Epidermal growth factor receptor/mitogen-activated kinase inhibitor treatment induces a distinct inflammatory hair follicle response that includes collapse of immune privilege.

BACKGROUND: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood. OBJECTIVES: To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization. RESULTS: The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, ß2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs. CONCLUSIONS: The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

About 75­90% of people with cancer who are treated with drugs called EGFR inhibitors (EGFRi) and MEK inhibitors (MEKi) will get a skin condition called folliculitis. This is where the hair follicles become inflamed. Despite this, the reasons why some patients develop this are not well understood. In this study, we had three goals. We wanted to understand how these medications alter the skin's immune response and genetic processes. We also wished to determine the impact of the medications on the immune protection of hair follicles. Finally, we wanted to find early signs of inflammation in hair follicles caused by the medications. We studied scalp samples from people who got folliculitis after long-term EGFRi treatment and compared them to samples of healthy scalp skin. We also examined patients before and after they began EGFRi treatment. In the lab, we exposed healthy hair follicles to an EGFRi called 'erlotinib' or a MEKi called 'cobimetinib'. We then carried out detailed imaging and genetic analyses. We found that long-term treatment with EGFRi increased certain immune cells (called CD8+ T cells) in the hair follicle area. This led to a breakdown in the immune protection around hair follicles. A similar breakdown was found in lab-treated healthy follicles. Genetic changes linked to inflammation were also found. Our findings suggest that EGFRi and MEKi treatments could affect the natural immune defence of hair follicles in the scalp and cause folliculitis. Protecting the immune system and controlling inflammation might be the key to treating people with these drug-related skin conditions.

Immunophenotyping comparison of inflammatory cells between Malassezia folliculitis and pityriasis versicolor lesions.

Immunophenotyping of inflammatory dermal infiltrates in Malassezia folliculitis (MF) and pityriasis versicolor (PV) lesions is less reported. Immunohistochemistry was performed on 21 MF lesions, 10 PV lesions, and 10 control skin. CD3+, CD4+, CD8+, CD20+, CD68+, and CD117+ cells were increased in MF compared with PV and normal skin (P < 0.01-0.05), while CD3+, CD4+, and CD20+ cells were higher in PV than in normal skin (P < 0.05). Dermal CD1a+ cells were higher only in PV (P < 0.05). Although both cellular and humoral immune responses are involved in pathogenesis of MF and PV, their difference may contribute to clinicopathological discrepancy between two disorders. LAY SUMMARY: Malassezia folliculitis and pityriasis versicolor are common Malassezia-induced superficial mycoses. Their clinicopathological discrepancy may be due to the difference of cellular and humoral immune responses.

High-fat diet induces a predisposition to follicular hyperkeratosis and neutrophilic folliculitis in mice.

BACKGROUND: Neutrophilic folliculitis is an inflammatory condition of hair follicles. In some neutrophilic folliculitis, such as in patients with acne and hidradenitis suppurativa, follicular hyperkeratosis is also observed. Neutrophilic folliculitis is often induced and/or exacerbated by a high-fat diet (HFD). However, the molecular mechanisms by which an HFD affects neutrophilic folliculitis are not fully understood. OBJECTIVE: Our aim was to elucidate how an HFD promotes the development of neutrophilic folliculitis. METHODS: Mice were fed an HFD, and their skin was subjected to histologic, RNA sequencing, and imaging mass spectrometry analyses. To examine the effect of an HFD on neutrophil accumulation around the hair follicles, phorbol 12-myristate 13-acetate (PMA) was used as an irritant to the skin. RESULTS: Histologic analysis revealed follicular hyperkeratosis in the skin of HFD-fed mice. RNA sequencing analysis showed that genes related to keratinization, especially in upper hair follicular keratinocytes, were significantly upregulated in HFD-fed mice. Application of PMA to the skin induced neutrophilic folliculitis in HFD-fed mice but not in mice fed a normal diet. Accumulation of neutrophils in the skin and around hair follicles was dependent on CXCR2 signaling, and CXCL1 (a CXCR2 ligand) was produced mainly by hair follicular keratinocytes. Imaging mass spectrometry analysis revealed an increase in fatty acids in the skin of HFD-fed mice. Application of these fatty acids to the skin induced follicular hyperkeratosis and caused PMA-induced neutrophilic folliculitis even in mice fed a normal diet. CONCLUSION: An HFD can facilitate the development of neutrophilic folliculitis with the induction of hyperkeratosis of hair follicles and increased neutrophil infiltration around the hair follicles via CXCR2 signaling.

A Case of Eosinophilic Pustular Folliculitis Associated With Herpes Zoster.

ABSTRACT: Patients with eosinophilic pustular folliculitis (EPF), a sterile eosinophilic infiltration of hair follicles, often present with papulopustules that tend to form annular plaques. Histopathologic examination revealed eosinophilic infiltration around the pilosebaceous units and eosinophilic microabscess formation. Although the pathogenesis of EPF is unknown, T-helper type 2 immune responses were suggested to be important based on their stimulating effect on the sebaceous glands. Here, we report the first case of EPF associated with herpes zoster, indicating that herpes zoster and EPF are correlated with T-helper type 2 immune responses.

Efficacy and Safety of Baricitinib Combined With Topical Corticosteroids for Treatment of Moderate to Severe Atopic Dermatitis: A Randomized Clinical Trial.

Importance: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced disease severity in moderate to severe atopic dermatitis (AD) in 2 phase 3 monotherapy studies. Objective: To assess the efficacy and safety of 4 mg and 2 mg of baricitinib in combination with background topical corticosteroid (TCS) therapy in adults with moderate to severe AD who previously had an inadequate response to TCS therapy. Design, Setting, and Participants: This double-blind, placebo-controlled, phase 3 randomized clinical trial, BREEZE-AD7 (Study of Baricitinib [LY3009104] in Combination With Topical Corticosteroids in Adults With Moderate to Severe Atopic Dermatitis) was conducted from November 16, 2018, to August 22, 2019, at 68 centers across 10 countries in Asia, Australia, Europe, and South America. Patients 18 years or older with moderate to severe AD and an inadequate response to TCSs were included. After completing the study, patients were followed up for up to 4 weeks or enrolled in a long-term extension study. Interventions: Patients were randomly assigned (1:1:1) to receive 2 mg of baricitinib once daily (n = 109), 4 mg of baricitinib once daily (n = 111), or placebo (n = 109) for 16 weeks. The use of low-to-moderate potency TCSs was allowed. Main Outcomes and Measures: The primary end point was the proportion of patients achieving a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of 0 (clear) or 1 (almost clear), with a 2-point or greater improvement from baseline at week 16. Results: Among 329 patients (mean [SD] age, 33.8 [12.4] years; 216 [66%] male), at week 16, a vIGA-AD score of 0 (clear) or 1 (almost clear) was achieved by 34 patients (31%) receiving 4 mg of baricitinib and 26 (24%) receiving 2 mg of baricitinib compared with 16 (15%) receiving placebo (odds ratio vs placebo, 2.8 [95% CI, 1.4-5.6]; P = .004 for the 4-mg group; 1.9 [95% CI, 0.9-3.9]; P = .08 for the 2-mg group). Treatment-emergent adverse events were reported in 64 of 111 patients (58%) in the 4-mg group, 61 of 109 patients (56%) in the 2-mg group, and 41 of 108 patients (38%) in the placebo group. Serious adverse events were reported in 4 patients (4%) in the 4-mg group, 2 (2%) in the 2-mg group, and 4 (4%) in the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and folliculitis. Conclusions and Relevance: A dose of 4 mg of baricitinib in combination with background TCS therapy significantly improved the signs and symptoms of moderate to severe AD, with a safety profile consistent with previous studies of baricitinib in AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03733301.

Clinical features and treatment of epidermal growth factor inhibitor-related late-phase papulopustular rash.

Papulopustular rash, an acneiform rash, appears on the seborrheic region during the first to second week of treatment with an epidermal growth factor receptor inhibitor (EGFRi). The rash gradually disappears after the fourth week; however, it persists or newly develops in other regions during EGFRi treatment. Because Staphylococcus aureus is frequently isolated from late-phase papulopustular rash, we assessed the incidence of bacterial infection and treatment outcomes of patients with late-phase papulopustular rash. Sixty-four cases treated with an EGFRi over 4 weeks who presented with papulopustular rash were assessed retrospectively. The median duration of EGFR inhibitor treatment was 5 months. Grade 2 and 3 papulopustular rash was observed in 47 and eight cases, respectively. Bacterial culture was performed in 51 cases, 50 of which yielded positive results: methicillin-sensitive S. aureus in 29, methicillin-resistant S. aureus in 14, Staphylococcus species in five, Pseudomonas aeruginosa in three, and other in four cases. Of the S. aureus isolates, 42% were resistant to minocycline and 40% to levofloxacin. After treatment with topical and/or oral antibiotics without topical corticosteroids, the papulopustular rash rapidly improved by an average of 2.9 ± 3.4 weeks. However, use of a combination of antibiotics and a topical corticosteroid prolonged the recovery period to an average of 18.9 ± 11.4 weeks. In conclusion, folliculitis that develops over 4 weeks after the initiation of EGFRi treatment is typically caused by staphylococcal infection. Bacterial culture is necessary due to the high rate of antibiotic resistance. It is important to distinguish late- from early-phase papulopustular rash and to treat using different approaches.

Eosinophilic dermatoses.

Eosinophilic dermatoses are a heterogeneous group of diseases, characterized by an eosinophil-rich infiltrate and/or degranulation of eosinophils. Blood eosinophilia may be an associated feature. Typical, albeit not specific histological findings include 'flame figures', which are caused by the accumulation of cationic proteins released by eosinophils and subsequent collagen denaturation. "Classic" eosinophilic dermatoses include eosinophilic cellulitis (Wells syndrome), granuloma faciale, eosinophilic fasciitis (Shulman syndrome) and eosinophilic folliculitis (Ofuji disease). In addition, there is a multitude of skin diseases that present with varying degrees of eosinophilic infiltration. These include atopic dermatitis, bullous pemphigoid, urticaria, allergic contact dermatitis, prurigo nodularis, arthropod bite reaction, parasitic infections, and drug hypersensitivity. Even though these disorders share a common characteristic (tissue eosinophilia), they differ greatly in their clinical presentation.

Downregulation of integrin-αvß6 on keratinocytes in the scar of lichen planopilaris and folliculitis decalvans: Relevance for the disappearance of epidermal Langerhans cells.

Primary cicatricial alopecia (PCA) is a group of poorly understood mechanisms in which the destruction of hair follicles leads to permanent hair loss. Lichen planopilaris (LPP) is a type of lymphocytic PCA and it has been known for epidermal Langerhans cells (LC) to disappear in the scar of LPP. We also found that epidermal LC also disappeared in the scar of folliculitis decalvans (FD), a type of neutrophilic PCA. Of note was that epidermal LC did not disappear in the scar of discoid lupus erythematosus, another type of lymphocytic PCA, suggesting that LC disappearance in the scar was not always a common feature of PCA. We found that the expression of integrin (ITG)-αvß6 in scar epidermis was significantly diminished in LPP and FD, but not in other PCA and disorders accompanied with scar formation. We also found that exogenous interleukin-1ß and α-interferon downregulated ITG-αvß6 expression in normal human epidermal keratinocytes. These data suggest that downregulation of ITG-αvß6 may be one of the causes of LC disappearance in the scar of LPP and FD.

Inflammasome Activation Characterizes Lesional Skin of Folliculitis Decalvans.

Folliculitis decalvans (FD) is a chronic inflammatory disease leading to scarring alopecia with poorly defined pathogenesis. The aim of this study was to investigate the expression of markers associated with the activation of innate immune signals, such as inflammasome (NALP1 and NALP3), interleukin (IL)-1ß and IL-8 and type I interferon (MxA). A retrospective monocentric study was conducted and included 17 patients with FD with available biopsies. Disease activity (stable vs. active) was defined clinically and histologically. Immunostaining was performed using antibodies directed against NALP1, NALP3, IL-1ß, IL-8, and MxA on FD skin biopsies. Results were compared with normal controls and lichen planopilaris. Eleven patients had active disease and 6 had stable disease. NALP1, NALP3, and IL-1ß expression were significantly increased in hair follicles in FD compared with controls and lichen planopilaris. This study highlights the predominant immune signal associated with inflammasome activation in FD, suggesting the use of IL-1ß blockade in FD.

Intravenous human immunoglobulin for treatment of folliculitis decalvans.

We report a case of folliculitis decalvans (FD) successfully treated with intravenous human immunoglobulin (HIG). Many conventional treatments with topical agents and oral antibiotics had failed to achieve disease remission, treatment with HIG at a dose of 2 g/kg for the first month, reduced to 1 g/kg for second to fourth months was therefore started, which resulted in rapid improvement and ultimately complete resolution of FD. Clinical improvement was noted after the first infusion of HIG and remission of inflammation was achieved after the fourth infusion. Disease remission was sustained for six months following the last HIG infusion. The exact mechanism of action of HIG is poorly understood. However, it is thought to act as an immunomodulatory agent by altering different components of immune functions. To our knowledge, this is the first case reported in the literature of FD successfully treated with intravenous HIG.

A case of refractory chronic neutrophilic pustular folliculitis treated with adalimumab.

Neutrophilic folliculitis is an often overlooked chronic condition characterized by a monomorphic eruption of "sterile" papulopustules. Neutrophilic folliculitis is often refractory to conventional treatment with topical and systemic antibiotics or isotretinoin. We report a case of severe pustular neutrophilic folliculitis successfully treated with the tumor necrosis factor-alpha inhibitor adalimumab.

Malassezia infections: a medical conundrum.

Malassezia yeasts have long been considered commensal fungi, unable to elicit significant damage. However, they have been associated with a diversity of cutaneous diseases, namely pityriasis versicolor, Malassezia folliculitis, seborrheic dermatitis, atopic dermatitis, psoriasis, and confluent and reticulate papillomatosis. Several hypotheses have been proposed to explain the pathogenic mechanisms of these fungi, but none have been confirmed. More recently, such organisms have been increasingly isolated from bloodstream infections raising serious concern about these fungi. Given the difficulty to culture these yeasts to proceed with speciation and antimicrobial susceptibility tests, such procedures are most often not performed and the cutaneous infections are treated empirically. The recurring nature of superficial skin infections and the potential threat of systemic infections raise the need of faster and more sensitive techniques to achieve isolation, identification, and antimicrobial susceptibility profile. This article reviews and discusses the latest available data concerning Malassezia infections and recent developments about diagnostic methods, virulence mechanisms, and susceptibility testing.

Histopathological study of cutaneous manifestations in HIV and AIDS patients.

OBJECTIVES: Most human immunodeficiency virus (HIV)-infected patients develop various skin diseases. These skin manifestations not only act as markers but also reflect the patient's underlying immune status. Investigating CD4 counts is costly and not always possible. Thus, the potential value to be gained by using skin manifestations as predictors of low CD4 counts and disease progression should be explored. The present study attempted to correlate the association of various cutaneous disorders found in HIV patients with CD4 and CD8 counts, the CD4 : CD8 ratio and stage of HIV infection. METHODS: This was a prospective study involving 61 patients who were HIV-positive and demonstrated skin lesions. Punch biopsies of skin were taken for histopathological diagnosis. CD4 and CD8 T cell counts were performed. RESULTS: The study sample included a majority of male patients, most of whom were aged 21-40 years. Pruritic papular dermatitis was the most common skin manifestation, followed by molluscum contagiosum, eosinophilic folliculitis, and Hansen's disease. Most of the lesions were associated with CD4 counts of <220/µl (n = 38). All skin lesions associated with HIV or acquired immune deficiency syndrome (AIDS) showed a CD4 : CD8 ratio of <0.50. CONCLUSIONS: The study findings demonstrate an inverse relationship between CD4 counts and the occurrence of skin lesions. The majority of lesions were associated with stage 3 or stage 4 infection. Thus, specific cutaneous manifestations can be considered as good clinical indicators for predicting underlying immune status in resource-poor countries.