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.

EGFR inhibitor-induced folliculitis decalvans: a case series and management guidelines.

Epidermal growth factor receptor (EGFR) is one of therapeutic targets in oncology for solid tumors originating from epithelial tissue, such as non-small-cell lung carcinoma (NSCLC) and breast cancer. EGFR inhibitors used in cancer treatment may cause a broad spectrum of dose-dependent cutaneous adverse events, including acneiform papulopustular rash, nail and hair disturbances, xerosis, and mucositis. The pathogenesis of the EGFR inhibitor-induced adverse reactions originates from disturbances in keratinocyte differentiation, cytokine secretion, and neutrophil chemotaxis. One of the rare, yet distressing adverse events may be folliculitis decalvans, a progressive neutrophil-driven scarring alopecia with hair tufts formation resembling doll's hair. Early diagnosis and introduction of treatment are crucial for disease prognosis since a long course of the disease leads to decreased quality of life. Here, we review the literature cases of EGFR inhibitor-induced folliculitis decalvans and provide guidance on management and prevention of this condition in oncologic patients. Furthermore, we report the first afatinib-associated folliculitis decalvans in three female patients with NSCLC.

Acneiform Eruption Following Elexacaftor-Tezacaftor-Ivacaftor Treatment in Patients With Cystic Fibrosis.

Importance: A new treatment for cystic fibrosis combining 3 CFTR modulators-elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)-has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature. Objective: To describe the clinicopathological features and treatment response of ELX-TEZ-IVA-associated acneiform eruptions in patients with cystic fibrosis. Design, Setting, and Participants: This case series study was conducted in the Dermatology Department of Cochin Hospital, Paris, France, from July 2021 to June 2022 in collaboration with the Cochin Reference Center for Cystic Fibrosis. Referred patients were examined by senior dermatologists. All patients with cystic fibrosis treated with ELX-TEZ-IVA and referred for an acneiform rash were included. Exposures: Treatment with ELX-TEZ-IVA. Main Outcomes and Measures: Onset of acneiform rash, type of lesions, and degree of severity, as well as treatments initiated and response, were evaluated. When performed, skin biopsies were reviewed. Results: This study included 16 patients (11 women [68.7%]) with a median (range) age of 27 (22-38) years. Six patients (37.5%) developed new-onset acneiform rashes, whereas 10 patients (62.5%) had a relapse (5 patients) or worsening (5 patients) of previous acne. The median (range) onset of acneiform rash was 45 (15-150) days. At inclusion, 11 patients (68.7%) had facial hyperseborrhea, 15 patients (93.7%) had noninflammatory lesions, and 14 (87.5%) had inflammatory lesions of seborrheic regions. Four patients (25.0%) had severe acne with deep inflammatory lesions and pitted scars. A specific pathological pattern of necrotizing infundibular crystalline folliculitis was observed in 4 patients. Topical acne treatments, antibiotics, and isotretinoin were used successfully in these patients, resulting in partial or complete remission in 12 patients (85.7% of patients reevaluated). Conclusions and Relevance: This case series study found that acneiform eruption is an adverse event associated with ELX-TEZ-IVA treatment in patients with cystic fibrosis. Most patients developed mild lesions. However, isotretinoin treatment may be necessary in some patients. The mechanism of ELX-TEZ-IVA-associated acneiform eruption is currently unknown, but the observation of necrotizing infundibular crystalline folliculitis in biopsied patients may guide further exploration.

Malassezia Folliculitis following Triple Therapy for Cystic Fibrosis.

Triple-combination therapy with elexacaftor, tezacaftor and ivacaftor has been recently approved for cystic fibrosis patients with at least one F508del mutation in the transmembrane conductance regulator of the cystic fibrosis gene. Among the adverse events of elexacaftor, tezacaftor and ivacaftor, the cutaneous ones have been rarely reported, mainly dealing with urticarial-like rashes. On this topic, we report two cases of Malassezia folliculitis following triple therapy administration in two young females. In the first patient, a papulopustular rush appeared before the folliculitis while in the second patient it was not preceded by other skin manifestations. The diagnosis was confirmed both by dermoscopy and histology. The prompt response to systemic antimycotic drugs provided further evidence for the causative role of Malassezia, requiring no discontinuation of cystic fibrosis therapy. We could hypothesize that the triple regimen treatment may induce changes in the skin microbiome, potentially able to favor colonization and proliferation of Malassezia species. Physicians should be aware of such associations to allow prompt diagnosis and early interventions, avoiding useless drug removal.

Eosinophilic pustular folliculitis due to naltrexone: A case report.

BACKGROUND: The effectiveness of naltrexone in treating both alcohol and opioid use disorders is unique when compared with other agents used for substance use disorder (SUD). It is estimated that 2 million Americans suffer from opioid use disorder, and 14.5 million have alcohol use disorder, underscoring the need for medication-supported SUD treatment. The aims of this case report are 2-fold: (1) to underscore the importance of conducting a thorough medication history when considering a recent adverse drug reaction and(2) to report a novel cutaneous reaction to naltrexone oral tablet. CASE SUMMARY: A 20-year-old female with a medical history significant for bipolar disorder, obsessive compulsive disorder, major depression disorder, and polysubstance use disorder experienced a drug-induced cutaneous adverse reaction on 2 separate occasions, about 3 months apart. Drug-induced adverse reactions can lead to treatment modifications, resulting in differences in efficacy and undesirable adverse effects. The purpose of this case report is to introduce naltrexone-induced skin reactions and emphasize the importance of a careful medication history when determining which medication is related to an adverse reaction. PRACTICE IMPLICATIONS: Naltrexone will continue to be used to manage cravings related to SUD. This case brings awareness to severe cutaneous adverse reactions associated with enteral naltrexone. Monitoring upon initiation for any adverse effects should be part of a holistic treatment plan. In addition to conducting a complete and thorough medication history, adverse drug reactions can be correctly attributed to the offending agent and prevent future adverse reactions.

Eosinophilic pustular folliculitis developing at the site of COVID-19 vaccination.

We present a rare case of eosinophilic pustular folliculitis due to mRNA-based vaccines for COVID-19. Histology of the biopsy specimen was very interesting.

Eruptive Necrotizing Infundibular Crystalline Folliculitis: An Expression of an Abortive Sebaceous Follicular Repair Pathway Linked to Committed Infundibular Stem Cells?

ABSTRACT: Necrotizing infundibular crystalline folliculitis is a rare entity, which is a distinctive clinical and histopathological entity. Eruptive yellow waxy umbilicated folliculocentric plugs clinically correspond to pale crystalline filaments embedded in an amorphous sebum-rich material. Remarkably, only the superficial infundibular ostia remain, and the distended cavity is devoid of a follicular or sebaceous gland remnant. The pathogenesis of this enigmatic event remains to be established. The emergence of necrotizing infundibular crystalline folliculitis (NICF) as a paradoxical side effect of antitumor inhibitors epidermal growth factor receptor vascular endothelial growth factor and more recently programmed death-1 represents the expression of altered molecular pathways that underpin the pathogenesis of NICF. To explore these pathways, it is necessary to explore the hierarchy of follicular stem cells, particularly the potential role of committed infundibular stem cells that play a key role in wound healing. Committed infundibular stem cells are closely linked to the sebaceous gland stem cell axis, and this has relevance in the process of homeostatic repair of sebaceous follicles in the wake of folliculitis. The unscheduled modulation of this infundibular homeostatic sebaceous repair axis by epidermal growth factor receptor vascular endothelial growth factor, and programmed death-1 may lead to an aberrant outcome with metaplasia of infundibular keratinocytes to sebocytes. In the absence of sebaceous gland differentiation, these metaplastic infundibular sebocyte cells would lead to the consumption and loss of the infundibulum as a result of holocrine sebum production. This conceptual pathogenic pathway for NICF is constructed by incorporating recent advances in the fields of follicular stem cells, wound repair, follicular homeostasis, regulatory T cells, and molecular pathways linked to the biologicals inducing NICF.

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.

Intravenous immunoglobulins as first-line treatment in idiopathic inflammatory myopathies: a pilot study.

OBJECTIVES: We explored efficacy and safety of IVIg as first-line treatment in patients with an idiopathic inflammatory myopathy. METHODS: In this investigator-initiated phase 2 open-label study, we included 20 adults with a newly diagnosed, biopsy-proven idiopathic inflammatory myopathy, and a disease duration of less than 9 months. Patients with IBM and prior use of immunosuppressants were excluded. The standard treatment regimen consisted of IVIg (Privigen) monotherapy for 9 weeks: a loading dose (2 g/kg body weight) and two subsequent maintenance doses (1 g/kg body weight) with a 3-week interval. The primary outcome was the number of patients with at least moderate improvement on the 2016 ACR/EULAR Total Improvement Score. Secondary outcomes included time to improvement, the number of patients requiring rescue medication and serious adverse events. RESULTS: We included patients with DM (n = 9), immune-mediated necrotizing myopathy (n = 6), non-specific myositis/overlap myositis (n = 4) and anti-synthetase syndrome (n = 1). One patient was excluded from analyses because of minimal weakness resulting in a ceiling effect. Eight patients (8/19 = 42.0%; Clopper-Pearson 95% CI: 19.6, 64.6) had at least moderate improvement by 9 weeks. Of these, six reached improvement by 3 weeks. Seven patients required rescue medication due to insufficient efficacy and prematurely ended the study. Three serious adverse events occurred, of which one was pulmonary embolism. CONCLUSION: First-line IVIg monotherapy led to at least moderate improvement in nearly half of patients with a fast clinical response in the majority of responders. TRIAL REGISTRATION: Netherlands Trial Register identifier, NTR6160.

[Erlotinib-induced scarring alopecia with a folliculitis decalvans-like presentation]. / Alopécie cicatricielle à type de folliculite décalvante induite par l'erlotinib.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are targeted therapies that frequently induce skin eruptions such as acneiform rash. Due to their increasing use in oncology as well as the expanding number of exposed patients, new adverse events may emerge. PATIENTS AND METHODS: A 54-year-old female patient treated with erlotinib for 8 months for pulmonary adenocarcinoma presented inflammatory alopecia that had been ongoing for 1 month. Her condition did not improve with doxycycline 100mg/day. Diffuse erythema of the scalp was associated with painful keratotic plaques and several oozing lesions. A skin biopsy showed signs of acute suppurative and destructive folliculitis. Histology and dermatoscopy were consistent with a diagnosis of folliculitis decalvans. Marked improvement was observed after discontinuation of erlotinib followed by introduction of amoxicillin+clavulanic acid and application of a topical corticosteroid. Unfortunately, the lesions recurred after reintroduction of the anti-EGFR, despite a dosage reduction, requiring up-titration of doxycycline to 200mg/day. DISCUSSION: Scarring alopecia with a folliculitis decalvans-like presentation secondary to anti-EGFR is a rare adverse event. The exact pathophysiology remains poorly understood. Treatment is difficult, and while systemic antibiotics are effective, they must be maintained for a long duration in order to avoid recurrence. Early recognition is important to limit the development of scarring alopecia due to the difficulties of stopping treatment in advanced-stage carcinoma.

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.

Eosinophilic folliculitis of the scalp associated with PD-1/PDL1 inhibitors.

BACKGROUND: Immune checkpoint inhibitors are monoclonal antibodies which target immune "checkpoints" enhancing T cell-mediated cytotoxic and antitumor responses. Together to the amazing results, these drugs are associated with some peculiar adverse events called immune-related adverse events. Alopecia is one of these. It is usually reported to be clinically and histologically similar to alopecia areata. AIMS: We report a case of eosinophilic folliculitis of the scalp occurred during nivolumab therapy, its management and some pathogenetic hypotheses. PATIENT: Herein, we report the first case of eosinophilic folliculitis of the scalp occurred during nivolumab therapy, firstly appeared as a lichen planopilaris. Topical steroids and fusidic acid cream were applied with partial benefit and a scaring outcome. No discontinuation of nivolumab was required. CONCLUSION: Immune checkpoint inhibitors induced inflammatory response leads to the exposure of hair follicle antigens and a consequent loss of Immuno Privilege. We hypothesize a role of steroids in deviating a primarily lichenoid reaction toward a folliculitis.

Synthetic hair reactions and treatment of complications: Case reports.

BACKGROUND: Synthetic hair fiber implantation first achieved widespread use in the 1970s, but in 1983, the US Federal Drug Administration banned the fibers due to its complications. Currently available synthetic fibers consist of polyamide material, which has been claimed to be effective and safe. Nevertheless, its use for hair restoration is controversial because of complications such as recurrent infections; the rejection and the faster-than-anticipated loss of fibers; frequent allergic reactions; fears about carcinogenicity; cicatricial alopecia; granulomatous hypersensitivity; and cyst formation. AIMS: To report complications of synthetic hair implantation and treatments. METHODS: We report the clinical data, pathological studies, and treatment outcomes of two patients who developed complications after a synthetic hair implantation. RESULTS: Our case reports showed significant moderate-to-severe adverse events, including recurrent folliculitis, scalp crusting, scarring, the matting and breakage of fibers, and granulomatous reactions. The onset of the reactions varied between 1 and 8 weeks. Pathological studies showed that the implantation of the synthetic hair into the scalp produced a hyperplastic proliferation of epidermal cells, foreign body granuloma, and persistent acute inflammation due to bacterial infections. In our study, definitive treatment was ineffective until the synthetic fibers were removed from the scalp. CONCLUSION: These significant adverse reactions may limit the benefits of synthetic hair fiber implantation for some patients. Although the inflammations were initially controlled by oral and topical antibiotics, a variety of antibiotics were unable to control the folliculitis. The fibers were ultimately removed, following which, the inflammations improved.