The itchy scalp--scratching for an explanation

Scalp pruritus is a common complaint that is considered a diagnostically and therapeutically challenging situation. Scalp skin has a unique neural structure that contains densely innervated hair follicles and dermal vasculature. In spite of the recent advances in our understanding of itch pathophysiology, scalp itching has not been studied as yet. In this review, we summarize the current knowledge on the neurobiology of scalp and hair follicles as well as itch mediators and provide a putative mechanism for scalp itch with special emphasis on neuroanatomy and pathophysiology.     

A multidimensional assessment of the burden of psoriasis: results from a multinational dermatologist and patient survey

Psoriasis is a common, chronic, inflammatory skin disease which affects between 0.09% and 11.4% of the population worldwide. It causes symptoms such as itch and skin pain, but its effects can actually extend beyond the skin. It is often associated with additional co‐occurring diseases (comorbidities) such as cardiovascular disease, psoriatic arthritis (PsA), obesity, diabetes and anxiety or depression. Altogether psoriasis can cause significant negative impact on the quality of life (QoL) as well as work productivity of psoriasis patients. Additionally, the presence of common and bothersome symptoms such as itch and psoriasis lesions on different body areas can further increase the burden of disease on patients. In this large and multinational survey of dermatologists and their psoriasis patients, we estimated the incremental burden of comorbidities, itch, and affected body areas among patients with moderate to severe psoriasis. Anonymised responses were collected from 524 dermatologists and 3,821 psoriasis patients across 9 countries (UK, France, Germany, Spain, Italy, Russia, South Korea, Mexico and Brazil) using questionnaires and analysed to assess the impact of psoriasis on patients. Questionnaires collected data regarding psoriasis symptoms (presence/extent of itch, sleep disturbance due to itch, presence of skin pain), QoL and medical resource utilisation in the past 12 months (e.g. number of consultations that patients had with their dermatologist and number of hospitalisations). Overall, the results indicate that the presence of physical and psychological comorbidities, symptoms such as itch, presence of psoriasis lesions especially on visible (e.g. scalp, face, hands) and sensitive areas (e.g. genitals, scalp, face) significantly affect psoriasis patients’ QoL and cause significant financial burden due to work productivity impairment and increased usage of medical resources.     

Leptin of dermal adipose tissue is differentially expressed during the hair cycle and contributes to adipocyte‐mediated growth inhibition of anagen‐phase vibrissa hair

Adipose tissue encircles the lower portion of anagen hair follicles and may regulate hair cycle progression. As leptin is a major adipokine, its level of expression from the dermal white adipose tissue during hair cycle progression was studied. The result shows that leptin level is differentially expressed during hair cycle, the lowest in early anagen phase, upregulated in late anagen phase and the highest in the telogen phase. On the other hand, leptin receptor is detected in keratin 15‐positive hair bulge epithelium of both anagen‐ and telogen‐phase hair follicles of mice pelage and vibrissa hair, and hair from human scalp. Leptin contributes to adipocyte‐mediated growth inhibition of anagen‐phase vibrissa hair as demonstrated in organ culture and coculture system. Our data suggest that leptin of dermal white adipose tissue might regulate hair growth and, therefore, hair cycle progression via leptin receptor on the hair follicle epithelium.     

Evaluation of epidermal nerve density and opioid receptor levels in psoriatic itch

Background Psoriasis is a complex, multifactorial inflammatory skin disease with genetic and environmental interactions. Patients with psoriasis exhibit erythematous plaques with itch, but the mechanisms of psoriatic itch are poorly understood. Objectives This study was performed to investigate epidermal nerve density and opioid receptor levels in psoriatic skin with or without itch. Methods Twenty‐four patients with psoriasis aged between 39 and 82 years were included in this study. The number of epidermal nerve fibres, the levels of semaphorin 3A (Sema3A) and the expression patterns of μ‐ and κ‐opioid systems were examined immunohistologically in skin biopsies from psoriatic patients with or without itch and healthy volunteers as controls. Results The number of epidermal nerve fibres tended to increase in approximately 40% of psoriatic patients with itch compared with healthy controls, while such intraepidermal nerves were not observed in other itchy patients. In comparison with healthy controls, Sema3A levels also tended to decrease in the epidermis of psoriatic patients with itch. However, no relationship was found between nerve density and Sema3A levels in the epidermis of psoriatic patients with itch. The levels of μ‐opioid receptor and β‐endorphin in the epidermis were the same in healthy controls and psoriatic patients with or without itch. The levels of κ‐opioid receptor and dynorphin A were significantly decreased in the epidermis of psoriatic patients with itch compared with healthy controls. Conclusions Based on Sema3A levels in the epidermis, epidermal opioid systems, rather than hyperinnervation, may be involved in the pathogenesis of psoriatic itch.     

Itch: an under‐recognized problem in psoriasis

Psoriasis has historically been considered a nonpruritic dermatosis, in contrast with atopic dermatitis. Thus, itch has often been underappreciated and overlooked in psoriasis. However, increasing evidence over the past decade has shown that itch can be one of the most prevalent and burdensome symptoms associated with psoriasis, affecting almost every patient to some degree. Itch can involve the entire body, although it predominantly affects the legs, hands, back, body and especially the scalp. Uncontrolled itch can significantly impact all aspects of the well‐being and quality of life of the patient. While there has been some progress in trying to better understand the pathophysiology of itch in psoriasis, more research effort and interest are needed. This under‐recognition of itch in psoriasis is clearly reflected in the dearth of treatment options targeting itch despite significant advancement in treating the lesions themselves. Recently, however, clinical studies have begun to include itch as a study outcome. The resulting data have demonstrated concomitant antipruritic benefits and improved Psoriasis Area and Severity Index (PASI) scores with mainstay treatments for psoriasis, such as topical corticosteroids and vitamin D analogs, phototherapies, and various systemics and biologics. This article takes a closer look at this debilitating symptom, reviewing the available epidemiology data for psoriatic itch, presenting the current understanding of psoriatic itch pathophysiology and highlighting important clinical data for various treatment options for itch. Practical considerations for increasing the recognition of itch as well as improving its management in psoriasis are also provided.     

Alopecia as a rare but distinct manifestation of pemphigus vulgaris

Background Pemphigus vulgaris (PV) patients may develop scalp erosions, however, the development of alopecia has been reported to be extremely rare. Objective To delineate the clinicopathological features of alopecia in PV and provide insight into the pathogenesis of this rarely observed manifestation. Methods A retrospective case note review was performed on five PV patients presenting with progressive hair loss and alopecic patches. Data were collected on demographics and clinical findings. Results for hair pull tests, direct immunofluorescence study of plucked hairs, established laboratory tests to detect anti‐desmoglein 1 and 3 autoantibodies and scalp swab culture were recorded. A combination of vertical and horizontal sectioning technique enabled detailed histopathological analysis of alopecic patches. Clinical course was monitored. Results Anagen hair follicles with the outer root sheath structure were easily pulled from perilesional scalp, with intercellular IgG deposition on the outer root sheath keratinocytes. Acantholysis between outer root sheath keratinocytes extending from the infundibulum to suprabalbar level was evident in anagen hair follicles of affected lesions. Perifollicular cell infiltration was observed in the lesions where scalp swabs detected micro‐organisms. The bulge stem cell area was mostly intact. Alopecia was non‐scarring and following 4 weeks of therapy hair re‐growth was seen in all patients. Conclusion In PV, the combination of anti‐desmoglein autoantibody‐mediated acantholysis in conjunction with secondary factors, such as inflammatory changes due to infection, may cause weakening of hair follicle anchorage resulting in hair loss and alopecic patches. This unusual clinical phenotype should alert physicians to PV as a potential diagnosis.     

Alopecia Neoplastica due to Gastric Adenocarcinoma Metastasis to the Scalp,Presenting as Alopecia: A Case Report and Literature Review

Alopecia neoplastica is defined as hair loss secondary to a visceral malignancy that has metastasized to the scalp. The scalp is a relatively common site of cutaneous metastasis, usually presenting as a single or multiple firm scalp nodules. Alopecia neoplastica is a well-recognized but rare presentation, and its pathogenesis is incompletely understood. Atrophy of the hair follicles due to tumor invasion of the scalp plays a role in the development of alopecia. Herein, we describe a 33-year-old woman with gastric adenocarcinoma who developed alopecia neoplastica while receiving cancer chemotherapy. Scalp biopsy revealed metastatic adenocarcinoma cells interspersed between collagen bundles and around hair follicles. Immunohistochemical analysis indicated that the tumor cells originated from the primary gastric adenocarcinoma. Therefore, she was diagnosed with alopecia neoplastica due to gastric adenocarcinoma. The findings from this report may be helpful for understanding the mechanism of alopecia neoplastica.     

The role of the microbiome in scalp hair follicle biology and disease

The skin surface microbiome and its role in skin diseases have received increasing attention over the past years. Beyond, there is evidence for a continuous exchange with the cutaneous immune system in healthy skin, where hair follicles (HFs) provide unique anatomical niches. Especially, scalp HFs form large tubular invaginations, which extend deeply into the skin and harbour a variety of microorganisms. The distinct immunology of HFs with enhanced immune cell trafficking in superficial compartments in juxtaposition to immune-privileged sites crucial for hair follicle cycling and regeneration makes this organ a highly susceptible structure. Depending on composition and penetration depth, microbiota may cause typical infections, but may also contribute to pro-inflammatory environment in chronic inflammatory scalp diseases. Involvement in hair cycle regulation and immune cell maturation has been postulated. Herein, we review recent insights in hair follicle microbiome, immunology and penetration research and discuss clinical implications for scalp health and disease.     

Clinical diagnosis of common scalp disorders

Scalp skin is unique on the body due to the density of hair follicles and high rate of sebum production. These features make it susceptible to superficial mycotic conditions (dandruff, seborrheic dermatitis, and tinea capitis), parasitic infestation (pediculosis capitis), and inflammatory conditions (psoriasis). Because these scalp conditions share similar clinical manifestations of scaling, inflammation, hair loss, and pruritus, differential diagnosis is critically important. Diagnostic techniques and effective treatment strategies for each of the above conditions will be discussed.     

Psoriatic alopecia

Alopecia and other hair abnormalities occurring in patients with psoriasis were first recognized over four decades ago, yet psoriatic alopecia is not a well‐known concept among clinicians. Alopecia may be directly related to the psoriasis itself, and can affect both the scalp and other parts of the body. On the scalp, psoriatic alopecia most commonly affects lesional skin, but may present as a generalized telogen effluvium. In most cases, there is regrowth of hair, but in rare cases it can cause scarring alopecia. Histological findings include features of psoriasis in the interfollicular epithelium, along with perifollicular inflammation and atrophy or loss of the sebaceous glands. Late changes include destruction of the hair follicle, with perifollicular fibrosis and ‘naked’ hair shafts lying free in the dermis. In addition to the hair loss caused by the psoriasis itself, data from population and genetic studies reveal that patients with psoriasis are at greater risk of developing alopecia areata. Psoriasis treatments may also contribute to hair loss. Application of topical preparations may cause hair loss through friction, and many of the systemic treatments used for psoriasis can also cause hair problems. Treatment with anti‐tumour necrosis factor‐α agents can precipitate de novo psoriasis and subsequent psoriatic alopecia.     

Alopecia areata

Alopecia areata (AA) is a nonscarring, autoimmune, inflammatory, hair loss on the scalp, and/or body. Etiology and pathogenesis are still unknown. The most common site affected is the scalp. Histopathology is characterized by an increased number of the catagen and telogen follicles, the presence of inflammatory lymphocytic infiltrate in the peribulbar region ("swarm of bees"). Corticosteroids are the most popular drugs for the treatment of this disease. Etiologic and pathogenic mechanisms, as well as other current treatments available will be discussed in this article.     

Inflammatory mediators causing cutaneous chronic itch in some diseases via transient receptor potential channel subfamily V member 1 and subfamily A member 1

Chronic itch with an itch–scratch vicious circle is a significant problem in a large amount of diseases. Some of these diseases, such as psoriasis, atopic dermatitis, prurigo nodularis, Sézary syndrome, uremic pruritus, diabetes and jaundice, are common. For a very long time, chronic itch has been a thorny problem with few effective treatments. Because of this, itch researchers and dermatologists seek to find the mechanisms among chronic itch, inflammatory cytokines and neurons. As an immediate area of research focus, we are going to find the peripheral cross‐talk between neurons and skin cells. Two receptors, named transient receptor potential channel vanilloid 1 and transient receptor potential channel ankyrin transmembrane protein 1, have been shown to play important roles in chronic itch. Many advances have been made so far this decade. This review talks about the updated mechanism of itch‐related inflammatory cytokines via transient receptor potential channels in cutaneous chronic itch and corresponding diseases. The search for itch‐related inflammatory mediators and the structure of transient receptor potential channels this decade could deepen our understanding of the mechanism of itch and help us find more treatments of chronic itch in the future.     

Keratinocyte differentiation in psoriatic scalp: morphology and expression of epithelial keratins

The morphology of hair follicles was examined in psoriatic scalp biopsies and compared with normal scalp. In scalp psoriasis the lower outer root sheath and hair matrix were not affected by the psoriatic changes, although there was an irregular expansion in the proximal lower outer root sheath. This area has been characterized, by the presence of keratin K19-containing cells, as the putative stem cell region. In addition, marked shrinkage of the sebaceous glands was seen in the psoriatic scalp, as previously reported. A panel of monospecific monoclonal antibodies to individual epithelial keratins was used to analyse scalp specimens immunohistochemically. Keratin expression in scalp was generally unaffected by psoriasis, except for widespread expression of suprabasal keratins K16 and K17 in suprabasal interfollicular psoriatic scalp epidermis. Simple epithelial keratins K8 and K18 were not found in follicular epithelium from either normal or psoriatic scalp, using multiple monospecific antibodies. This study shows that keratin K17 is induced suprabasally during epidermal hyperproliferation, and cannot therefore be considered a hair follicle-specific keratin.     

Histopathologic study of scalp psoriasis: peculiar features including sebaceous gland atrophy

In a study on scalp psoriasis of 19 patients (11 males and 8 females, 15-64 years of age, psoriasis area severity index partial score of the head ranging from 0.5 to 2.8), we came to notice that, apart from the classical criteria for the diagnosis of psoriasis which were present in all cases, in a majority of patients, sebaceous glands were extremely reduced in size. We compared findings of follicular counts and sebaceous glands with a nonpsoriatic group of individuals (n = 26). Ten cases from the psoriatic population presented with completely atrophic glands, most of the time intermingled with larger glands (P = 0.03); not a single case showed sebaceous gland atrophy in the control group. There were no statistical differences regarding total number of hair follicles (P = 0.08), terminal follicles (P = 0.15), vellus follicles (P = 0.39), and telogen follicles (P = 0.58) between the groups. Other unusual features observed in the scalp psoriasis group were dilation of infundibula in 11 cases, a papillomatous epidermal surface in 8 specimens, parakeratosis at the lips of infundibular ostia in 8 specimens, mitotic figures in 7 cases, and necrotic keratinocytes in 14 cases. We conclude that psoriasis of the scalp may present itself with unexpected microscopic findings, among them being atrophy of sebaceous glands. Further studies are necessary to clarify why this atrophy develops and if it is specific to psoriasis.     

Itch in dermatomyositis: the role of increased skin interleukin‐31

Patients with dermatomyositis often suffer from itching, but the mechanism is unknown. The authors of this study, based in USA, Korea and Italy, aimed to find out how common itch is in patients with dermatomyositis, and whether a cytokine called IL‐31 is increased in affected skin. Cytokines are proteins produced by cells in the immune system and a delicate balance of cytokines is needed to maintain health. In some skin disorders, such as atopic eczema, this balance is disrupted, and too many pro‐inflammatory cytokines (meaning ones which cause inflammation) are produced. 191 patients with the condition were surveyed, and the authors took biopsy samples from skin lesions, compared with four healthy controls (people without dermatomyositis). They found that half of the patients had moderate to severe itch, and itch was linked to the severity of the disease. In skin lesions from patients with itchy dermatomyositis, there was increased gene expression of IL‐31and its receptor (meaning more IL‐31 and the receptor that helps it work were released), and this expression was stronger in patients with more severe itch. A new drug under investigation for dermatomyositis, lenabasum, reduces or ‘downregulates’ the expression of IL‐31, and the authors conclude that it may prove to be of value in the treatment of itch in this condition.     

Expression of hair follicle stem cells detected by cytokeratin 15 stain: implications for pathogenesis of the scarring process in cutaneous lupus erythematosus

Background Discoid lupus erythematosus (DLE) is a scarring disease. Although the scarring and deformity may affect any part of the body, such changes have been reported to be most obvious on the face and scalp. The pathogenesis behind this scarring process is not well understood. Once lesions have scarred, recurrent disease tends to occur at the edge of the scarred lesions but not within them. Objectives The fact that inflammation in DLE generally involves the bulge area of the follicles raises the possibility that damage to the stem cells of the bulge region may be one process leading to the permanent loss of follicles. The aim of this study was to investigate the role of the hair follicle stem cells which reside in the bulge region in the scarring process in cutaneous lupus erythematosus (CLE). Methods We studied the reactivity of an antibody to the CD8 antigen (C8/144B), which recognizes cytokeratin (CK) 15 and preferentially immunostains hair follicle stem cells without staining the remaining hair follicle, on skin biopsies (scalp and body lesions) from patients with CLE (36 with discoid lesions and 10 with subacute lesions). Normal scalp and body biopsy specimens served as controls. The correlation between the extent of the cytotoxic inflammatory cell infiltrate (CD8+) and the presence of stem cells was investigated. Results were analysed semiquantitatively. Results The expression of CK15 in hair follicle stem cells was variable in the DLE lesions; there was normal to moderate CK15 expression at the bulge region of hair follicles when surrounded by mild or moderate inflammatory infiltrate (CD8+), but in cases of severe inflammation, CK15 expression was weak or absent. Conclusions The bulge region appears to be involved in this disease as part of a broader involvement of the hair follicles; it is secondarily affected by the surrounding inflammatory cell infiltrate. Expression of C8/144B diminished and was then absent, indicating either damage to stem cells or differentiation to help in the repair process. Damage to follicular stem cells may help to explain the irreversible alopecia and the scarring process which characterize this disease.     

Biomarkers of alopecia areata disease activity and response to corticosteroid treatment

Alopecia areata (AA) is a common inflammatory disease targeting the anagen‐stage hair follicle. Different cytokines have been implicated in the disease profile, but their pathogenic role is not yet fully determined. We studied biopsies of pretreatment lesional and non‐lesional (NL) scalp and post‐treatment (intra‐lesional steroid injection) lesional scalp of 6 patchy patients with AA using immunohistochemistry and gene expression analysis. Immunohistochemistry showed increases in CD3⁺, CD8⁺ T cells, CD11c⁺ dendritic cells and CD1a⁺ Langerhans cells within and around hair follicles of pretreatment lesional scalp, which decreased upon treatment. qRT‐PCR showed in pretreatment lesional scalp (compared to NL) significant increases (P < 0.05) in expression of inflammatory markers (IL‐2, IL‐2RA, JAK3, IL‐15), Th1 (CXCL10 and CXCL9), Th2 (IL‐13, CCL17 and CCL18), IL‐12/IL‐23p40 and IL‐32. Among these, we observed significant downregulation with treatment in IL‐12/IL‐23p40, CCL18 and IL‐32. We also observed significant downregulation of several hair keratins in lesional scalp, with significant upregulation of KRT35, KRT75 and KRT86 in post‐treatment lesional scalp. This study shows concurrent activation of Th1 and Th2 immune axes as well as IL‐23 and IL‐32 cytokine pathways in lesional AA scalp and defined a series of response biomarkers to corticosteroid injection. Clinical trials with selective antagonists coupled with cytokine‐pathway biomarkers will be necessary to further dissect pathogenic immunity.