Nivolumab-Induced Lichen Planopilaris: Case Report and Literature Review of Hair Disorders Associated with Targeted Oncological Therapies.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapies. Their mechanism promotes a cytotoxic T-cell activation against the tumor cells, but as a consequence, immune-mediated toxicities are increasingly being identified. Cutaneous immune-mediated adverse events (AE) occur in 32% of patients, with possible higher grade AEs seen with anti-programmed cell death protein 1, such as nivolumab. A 67-year-old woman with metastatic melanoma, previously treated for 2 years on dual ICI (ipilimumab and nivolumab), had her treatment interrupted due to grade-3 hepatitis. She was subsequently recommenced on single-agent nivolumab with good response, before discontinuation due to remission. She reported worsening scalp pruritus with associated erythema, scaling, and global hair thinning. On examination, she had significant erythema throughout the scalp with perifollicular scaling and evidence of scarring. She reported severe distress from her symptoms. Her scalp biopsy demonstrated features of scarring alopecia with infundibular and isthmic inflammation and interface change in keeping with lichen planopilaris. Follicular toxicities are rarely reported, possibly due to imprecise AE phenotyping or underreporting. However, growing evidence suggests that patients can develop follicular pigmentary changes and nonscarring alopecia. To our knowledge, this is the first case of scarring alopecia reported with nivolumab. Current treatments for ICI-induced toxicities are limited.

Clinicopathologic Characteristics and Response to Treatment of Persistent Chemotherapy-Induced Alopecia in Breast Cancer Survivors.

IMPORTANCE: Alopecia induced by classic chemotherapy affects up to 65% of patients and is usually reversible. However, there are increasing reports of persistent chemotherapy-induced alopecia (pCIA), especially for patients treated with taxane-containing chemotherapy regimens. OBJECTIVE: To analyze the clinicopathologic characteristics and response to treatment of patients with pCIA after chemotherapy for breast cancer. DESIGN, SETTING, AND PARTICIPANTS: In this case series, a retrospective evaluation was performed of patients with a diagnosis of pCIA after chemotherapy for breast cancer in 4 specialist hair clinics from November 1, 2011, to February 29, 2020. MAIN OUTCOMES AND MEASURES: Clinical, trichoscopic, and histopathologic characteristics and treatment outcomes were analyzed. For patients who presented with diffuse alopecia or diffuse rarefaction of hair over the midfrontal scalp with widening of the central part line and preservation of the frontal hairline, the Sinclair scale (grades 1-5, where 1 indicates normal hair density and 5 indicates the most severe stage of hair loss, with little or no hair in the centroparietal region) was used to assess severity. RESULTS: One hundred patients (99 women [99%]; mean age at presentation, 54.0 years [range, 29.0-74.1 years]) were included. Most patients had diffuse nonscarring alopecia (n = 39), female pattern hair loss (n = 55), or male pattern hair loss (n = 6). Six patients developed cicatricial alopecia. Taxane-containing regimens were used for most patients (92 [92%]) and were associated with more severe alopecia than regimens that did not contain taxanes (median Sinclair grade, 4 [IQR, 3-5] vs 2 [IQR, 2-2.5]; P < .001). A total of 76 of 86 patients (88%) had trichoscopic signs indistinguishable from those of androgenetic alopecia. Of 18 patients who had biopsies, 14 had androgenetic alopecia-like features, 2 had cicatricial alopecia, and 2 had features of both. Both topical and oral minoxidil, sometimes combined with antiandrogen therapy, were associated with an improvement in hair density (median Sinclair grade, 4 [IQR, 3-5] before treatment vs 3 [IQR, 2-4] after treatment; P < .001). CONCLUSIONS AND RELEVANCE: This case series outlines previously unreported features of pCIA in patients with breast cancer, including a trichoscopic description. Cosmetically significant regrowth was achieved for a significant proportion of patients with topical or systemic treatments, suggesting that pCIA may be at least partly reversible.

Lichen Planopilaris and Frontal Fibrosing Alopecia as Model Epithelial Stem Cell Diseases.

Inflammation-associated, irreversible damage to epithelial stem cells (eSCs) of the hair follicle in their immunologically privileged niche lies at the heart of scarring alopecia, which causes permanent difficult-to-treat hair loss. We propose that the two most common and closely related forms, lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA), provide excellent model diseases for studying the biology and pathology of adult human eSCs in an easily accessible human mini-organ. Emphasising the critical roles for interferon (IFN)-γ and peroxisome proliferator-activated receptor (PPAR)-γ-mediated signalling in immune privilege (IP) collapse and epithelial-mesenchymal transition (EMT) of these eSCs respectively, we argue that these pathways deserve therapeutic targeting in the future management of LPP/FFA and other eSC diseases associated with IP collapse and EMT.

Lichen planopilaris is characterized by immune privilege collapse of the hair follicle's epithelial stem cell niche.

Lichen planopilaris (LPP) is a chronic inflammatory disease of unknown pathogenesis that leads to permanent hair loss. Whilst destruction of epithelial hair follicle stem cells (eHFSCs) that reside in an immunologically protected niche of the HF epithelium, the bulge, is a likely key event in LPP pathogenesis, this remains to be demonstrated. We have tested the hypotheses that bulge immune privilege (IP) collapse and inflammation-induced eHFSC death are key components in the pathogenesis of LPP. Biopsies of lesional and non-lesional scalp skin from adult LPP patients (n = 42) were analysed by quantitative (immuno)histomorphometry, real-time quantitative polymerase chain reaction (qRT-PCR), laser capture microdissection and microarray analysis, or skin organ culture. At both the protein and transcriptional level, lesional LPP HFs showed evidence for bulge IP collapse (ie increased expression of MHC class I and II, ß2microglobulin; reduced TGFß2 and CD200 expression). This was accompanied by a Th1-biased cytotoxic T cell response (ie increased CD8(+) GranzymeB(+) T cells and CD123(+) plasmacytoid dendritic cells, with increased CXCR3 expression) and increased expression of interferon-inducible chemokines (CXCL9/10/11). Interestingly, lesional LPP eHFSCs showed both increased proliferation and apoptosis in situ. Microarray analysis revealed a loss of eHFSC signatures and increased expression of T cell activation/binding markers in active LPP, while bulge PPARγ transcription was unaltered compared to non-lesional LPP HFs. In organ culture of non-lesional LPP skin, interferon-γ (IFNγ) induced bulge IP collapse. LPP is an excellent model disease for studying and preventing immune destruction of human epithelial stem cells in situ. These novel findings raise the possibility that LPP represents an autoimmune disease in whose pathogenesis IFNγ-induced bulge IP collapse plays an important role. Therapeutically, bulge IP protection/restoration may help to better manage this highly treatment-resistant cicatricial alopecia.

The pathogenesis of primary cicatricial alopecias.

Cicatricial (scarring) alopecia results from irreversible damage to epithelial stem cells located in the bulge region of the hair follicle, generally as a result of inflammatory mechanisms (eg, in the context of autoimmune disease). In primary cicactricial alopecia (PCA), the hair follicle itself is the key target of autoaggressive immunity. This group of permanent hair loss disorders can be classified into distinct subgroups, characterized by the predominant peri-follicular inflammatory cell type. In none of these PCA forms do we know exactly why hair follicles begin to attract such an infiltrate. Thus, it is not surprising that halting or even reversing this inflammation in PCA is often extremely difficult. However, increasing evidence suggests that healthy hair follicle epithelial stem cells enjoy relative protection from inflammatory assault by being located in an immunologically "privileged" niche. Because this protection may collapse in PCA, one key challenge in PCA research is to identify the specific signaling pathways that endanger, or restore, the relative immunoprotection of these stem cells. After a summary of pathobiological principles that underlie the development and clinical phenotype of PCA, we close by defining key open questions that need to be answered if more effective treatment modalities for this therapeutically very frustrating, but biologically fascinating, group of diseases are to be developed.

Hair loss as a result of cutaneous autoimmunity: frontiers in the immunopathogenesis of primary cicatricial alopecia.

Primary cicatricial alopecias (PCA) represent uncommon inflammatory disorders that result in permanent loss of scalp hair. Cutaneous autoimmunity, most prominently chronic cutaneous lupus erythematosus (CCLE), can result in this kind of scarring hair loss. The cosmetic disfigurement caused by PCA and the very unsatisfactory therapeutic options available to date all demand a better understanding of the obscure pathobiology of PCA so as to define new therapeutic targets and strategies. Hair follicle (HF) cycling and regeneration are abolished in PCA due to irreversible, epithelial hair follicle stem cell (eHFSC) damage, triggered by major, yet unclear pro-inflammatory events (e.g. type I interferon-associated cytotoxic inflammation, loss of HF immune privilege, loss of immunosuppressive "no danger" signals). Therefore, immuno-protection of eHFSC and restitution of their immune privilege are attractive future therapeutic strategies in PCA. Chronic cutaneous lupus erythematosus-associated PCA may serve as a model system for other diseases where epithelial stem cells undergo immuno-destruction.

Allergic contact dermatitis to methyl aminolevulinate (Metvix) cream used in photodynamic therapy.

Topical photodynamic therapy (PDT) is increasingly used in the treatment of superficial skin malignancies including actinic keratosis, Bowen's disease and superficial basal cell carcinoma. Contact allergy to the prodrug is rarely reported. We report a case of allergic contact dermatitis to methyl aminolevulinate cream used in PDT.

Failure to normalize parathyroid hormone during treatment of vitamin D deficiency in Asian patients.

OBJECTIVE: Vitamin D deficiency and osteomalacia remain commonplace within the Asian community in Bradford. The treatment of vitamin D deficiency and osteomalacia is cheap and effective, but there are few data on long-term outcomes. Studies have suggested that a minority of patients fail to normalize parathyroid hormone (PTH) levels during therapy with vitamin D. This study aimed to determine what proportion of Asian patients with vitamin D deficiency and secondary hyperparathyroidism normalize PTH levels following therapy with oral vitamin D and to examine reasons for failure to normalize PTH. DESIGN: This study examined the impact of an oral regimen of vitamin D 800 i.u. (20 micrograms) and calcium 1000 mg daily, on PTH levels within an endocrinology outpatient clinic. patients 51 (4M:47F) Asian patients, median age 39 years (range 16-77 years) with vitamin D deficiency (25-hydroxyvitamin D < 25 nmol/l) and secondary hyperparathyroidism (PTH > 5.7 pmol/l). MEASUREMENTS: All patients had at least one follow-up measurement of PTH and calcium during treatment. A subgroup of patients gave consent for examination of GP-prescribing records to indirectly asses adherence to therapy. RESULTS: PTH normalized in only 28/51 (55%) patients (group N) and failed to normalize in 23/51 (45%) patients (group F). Baseline patient characteristics including: age, basal serum 25-hydroxyvitamin D (25OHD), basal serum PTH, basal serum calcium and post treatment serum calcium, were similar in groups N and F. Mild hypercalcaemia occurred in only two (3.9%) patients. The proportion of prescriptions collected by patients in group N was 75 (17-100)% and in group F was 17 (0-100)%, P < 0.0001. CONCLUSIONS: This study has demonstrated that long-term oral treatment with vitamin D and calcium, fails to normalize PTH in a significant proportion of patients with vitamin D deficiency and osteomalacia. This is most likely related to lack of adherence to long-term treatment. Improved ways of treating this condition need to be explored.