed between the 2 groups. African American patients also reacted with statistically significant greater frequency to disperse dye blue (P = 0.019) and textile dye mix (P = 0.001). The most common source of positive patch tests for all patients was personal care products (72%). Occupational allergy was greater in African American male patients, and personal care product exposure was greater in White male patients (P = 0.009). CONCLUSIONS: Our study highlights the differing patterns of sensitization seen in African American and White patients. This is likely due to differences in personal care product use or occupational allergy. Additional studies with larger sample sizes are needed to expand upon these differences.

A central role for transcription factor C/EBP-beta in regulating CD1d gene expression in human keratinocytes.

CD1d is a nonclassical Ag-presenting molecule that presents glycolipid Ags to NKT cells that are involved in immune defense and tumor rejection. It also plays a role in immunoregulatory functions in the epidermis. The mechanisms controlling the expression of CD1d are not well understood. Therefore, we cloned the CD1d gene promoter and characterized its activities in primary human keratinocytes and other cell lines of epithelial origin. We found that a CCAAT box in the CD1d promoter is required for its expression in keratinocytes. We show here that transcription factor C/EBP-beta binds to the CCAAT box in the CD1d promoter in vitro and in vivo. Consistent with these observations, deletion of the gene encoding for C/EBP-beta caused a loss of CD1d expression. The in vivo regulation of CD1d has significant implications for the pathologic mechanisms of certain immunologic skin diseases in which NKT cells play a role, such as allergic contact dermatitis and psoriasis. Together, these data show a central role for C/EBP-beta in regulating CD1d transcription.

Mycobacterium fortuitum infection following adalimumab treatment for psoriasis and subsequent complication-free treatment with alternate TNF-a blockers.

Tumor necrosis factor-a (TNF-a) inhibitors, such as adalimumab, are often used to treat psoriasis and psoriatic arthritis. While it is well known that these agents increase the risk of reactivation tuberculosis, recent evidence suggests that the risk of other nontuberculous mycobacterial (NTM) infections is on the rise. We report cutaneous Mycobacterium fortuitum in a 60-year-old woman with psoriasis who had been receiving adalimumab therapy for psoriatic arthritis for six months. No other risk factors were identified. M. fortuitum was cultured from a lesion on the right leg. Following resolution of the lesion, the patient has been successfully treated with infliximab infusions and subsequently certalizumab without complication for the past three years. To our knowledge, this is the first report of M. fortuitum occurring in a patient receiving adalimumab with successful subsequent treatment without complication while on another TNF-a inhibitor.

Patch testing: Uses, systems, risks/benefits, and its role in managing the patient with contact dermatitis.

Patch testing is the gold standard diagnostic tool for cell-mediated type IV hypersensitivity reactions like allergic contact dermatitis. Sensitized individuals have primed antigen-specific T lymphocytes that cause a reaction when antigens are applied to the skin owing to prior sensitization. Patch testing can be used in the adult and pediatric populations, but it is contraindicated in patients with a known history of severe allergic reactions to suspected allergens, generalized active dermatitis, or extensive eczema. Patch test systems can be a comprehensive panel (70-80 allergens), but they can also be targeted and limited to a more common allergen series (35 allergens). The decision for allergen selection should be based on an accurate patient history, physical examination, and availability of allergens. Measurement and interpretation of the test results requires training and experience, as well as consideration of relevance and clinical history. Patch testing is generally considered safe with just a few known complications: excited skin syndrome, active sensitization, and rarely anaphylaxis or other cutaneous complications. Appropriately pretesting patient education can help to mitigate some of these complications. Based on patch testing results, patients should be educated regarding proper allergen avoidance measures to resolve symptoms of allergic contact dermatitis.