Cicatricial alopecia: What’s new in etiology?

Clinical features of cicatricial alopecia

Cicatricial alopecia is a rare, clinically diversified set of disorders causing permanent and irreversible hair loss, which often results in serious discomfort and patient’s mental problems. The classification is based on the clinical picture and histopathology results. ¹

Clinically, this form of irreversible hair loss is characterized by visible loss of hair follicle openings in the bald spots. Histologically, it consists in destroying a hair follicle and replacing it with fibrocartilage. Such disorders are perceived as primary if a hair follicle itself is the target of the disease process and secondary if hair follicles are damaged incidentally in the context of more general tissue damage (e.g. deep skin infections, thermal burns, trauma, or ionizing radiation) (Table 1).^1–3

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Table 1.

Etiology of cicatricial alopecia (Braun-Falco et al.).

Genetic	Physical causes	Tumors	Infectious diseases	Various
Darier disease	Radiation	Metastases	Furunculus	DLE
Folliculitis decalvans	Burns	Carcinoma basocellulare	Lepra	Pemphigoid cicatricans
EBH	Chemical causes	Other tumors of the skin	Syphilis	Pustulosis eosynophylica
Ichthyosis	Mechanical causes	Carcinoma spinocellulare	Perifolliculitis abscendens et suffodiens	GVHD
Chondrodysplasia punctate		Hemangiomas	Tinea	LSA
Incontinentia pigmenti		Lymphomas	Herpes zoster	Lichen planus
				Sarcoidosis
				Sarkoidoza
				Morphea

Classification of cicatricial alopecia

According to the European classification, the group of cicatricial alopecia also includes an atrophic alopecia with inflammation as a damaging agent. Clinically, skin becomes thinner and the number of hair follicles decreases. A so-called brush symptom caused by the remaining tufts of hair, is also typical for atrophic alopecia. Histopathology is dominated by the decrease or complete disappearance of hair follicles with preserved arrector pili muscles and fibrous sheaths, perpendicular to the epidermis. There may be also perivascular lymphocytic infiltrates. The infiltrates around a hair follicle indicate concomitant disease. Some authors as the prototype of atrophic alopecia consider Pseudopelade of Brocq as well as alopecias including lichen planus and discoid lupus erythematosus (DLE).^1,3,4

In the American nomenclature, pseudopelade is diagnosed only when all other diseases are excluded. However, it is not known whether it is a separate disease entity or the end stage of other dermatoses (Table 2). ¹

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Table 2.

Differentation of the pseudopelade (Braun-Falco et al.).

Common causes	Rare causes
Folliculitis decalvans	Necrobiosis lipoidica
Lichen planus	Granuloma annulare
DLE	Sarcoidosis
Morphea	Metastases
	Tinea

In 2011, Sperling presented an alternative classification of cicatricial alopecia. It was divided into five separate subtypes: (1) chronic lupus erythematosus (DLE); (2) lichen planus; (3) perifolliculitis capitis abscedens et suffodiens; (4) acne keloidans nuchae; and (5) pseudopelade.^5,6

Etiology of cicatricial alopecia

There are numerous theories regarding the etiology of cicatricial alopecia.

Given a great number of separate populations of hair follicles’ stem cells, their ability to induce angiogenesis and the growth of nerve fibers, an important role in wound healing and underestimated impact on the overall skin architecture and physiology – permanent loss of pilosebaceous units is a problem of the whole skin that affects its normal functioning and regenerative potential. The result of such alopecia is an irreversible damage of epithelial hair follicle stem cells to such extent that this mini organ is no longer able to grow and regenerate due to an inflammatory attack on follicle. Therefore, cicatricial alopecia is a good subject for studies on immune deregulations resulting in the inflammatory damage of epithelial stem cell populations. In addition, it is an exemplary system in which the attack is caused by unknown factors. It can be observed in humans and in mouse models, showing the phenotype of cicatricial alopecia, how the epithelial stem cells are protected in the event of self-harm, and what recovery strategies apply. It can also be noted what exactly defines the place where the damage of the epithelial stem cells becomes irreversible and leads to their apoptosis or necrosis.^7–9

Mammalian hair growth cycle includes the phases of active growth (anagen) intertwining with massive apoptosis of hair follicle (catagen) and periods of relative calm (telogen). This constant lifelong activity of hair follicle rebuilding depends on the presence of its functional stem cells (eHFSCs). The cells are located at the site of the arrector pili muscle attachment, in the outermost layer of the hair root, that is, hair bulb.^9,10

An abnormal immune response that destroys eHFSCs, probably plays a role in the etiology of cicatricial alopecia. It is believed that hair follicles can be the gate to the microbial invasion on the mammal skin. However, in the case of the immunocompetent patients, a clinical consequence of this invasion (e.g. bacterial or fungus folliculitis) is exceptionally rare. Such observation suggests that hair follicle must have the efficient anti-infection mechanisms. ¹¹

The hair follicle epithelium is richly endowed with T lymphocytes and the Langerhans cells and surrounded by elements of the innate and cellular immunity (e.g. follicular mast cells and macrophages). It also indicates the activity of such antimicrobial peptides as human β2 defensin and cathelicidin. The last two inform about the danger and, together with pro-inflammatory cytokines and chemokines released by the hair follicle epithelium, can cause the accumulation of immunocytes to the point at which neutrophils, macrophages, and T-lymphocytes attack and potentially destroy the hair follicle epithelium.^11,12

On the other hand, the hair follicle immune system has created a complex system of control and balance and the latter inhibits inflammation. Large areas of hair follicle epithelium are subjected to the action of endogenous immunosuppressive factors such as transforming growth factor (TGF)-β1/2 and α-melanocyte stimulation hormone (MSH). In the physiological conditions, even the follicular mast cells can have the inhibitory effect on the immune system.

The divisions of the hair follicle epithelium (anagen) create the space of relative privilege (immune IP). This condition is characterized by low or complete lack of the expression of major (MHC) class I and class II antigens, as well as this of local immunosuppressant molecules including the synthesis of interfollicular cortisol. All of this can not only be used for the defence against damaging inflammation of a hair follicle, resulting from minor trauma, skin irritation, or microbial invasion, but also to eliminate potentially immunogenic autoantigens.^13–15

In the context of the pathogenesis of primary cicatricial alopecia, it seems to be important that a so-called immune privilege concerns also a hair bulb and eHFSCs. The levels of the expression of MHC class I antigens and β2-microglobulin and MHC class II are significantly reduced, whereas the immunoreactivity for locally generated immunosuppressant such as TGF-β2 and the factor inhibiting macrophage activity is increasing. ¹⁶

However, a functional meaning of these protective mechanisms in hair follicles remains the subject of speculation. They have probably evolved to reduce the risk of autoimmune alopecia developing in mammals and possibly endangering their lives (e.g. consequences of hair loss for polar bears). Another theory is that a hair follicle protects eHFSCs in order to maintain at least a critical regeneration level of stem cells.^17,18

The key to understanding the pathogenesis of primary cicatricial alopecia is the location of follicular inflammatory infiltrate in relation to the two main structures of a hair follicle, namely a hair bulb and the location of eHFSCs. In reversible conditions like alopecia areata, an inflammatory infiltrate centers on a hair bulb; whereas in the case of cicatricial alopecia it concerns a hair bulb and a distal part of a hair follicle. This considerable difference in the location of inflammatory infiltrate has serious clinical consequences (reversible versus permanent hair loss).

The damage of eHFSCs seems to be a key element in the pathogenesis of cicatricial alopecia. Additionally, the cells in an inflammatory infiltrate are mainly located around the dystal part of a hair follicle, saving proximal elements. Interesting as it is, permanent hair loss may also occur in the case of prolonged androgenic alopecia and acute form of Graft versus Host disease in which an inflammatory infiltrate around the hair bulb is often observed.

These results, together with the model of transgenic mice K15 22, support the theory of the key role of destroying or damaging eHFSC in the case of cicatricial alopecia. However, as pointed out in the mouse model, the destruction of eHFSC does not fully explain the phenotypic profile of alopecia (e.g. atrophy, erythema). Therefore, other pathogenic processes should also be considered in the etiology. The question is why the hair follicle is the first to be attacked (which is a target antigen). It still has not been established what prevents the damage of eHFSCs in regular follicles. Are normal mechanisms of immune protection significantly disrupted and therefore whether eHFSCs are at risk of being damaged by the immune system attack? An unknown trigger may possibly be a signal to destroy eHFSCs which would eliminate hair follicle ability to regenerate and self-repair and at the same time to stimulate all other clinical and histopathological features of the disease.^19–22

The theory of the immune attack on eHFSCs is crucial for the etiology of cicatricial alopecia. MHC class I, β2- macroglobulin and MHC class II are subjected to different regulation within a hair bulb in the various cicatricial alopecia units compared to those in the not affected skin. However, it is still not clear whether this phenomenon develops at the onset of the disease or as the second component of the response induced by the environment of pro-inflammatory cytokines.

Due to the inflammation theory of cicatricial alopecia, many authors try to examine the potential role of cellular cytotoxicity in the pathogenesis of the disease. The inflammatory infiltrate is composed mainly of activated T lymphocytes. T cells with active chemokine receptors are often found within the scars, which suggests that they are involved in damaging a tissue through the attack and induction of apoptosis.^23,24

Other noticeable cellular changes are, among others, increased number of plasmacytoid dendritic cells along with the increase in the expression of adhesion molecules (e.g. intercellular adhesion molecule-1, vascular molecule of cell adhesion, and E-selectin). As in the case of many inflammatory diseases, INF is a key cytokin in the pro-inflammatory response. Local production of INF induced the Th1 chemotaxis via different chemokines (e.g. CXCL9,10) to affected areas of the skin. Interestingly, CXCL10 is expressed mainly in the stratum basale, in the areas of cytotoxic T cell invasion. There is also an increase in the activity of tumor necrosis factor (TNF), interleukin-2 and INF-γ.^25–27

Wenzel suggested the following mechanism of the initiation of an inflammatory response: the Type 1 of the INF expression is caused by the absence of a stimulus which induces chemokines and the production of antiviral proteins, which, in turn, attracts T cells and dendritic cells to the skin. What is more, an ongoing inflammatory response^28–30 is fixed by the release of inflammatory cytokines from dendritic cells and accumulated apoptotic cells, together with the direct chemokine release from T cells.

Apoptosis is increased in the hair follicle, epidermis, and inflammatory infiltrate. Interesting as it is, the expression of the apoptosis Bcl-2 inhibitor is also reduced, which predisposes to apoptosis related to the tissue damage. ³¹

The hypothesis that disorders of the sebaceous gland may play a role in the pathogenesis of cicatricial alopecia comes from the observations of spontaneous mutations in mice assigned the name asebia (SCD1 AB), which exhibit the phenotype of cicatricial alopecia. In this model, hair is sparse, whereas hair follicles are either absent and replaced by fibrous tissue. The defect of stearoyl-CoA desaturase 1, a crucial component of fatty acids, causes the atrophy of the sebaceous glands, which leads to the hair growth disorder and potential destruction of the hair follicle. However, even though the sebaceous glands are atrophic or absent in the early stages of the disease, the phenomena has not been described in humans. However, despite the fact that the mice model explains general pathologic mechanisms of cicatricial alopecia, promoting the hypothesis that the dysfunction of the sebaceous gland is crucial, there is no evidence that it also applies to humans.^32,33

The research carried out on 90 skin samples from patients suffering from cicatricial and non-cicatricial alopecia showed that the number of sebaceous glands has decreased. The study also specified the role of the glands and their inflammation in the pathogenesis. The loss of the sebaceous glands was significantly more frequent in patients diagnosed with pseudopelade (more than 53%) than in the case of patients with non-cicatricial alopecia ( less than 5%). According to the quoted statement, the loss of the sebaceous glands and excretory duct inflammation may be important in initiating or accelerating damaging hair follicles during the development of the disease. ³⁴

These possible mechanisms divided researchers into two groups: supporters of destroying eHFSC and those who claim that sebaceous gland dysfunction is a key matter. The analysis of the human genes expression confirmed a shortage of the peroxisome proliferator-activated receptor (PPAR)-γ, which indicates that also the damage of the lipid metabolism and peroxisome processing may be important in the pathogenesis of cicatricial alopecia. PPAR-γ mediates in transferring the signals via corresponding endogenous ligands, which may be necessary in order to maintain a regular functioning of hair follicle stem cells. Since we have access to the PPAR-γ antagonists such as pioglitazone, this treatment strategy may turn out effective in treating some forms of cicatricial alopecia. ³⁵

Karnik et al. ³⁶ presented the gene expression profile, which confirmed that changes in lipid metabolism are typical for every subtype of cicatricial alopecia. He also emphasized the role of PPAR-γ and other nuclear receptors in the pathogenesis. PPAR-γ is a transcription factor, which constitutes the family of nuclear receptors and turned out to be a vital regulator of the genes responsible for lipid metabolism and inflammation. It is most likely that lipid metabolism disorders in cicatricial alopecia precede inflammation and are caused by an error in the PPAR-γ signaling in the stem cells of the hair follicle and sebaceous glands. Other authors pointed out that PPAR transcription factor, which integrates lipogenic factors, plays a role in the pathogenesis of primary cicatricial alopecia. It is unknown, however, what initiates inflammation and whether it is a primary or secondary phenomenon in the disease pathogenesis and whether the inflammation reflects the autoimmune process. In this article, the author presented that the cholesterol biosynthesis in the skin and hair follicles is weakened in patients suffering from cicatricial alopecia, and the treatment with cholesterol biosynthesis inhibitors or 7-dehydrocholesterol (7-DHC), the precursor of sterols, stimulates the expression of the genes encoding pro-inflammatory chemokines. The reaction associated with the induction of Toll-like receptor (TLR) probably initiates the damage of hair follicles. ³³

Programmed cell death is a crucial tool during tissues’ development and physiological remodeling, e.g. during morphogenesis and involution of the hair follicle in the catagen phase. Therefore, it was also suggested that apoptosis is a physiological mechanism for removing damaged abnormal hair follicles and thus primary cicatricial alopecia can be an uncontrolled variant of proper response pattern to serious damage. ³⁷

The psycho-emotional stressors in mice have a profound effect on hair growth through, among others, induction of nerve growth factor (NGF) and an increased release of substance P (SP), which increases the neurogenic skin inflammation. It results in severe follicular inflammatory infiltrates around a hair bulb, accumulation and degranulation of follicular mast cells, increased apoptosis of hair follicle keratinocytes, and reduction of the keratinocyte proliferation to premature entry into catagen.^38,39 It is also potentially important that the nerve fibers are particularly densely distributed around the arrector pilli muscle attachment and hair bulb. Follicular inflammation is often centered around these places. It was also shown that in the case of human hair follicles, stress induces catagen, increases mast cell degranulation in the anagen hair follicle, and regulates the expression of antigens MHC class I and β2-microglobuline.^40–43

Various environmental factors are concerned as triggers of cicatricial alopecia (e.g. infection, trauma, drugs). ⁴⁴

A particular importance has also been attached to the infectious factors, e.g. folliculitis decalvans, whereas Staphylococcus aureus is commonly isolated from the affected skin areas. However, taking into consideration the frequency of isolation of the above mentioned bacteria in the general population (20–30%), it is likely that an abnormal host response to staphylococcal infection plays a key role in the development of the disease. One of the theories says that S. aureus produces toxins, a so-called superantigen, which can create complexes with abnormal MHC class II antygens, which in turn stimulates the proliferation of T cells. ⁴⁵

Trauma also plays a role in the pathogenesis of different types of cicatrcial alopecia. In the parietal forms, the history of traumatic hair care practices is common (pulling). Folliculitis decalvans and erosive pustular dermatosis of the scalp are also associated with trauma and represent a so-called “nonspecific inflammatory reaction to trauma associated with solar radiation and with age”. ⁴⁶ Pharmacological treatment can be also associated with the development of cicatricial alopecia, e.g. Graham Little syndrome may occur following hepatitis B, vaccination. Folliculitis decalvans can be associated with anticonvulsant therapy and cyclosporine.^47–50

Genetic factors may be a key element of the pathogenesis of all the forms of cicatricial alopecia, either because of a person predisposed to some kind of disorder or through direct genetic influence. The influence of environmental and genetic factors can be confirmed by reviewing the family history of various diseases, e.g. folliculitis decalvans in the case of identical twins, family cases of pseudopelade Brocq. Interestingly, a leukocyte antigen DR1 ⁵¹ could be observed in the case of mother and daughter suffering from Graham Little syndrome. While describing two identical twins diagnosed with pseudopelade Brocq, Singh et al. ⁵² also discussed whether there may be a genetic cause associated with this type of hair loss.

Diagnosis of cicatricial alopecia

Cicatricial alopecia should be considered if the hair follicle openings in the balding area are not visible anymore. Also, dermatitis (including follicular erythema) associated with swelling, spots, and atrophic and hypertrophic scars are very often present. Histologically, increased inflammatory infiltrate is usually visible in the immediate vicinity of the follicles affected with scarring. The composition of an infiltrate indicates a given type of cicatricial alopecia. In fact, the current classification of primary cicatricial alopecia is mainly based on the predominating cells of the inflammatory infiltrate.^1,10–12

These disorders are divided into: lymphocytic, neutrophilic, mixed, or non-specific.

The results of immunofluorescence can be another diagnostic indicator, especially in the case of lupus erythematosus or bullous dermatoses in which damaged follicles will be eventually destroyed and replaced with scar-like fibrous tissue.^12,13

Dermatoscopy and direct immunofluorescence are also taken into consideration as alopecia diagnostic tools. Microarray analysis also enables to distinguish the subtypes of alopecia. Unfortunately, our understanding of the etiology and pathogenesis of cicatricial alopecia is still very incipient. The progress has been hindered by a poor understanding of the course of the disease, its incoherent and not precise description in the literature, absence of final molecular markers for any of the recognized form of the cicatricial alopecia, and finally because of an unpredictable and incomplete response to the treatment.^10,14,15

Therapeutic perspectives

Pseudopelade treatment is frustrating and usually does not bring satisfactory results. The main point of scarring alopecia therapy is stopping the progression of changes and possibly removal of their causes.^1,3

Therapy attempts to use antimalarial drugs, isoniazid, dapsone, and non-steroidal anti-inflammatory drugs. Relatively best results are obtained by oral steroids (e.g. Prednisone 40–80 mg for 2 weeks, followed by dose-reducing). These drugs are also recommended in topical therapy, especially for steroids having high potency in occlusion. Another way is intradermal administration of corticosteroids into the lesions.^1,32

Other methods are mainly experimental. Shapiro et al. ⁵³ reported promising results use of pioglitazone hydrochloride in a dose of 15 mg per day (PPAR-γ agonist) among patients with lichen planus on the scalp. A total of 50% of patients responded to treatment as determined by the reduction of inflammatory cells and the clinically based on the reduction of itching and skin inflammation. However, increased incidence of bladder cancer in rodents after systemic administration of pioglitazone led to topical recommendation as an alternative.

Surgical intervention is generally the best method of treatment for scarring alopecia. Such therapy may consist in:

We undertake surgical treatment mostly in young patients where scar is stable and does not exceed 30% of the surface of the scalp. Unfortunately these method are characterized by certain restrictions. First, in many cases you cannot be sure that there will be no recurrence and that the new process will affect the place after treatment. ⁵⁵

Promising results have been reported by adding 5% minoxidil to hair transplant therapy. However, neither group paid attention to the lasting effects of this type of therapy. ⁵⁶ Wang’s group ⁵⁷ evaluated the technique of synchronous transplantation of hair follicles in the treatment of scarring alopecia as consequences of burns. Transplanted hair grew well in a natural way in 96.5% of cases. The authors found that the perforation technique and synchronous transplantation of hair follicles was safe and effective. The hair transplanted into the cicatricial lesions grew well and showed a high survival rate.

Often, a sufficient form of action is covering unsightly scars by wearing a wig. This option is available and requires no large financial outlay. Also important to obtain good therapeutic results and enhance the wellbeing of the patient is support from the family and the patient’s environment as well as psychotherapy.^32,58,59

Conclusion

In this article we tried to summarize the knowledge on possible pathogenic mechanisms of cicatricial alopecia. The presented factors usually overlap and affect prognosis of particular patients. Their profound understanding may enable further research on the treatment methods of this challenging disease unit.