Precision Medicine and the Practice of Trichiatry: Adapting the Concept

Abstract

Evidence-based medicine (EBM) aims for the ideal that healthcare professionals make conscientious, explicit, and judicious use of the best available evidence gained from the scientific method to clinical decision-making. It seeks to assess the strength of the evidence for benefits of diagnostic tests and treatments, using techniques from science, engineering, and statistics, such as the systematic review of medical literature, meta-analysis, risk-benefit analysis, and randomized controlled trials. The limited success rate of EBM therapies suggests that the complex nature of hair loss may be inadequately served by the present levels of evidence, and that physicians treating hair loss may have fallen short of adequately researching a robust evidence to underpin their practices. Against this backdrop, the concept of precision medicine (PM) is evolving. PM refers to the customization of medical care to the patient's individual characteristics based on the patient's genetic background and other molecular or cellular analysis, while classifying patients into subpopulations that differ in their susceptibility to a particular medical condition, in the biology or prognosis of those medical conditions, or in their response to a specific treatment. With the advances in hair research, the powerful tools of molecular biology and genetics, and innovative technologies, we have the robust scientific data and tools to adapt the concept of PM to the practice of trichiatry. Finally, databases pertaining to the development and efficacy of PM must be analyzed and be used to form the basis of evidence-based personalized trichiatry.

The history of medical reasoning has been one of an evolution from magical medicine (e.g., tribal medicine and shamanism) through speculative medicine based on speculative philosophical systems rather than the empirical and experimental approach, pragmatic medicine dealing with things in a way that is based on practical rather than theoretical considerations, to today's evidence-based medicine (EBM) and precision medicine (PM).

EBM seeks to assess the strength of the evidence of risks and benefits of diagnostic tests and treatments, using techniques from science, engineering and statistics, such as the systematic review of medical literature, meta-analysis, risk-benefit analysis, and randomized controlled trials [1]. EBM aims for the ideal that healthcare professionals should make conscientious, explicit, and judicious use of the best available evidence gained from the scientific method to clinical decision-making. However, the limited success rate of evidence-based therapies in managing hair loss suggests both that the complex nature of hair loss may be inadequately served by the present levels of evidence for therapies, and that physicians treating patients with hair loss may have fallen short of adequately researching a robust evidence to underpin their practices.

Against this backdrop, the concept of PM is evolving. In contrast to EB, PM refers to the customization of medical care to the individual characteristics of the patient. It does not literally mean the creation of treatments that are unique to a particular patient, but rather the ability to classify patients at hand into subpopulations that differ in their susceptibility to a particular medical condition, in the biology or prognosis of those medical conditions they may develop, or in their response to a specific treatment. For this purpose, diagnostic testing is employed for selecting appropriate and optimal therapies based on the context of a patient's genetic background or other molecular and cellular analysis. The tools employed in PM include molecular diagnostics, biochemical analytics, and imaging [2]. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not. The concept has evolved from cancer medicine, where it is also referred to as precision oncology and has paved the way to targeted cancer therapies with success.

There is considerable overlap between the terms PM and personalized medicine. Personalized medicine is an older term, however, the word personalized may be misinterpreted to imply that treatments are being developed uniquely for each individual; while in PM the focus is on identifying subgroups of patients for which approaches will be effective based on the diagnostic tools of PM.

We have recently proposed the term trichiatry to describe physicians trained in the evaluation and management of patients with hair loss, who have complex and challenging needs. The quality and stringency of the trichiatrist's graduate medical training is identical to that of fellow physicians of any other discipline, allowing the trichiatrist to be comprehensive in counselling patients, prescribing medication, conducting physical examinations, ordering laboratory tests, and participating with the other medical disciplines in the diagnosis and treatment of hair problems as they may relate to systemic disease [3]. With the advances in hair research and clinics, the powerful tools of molecular biology and genetics, and innovative technologies, we now have enough robust scientific data and tools to adapt the concept of PM to the practice of trichiatry for the management of androgenetic alopecia, alopecia areata, and the scarring alopecias.

Ideally, we should strive to develop PM alongside EMB to ensure optimum clinical practice and to gain evidence base for personalized medicine. Indeed, PM must undergo the same rigorous analysis as EBM so that it too can form part of an evidence-based practice.

Androgenetic Alopecia

Androgenetic alopecia is the single most frequent cause of male and female hair loss. It is understood to represent a hereditary and androgen-dependent, progressive thinning of the scalp hair that follows a defined pattern, though there exist significant differences with respect to frequency, age of onset, and pattern of alopecia between male and female androgenetic alopecia. In fact, there is a considerable age- and sex-dependent, as well as interindividual variability in the clinical presentation, the course, and the response to treatment, suggesting heterogeneity of pathogenetic factors in androgenetic alopecia that have to be taken into account for a personalized therapy.

Gene polymorphism diagnostics have been suggested both for risk assessment [4], and for prognostication of response to treatment with the 5alpha reductase inhibitors [5], as well risk of long-lasting adverse effects [6].

Since the hair growth-promoting effect of minoxidil is due to the actions of its sulfated metabolite, minoxidil sulfate, for clinical efficacy, minoxidil has to be sulfated by a group of enzymes known as sulfotransferases, some of which are expressed in the hair follicle with wide interindividual variations in the level of enzyme activity. Therefore, enzymatic assay of sulfotransferase activity in plucked hair follicles may predict response to topical minoxidil therapy [7, 8, 9].

Relevance of dermoscopic [10] or histological evidence of associated follicular inflammation and fibrosis found in 40% of androgenetic alopecia has also been demonstrated [11]. Morphometric studies in male androgenetic alopecia treated with topical minoxidil showed that a significantly lesser proportion of those with associated microinflammation had regrowth in response to treatment, in comparison to those without inflammation and fibrosis [11].

Traditionally, the medical focus has been either on hair loss or on the condition of the scalp in terms of specific dermatological diseases. Indeed, the proximate structural arrangement of the scalp and hair leads to an interdependent relationship between the two. There is a wealth of observational data on specific dermatological conditions of the scalp providing the evidence for the role of the scalp condition in supporting the production of healthy hair [12]. The scalp is a rich environment for microbes. Ecologically, sebaceous areas have greater species richness than dry ones [13], with implications both for skin physiology and pathologic conditions. Specifically, the microbiome of the scalp and its relationship to the respective scalp pathologies, such as dandruff and seborrheic dermatitis [14], psoriasis [15], and atopic dermatitis are currently in the focus of investigation [16, 17, 18, 19, 20].

Finally, comorbidities, specifically elevated androgen levels in women with androgenetic alopecia, such as in the polycystic ovary syndrome, indicate the necessity for a respective adaptation of treatment to include antiandrogen therapy for efficacy [21], and assessment for associated abnormalities and risk factors (metabolic syndrome, cardiovascular disease, endometrial carcinoma).

Moreover, obvious differences in clinical response of female androgenetic alopecia to clinical trials with oral finasteride [22, 23, 24, 25, 26, 27, 28, 29] have led to the suggestion that not all types of hair loss in women have the same pathophysiology (i.e., a distinction should be made between alope­cia with early [premenopausal] or with late [postmenopausal] onset, and with or without hyperandrogenemia [30].

Hypothyroidism is one comorbidity with an adverse effect on androgenetic alopecia and a particularly high frequency in women [31, 32, 33, 34, 35, 36], another one is iron deficiency. The existing controversy surrounding the relevance of iron stores in androgenetic alopecia, and other types of hair loss such as telogen effluvium and alopecia areata [37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48], indeed highlights our premise of the limitation of EBM in managing patients with hair loss, since there is a paucity of clinical trials evaluating therapeutic response to iron supplementation in managing these disorders.

Alopecia Areata

Alopecia areata is understood to be of autoimmune origin with an organ-specific, T cell-mediated assault on the hair follicle at the level of the bulb. A peribulbar lymphocytic infiltrate induces hair follicle keratinocytes to undergo apoptosis resulting in inhibition of cell division in the hair matrix. Some patients lose hair in only a small patch, while others may have more extensive or less frequently diffuse involvement. Alopecia totalis is the loss of all scalp hair, alopecia universalis is the loss of all scalp and body hair. The progress of alopecia areata in an individual patient is unpredictable, though risk factors have been proposed for prognostication. From a clinical point of view, a large surface area, a long disease duration, and associated nail abnormalities (trachyonychia) have been connected with a poorer prognosis [49].

Ikeda [50]originally proposed a classification of alopecia areata depending on associated comorbidities (atopic disease, familial arterial hypertension, and autoimmune endocrine disease) again reflecting on heterogeneity of the disease with implications for prognosis and the risk of total loss of hair.

Today, laboratory investigations for comorbidities screening is suggested in alopecia areata to detect other associated autoimmune conditions, specifically autoimmune thyroid disease [51, 52, 53, 54], pernicious anemia [55], lupus erythematosus [56], and in children celiac disease [57, 58, 59, 60], and/or comorbidities that may affect the disease course, such as deficiencies of iron [40], of zinc [61, 62], or of vitamin D [63, 64, 65, 66], and HIV infection [67].

Contributing genetic factors have been implicated early in the observation of familial occurrence of alopecia areata. Alopecia areata fits the pattern of a complex genetic trait with specific genes contributing both to susceptibility and to disease severity [68]. More recently, genome-wide association studies have unraveled genetically controlled immunologic pathways [69, 70], deepening our understanding of the events leading to the disease and identifying possibilities for novel targeted treatments of alopecia areata, such as the inhibition of Janus kinases [71, 72, 73, 74, 75, 76].

In view of the high variability of clinical response of long-standing, widespread disease to the current treatment modalities (i.e., topical immunotherapy with diphencyprone), there is a clear need for genetic or immunological markers for prediction of treatment outcome in the individual patient.

Scarring Alopecias

The scarring alopecias represent a diverse group of disorders that cause permanent destruction of the pilosebaceous unit and irreversible hair loss. Scarring alopecias pose both a diagnostic and therapeutic challenge to the practitioner. Accurate diagnosis is a prerequisite to therapy and based on a careful patient history, clinical examination, microbiological studies, and scalp biopsy, while there is no diagnostic biological marker for most entities. Challenges related to the treatment of the scarring alopecias include patient's delay, when irreversible scarring has already occurred; empiric and nonspecific therapies, since the causes are mostly unknown; and low levels of medical evidence for published treatments and expert recommendations.

In folliculitis decalvans, imaging techniques using field emission scanning electron microscopy and confocal laser scanning microscopy have identified bacterial communities organized as biofilms in the infrainfundibular part of hair follicles [77]. It has long been known that Staphylococcus aureus is invariably found in folliculitis decalvans, but antibiotic treatments, irrespective of the type of antibiotic used, the protocol, and the treatment duration have all proven to not attain sustained results. Bacteria living in a biofilm have significantly different properties from free-floating bacteria of the same species. One benefit of this environment is increased resistance to antibiotics. Biofilms are involved in a wide variety of microbial infections in the body, and it has been found that bacterial biofilms may impair cutaneous wound healing and reduce topical antibacterial efficiency even in treating infected skin wounds. The presence of a bacterial biofilm at the interface of the hair shaft may provide an explanation for the chronicity and high relapse rate of folliculitis decalvans, and the rational basis for ablative laser therapy [78, 79] or surgical excision [80] for definitive healing.

Since structural changes in the course of scarring alopecia are irreversible, there is a clear need for early intervention. With the expanding technologies for dissecting the immunologic and molecular basis, there is hope for a deeper understanding of the underlying pathogenesis and novel therapeutic interventions. Among these, currently, microarray analysis is used to identify disease associated gene expression patterns with the aims of further clarification of nosologic classifications and development of targeted therapies of the scarring alopecias.

A prototypical example is the identification of decreased expression of peroxisome proliferator-activated receptor (PPAR) gamma in lichen planopilaris, suggesting PPARgamma-targeted therapy with oral pioglitazone for lichen planopilaris [81, 82, 83].

Conclusions and Perspectives

For centuries, physicians propagated the viability of a complex approach in the diagnosis and treatment of disease, while modern medicine, which boasts a wide range of diagnostic methods and variety of therapeutic procedures, stresses specification. This raises the issue of how to wholly evaluate the state of a patient who suffers from a number of diseases simultaneously? For this purpose, the concept of comorbidity was created, which is defined as presence of one or more additional diseases co-occurring with a primary disease, or the effect of such additional diseases [84, 85, 86]. The effect of comorbid pathologies on clinical implications, diagnosis, prognosis, and therapy is polyhedral and patient specific. The interrelation of disease, age, and drug pathomorphisms greatly affects the clinical presentation and progress of the primary nosology, character, and severity of complications, and can challenge the diagnostic and therapeutic process. Therefore, the presence of comorbidity must be taken into account when selecting the algorithm of diagnosis and treatment, and the trichiatrist must participate with the other medical disciplines in the diagnosis and treatment of all types of hair problems as they may relate to systemic disease [87].

Further etiologies beyond the comorbid conditions are likely to be exposed by panomics [88], and these should be borne in mind when addressing the biological conditions contributing to hair loss, and when designing PM-based trichiatric treatment for optimum therapeutic efficacy. Finally, databases pertaining to the development and efficacy of PM must be analyzed and be used to form the basis of an evidence-based practice of personalized trichiatry.

Statement of Ethics

The authors have no ethical conflicts to disclose.

Disclosure Statement

The authors have no conflicts of interest to disclose.