Alopecia Areata Incognita: Current Evidence

Abstract

Introduction

Alopecia areata incognita (AAI) represents a distinct subtype of alopecia areata (AA), characterized by profound hair shedding and diffuse thinning. Despite being initially described in 1987, AAI remains underdiagnosed, with limited published reports. This comprehensive review aims to consolidate the current evidence concerning AAI pathogenesis, clinical presentation, trichoscopic and histopathologic attributes, differential diagnoses, and available treatment modalities.

Methods

PubMed searches were performed to identify all articles discussing AAI published up to September 2024.

Results

We identified 28 articles encompassing AAI epidemiology, pathogenesis, clinical presentation, trichoscopic findings, histopathologic characteristics, diagnosis, and treatment options.

Limitations

The data primarily stem from observational studies, case reports, case series, and a pilot study. The establishment of diagnostic criteria and treatment protocols necessitates more extensive and well-controlled studies.

Conclusion

Alopecia areata incognita is a distinctive form of AA, sharing similarities with telogen effluvium (TE) and showing potential associations with androgenetic alopecia (AGA). It has an acute onset and results in sudden diffuse hair loss. While diagnostic challenges persist, combining clinical, trichoscopic, and histopathologic evaluations aids in accurate identification. AAI typically responds favorably to topical steroids and has a better prognosis than other subtypes of AA.

Key Summary Points

Alopecia areata incognita (AAI) is a subtype of alopecia areata that closely resembles acute telogen effluvium (ATE), making diagnosis challenging.

Trichoscopic findings reveal numerous round or polycyclic yellow dots, regrowing hairs, and pigtail hairs.

Diagnosis is established upon clinical, trichoscopic, and histopathologic findings. A dermoscopy-guided biopsy in an area with multiple yellow dots is highly recommended.

In cases of diffuse hair loss, clinicians should consider AAI as a potential differential diagnosis and perform a dermoscopy-guided biopsy to avoid misclassification as telogen effluvium (TE) or androgenetic alopecia (AGA).

Introduction

AAI is a non-scarring alopecia considered a subtype of AA [1]. It is characterized by diffuse thinning and severe hair shedding in the absence of classic AA patches. Due to its clinical presentation, it can be challenging to distinguish AAI from TE or diffuse AGA [2]. Since its first description by Rebora et al. in 1987, several authors have reported additional characteristics of this newly described entity [3]. Nevertheless, to date, no consensus regarding diagnostic criteria or a treatment algorithm has been established. This review aims to consolidate the current available evidence on AAI pathogenesis, clinical presentation, trichoscopic and histopathologic features, differential diagnoses, and treatment options.

Methods

A comprehensive search of PubMed/MEDLINE up to September 2024 for articles discussing alopecia areata incognita was conducted. The search encompassed MeSH terms like “alopecia areata incognita,” “alopecia areata incognito”, “alopecia areata,” “incognita,” “histopathology”, “dermoscopy,” “trichoscopy,” and “therapy.” The search yielded 34 articles, including observational studies, case reports, reviews, original articles, and letters to the editor. Articles were limited to those available in English language. The relevance of published, peer-reviewed articles was evaluated, supplemented by exploring reference lists from identified articles. Irrelevant references were excluded from consideration. In total, we identified 28 articles covering the epidemiology, pathogenesis, clinical presentation, trichoscopic findings, histopathologic characteristics, diagnosis, and treatment options of AAI (Fig. 1). This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Ethical approval was not required.

Fig. 1.

Flow diagram of study identification, inclusion and exclusion criteria

Epidemiology

The exact prevalence of AAI is unknown; however, some authors believe it is an underdiagnosed disease [4]. AAI predominantly affects women, particularly those aged 20–40, with an average age of 29.41 years [1]. Associations have emerged between AAI and positive thyroglobulin and thyroperoxidase antibodies as well as autoimmune conditions such as thyroiditis, celiac disease, and rheumatoid arthritis [1, 5]. Additionally, personal history of atopic dermatitis and lichen planus have been reported [6].

Pathogenesis

The pathogenesis of AAI has not been fully elucidated. However, as a subtype of AA, several factors such as genetic predisposition, autoimmune disease history, and environmental triggers may play a role in its development [1]. Regarding its autoimmune nature, Mofta et al. reported an upregulation of UL16-binding protein-3 (ULBP3) in patients with AAI, a marker that has been previously identified as a contributor to inflammatory cascade initiation in AA. These findings support the immunopathogenesis theory in AAI [7].

According to Rebora’s hypothesis, AAI develops when the trigger event occurs in patients who have a high percentage of telogen hairs. In classic AA, the anagen:telogen ratio is normal before disease development, and early anagen follicles are affected by abrupt damage, which translates into dystrophic anagen hair loss with typical AA patches [3]. In contrast, patients who develop AAI have a reduced anagen:telogen ratio, and the insult might be translated as a diffuse telogen hair loss [1, 3]. This hypothesis may explain the association of AAI with AGA, which has been observed in up to 73% of patients in some studies [6, 8].

Clinical Presentation

AAI predominantly emerges in young women, with patients experiencing abrupt diffuse hair loss over several weeks [5, 9]. Though diffuse in distribution, Alessandrini et al. demonstrated a predilection for the occipital and parietal regions [8]. In cases with concomitant AGA, hair thinning may be more pronounced in androgen-sensitive areas [6]. The hair pull test typically yields a strong positive result [5] (Table 1). The modified wash test, which involves washing and collecting hairs in a basin after 5 days of not shampooing, may reveal 350–800 terminal telogen hairs, occasionally accompanied by dystrophic hairs [2]. Given the time-consuming nature of the modified wash test, evaluating hair shedding through tools such as the Sinclair shedding scale or the Hair Shedding Visual scale can be beneficial in clinical practice [10, 11]. Examination of the skin, mucosa, and nails is typically normal, although nail pitting has been reported [6]. Some cases exhibit a typical AA patch together with diffuse thinning or may transition from diffuse thinning to patch formation over time. Moreover, a localized variant of AAI has been reported in the literature, known as circumscribed AAI [12–14]. Family history of AA or another autoimmune disease is often positive.

Table 1.

Summary of AAI studies including clinical presentation, trichoscopic findings and therapeutic approach

Study	Number of cases	Clinical features	Trichoscopy findings	Treatment
1. Tosti et al. [5] 2008	70 cases 58 females 12 males	Severe and diffuse hair loss (70/70) Hair thinning (70/70) Strongly positive hair pull test (70/70)	Diffuse round or polycyclic yellow dots Short regrowing hairs	Not reported
2. Molina et al. [9] 2011	1 case Female	Rapidly progressive diffuse hair loss Positive hair pull test	Yellow dots	Clobetasol under occlusion Biotin 10 mg -Hair regrowth
3. Quercetani et al. [2] 2011	39 cases Proportion male: females not specified	Hair shedding Anagen dystrophic hairs at modified wash test Typical AA patches on follow up	Not reported	Not reported
4. Park et al. [12] 2012	2 cases All females	Localized hair thinning and shedding without a bald patch “circumscribed AAI” Positive hair pull test	Broken hairs	Systemic corticosteroids Intralesional triamcinolone
5. Miteva et al. [4] 2012	46 cases All females	Acute diffuse hair loss Hair thinning Positive hair pull test Typical AA patches on follow up (6/46)	Yellow dots Short regrowing hairs	Systemic corticosteroids Topical corticosteroids under occlusion (clobetasol)
6. Ong et al. [25] 2015	1 case Female	Sudden extensive hair loss Loss of eyebrows and eyelashes Polyposis and nail abnormalities (Cronkhite-Canada Syndrome)	Not reported	Systemic prednisolone -Hair regrowth
7. Asz-Sigall et al. [13] 2016	1 case Female	Diffuse hair los and thinning Positive hair pull test	Diffuse yellow dots Hair shaft thinning	No treatment (patient rejected)
8. Moftah et al. [17] 2016	36 cases All females	Acute diffuse hair loss Hair thinning	Diffuse yellow dots Thin circular short hairs Short regrowing hairs Black dots	Not reported
9. Kinoshita-Ise et al. [14] 2018	1 case Female	Diffuse scalp hair los Positive hair pull test	Color-transition sign	No treatment -Spontaneous regrowth
10. Alessandrini et al. [8] 2019	107 cases 105 females 2 males	Diffuse hair thinning without AA patches Concomitant AGA (102/107) Positive hair pull test (32/107)	Empty yellow dots Yellow dots with vellus hairs Small regrowing hairs Pigtail hairs	Topical corticosteroids under occlusion (clobetasol) Intramuscular triamcinolone acetonide Minoxidil 2% solution
11. Pinegin et al. [26] 2021	1 case Female	Hair loss and thinning in frontal and parietal scalp Positive hair pull test	Anisotrichosis Vellus hairs Multiple yellow dots Solitary black dots	Intralesional corticosteroids Topical corticosteroids Minoxidil 5% solution -Complete regrowth
12. Starace et al [1] 2021	12 cases All females	Diffuse hair thinning (12/12) Positive hair pull test (11/12)	Empty yellow dots pattern Pigtail hairs Yellow dots with vellus hairs Short regrowing hairs	Topical immunotherapy with SABDE -Complete regrowth (8/12) -Clinical stability (3/12) -Worsened (1/12)
13. Collins et al. [10] 2022	4 cases All females	Diffuse hair shedding (Sinclair shedding scale Grade 6 = 750 hairs per day) Classic AA patches during follow-up (1/4)	Unrevealing	Intralesional scalp corticosteroid injection -Favorable response
14. Starace et al. [24] 2024	5 cases All females	Strongly positive hair pull test No further clinical findings reported	Yellow dots Short regrowing hairs Pigtail hairs Vellus hairs	Skin patting and iontophoresis in combination with topical acetonide triamcinolone -Favorable response (4/4)
15. Batrani et al. [6] 2024	30 cases 11 females 9 males	Diffuse hair thinning Acute hair loss Typical AA patches in limbs, beard and occipital scalp (3/30) Concomitant AGA (22/30) Positive hair pull test	Diffuse yellow dots Short upright regrowing hairs Vellus hairs Pigtail hairs Black dots Exclamation mark hairs	Topical corticosteroids Hydroxychloroquine Azathioprine Tofacitinib -Satisfactory response (22/30)
16. Reyes-Soto, Pirmez [14] 2024	1 case Female	Localized hair thinning in parietal scalp Strongly positive hair pull test	Yellow dots Short thin hairs Coudabililty hair	Topical clobetasol 5% topical minoxidil Oral mini-pulses of dexamethasone Oral minoxidil -(Recurrence with previous treatments) Oral tofacitinib 5 mg twice daily -Complete response

Trichoscopy

Trichoscopy is a valuable tool for assessing AAI; however, its effectiveness is highly dependent on the clinician's expertise and proper training. Trichoscopic examination shows numerous round or polycyclic yellow dots, which are diffuse all over the scalp regions and not just limited to the frontal scalp. It also shows regrowing tapered terminal hairs of normal thickness. The presence of numerous circle/pigtail hairs is also highly suggestive of the diagnosis (Fig. 2). These features may be associated with hair shaft variability in cases of concomitant AGA [5]. Additional findings include short vellus hairs and, less frequently, black dots or broken hairs as wellas pili torti [1, 5, 8, 15, 16]. Inui et al. reported a diagnostic sensitivity of 96% for AAI in the presence of yellow dots or short hairs in regrowth [15]. Furthermore, the color transition sign, indicative of a color shift along the hair shaft, may aid in distinguishing AAI from ATE [17].

Fig. 2.

A, B Trichoscopic examination of AAI. Note the round yellow dots (black asterisks), short regrowing hairs (red arrows), black dots (red asterisk), and color transition sign (blue arrows) consistent with AAI

Histopathology

Histopathologic features in AAI are different from classical AA. Scalp biopsies reveal subtle lymphocytic infiltrates surrounding terminal hair bulbs [2, 5, 18]. Follicular units are preserved, yet terminal follicles, particularly in anagen, are decreased. Other findings include an increased number of telogen germinal units, vellus hair follicles, and miniaturized follicles [4, 7, 8]. Additionally, the anagen-telogen and terminal-vellus ratios are inverted and may be the only evidence in long-standing disease [5, 9]. A characteristic histologic finding is the presence of dilated infundibular ostia, either empty or filled with sebum and/or keratin, which corresponds to the yellow dots seen on trichoscopy [4–6, 8]. The number of vellus hair follicles and miniaturized follicles is also increased [8]. Moreover, a high percentage of nanogen hairs has been recently reported as a common finding [6]. Since histopathologic findings might be subtle, dermatologists should always provide sufficient clinical information to the dermatopathologist. A proper clinicopathologic correlation is mandatory for AAI diagnosis.

An additional emergent confirmatory test could include the determination of ULBP3 in scalp tissue [6]. ULBP3 is a natural killer cell ligand, and under normal conditions, is absent or low in the hair follicle because of its immunologic privilege. However, high expression of ULBP3 in the dermal sheath and dermal papilla has been previously linked to the initiation of the immune response in AA [7, 9].

Diagnosis

AAI diagnosis is based on the clinical, trichoscopic, and histopathologic findings, as previously described. We recommend a dermoscopy-guided biopsy in an area that shows multiple yellow dots.

Differential Diagnosis

AAI differential diagnoses include common causes of diffuse hair loss: ATE, diffuse AGA, and diffuse alopecia areata (DAA) (Table 2). ATE manifests as diffuse hair shedding 3 months after a noxious event, and in severe cases it can produce a diffuse alopecia with poor scalp coverage. Clinical history aids in event identification [19]. Hair pull tests yield positive results, and trichodynia is a possible symptom [18]. Trichoscopy typically reveals upright regrowing hairs. ATE as AAI is commonly associated with androgenetic alopecia. Trichoscopy might not be specific enough to establish diagnosis if the history is not clear [19, 20].

Table 2.

Summary of AAI findings and comparisons with differential diagnoses of DAA, ATE, CTE, and AGA

*Trigger: COVID-19 infection, iron deficiency, medications, postpartum, fever, thyroid disease, vitamin D deficiency, etc.

Δ Association AGA + AI

Distinguishing AAI from diffuse AGA can be challenging since they often coexist [8]. On clinical examination, diffuse AGA may not be easily distinguishable from AAI [18]. However, a history of chronic hair loss with an acute sudden exacerbation suggests AAI in a patient with AGA. Trichoscopy features of AGA include hair shaft diameter variability (with > 20% anisotrichosis), vellus hairs, single-hair follicular units, yellow dots, and reduced hair density—all of which are also observable in AAI [21]. However, in AAI, yellow dots are numerous all over the scalp, not just in the frontal scalp, and the association of multiple diffuse yellow dots with numerous circle/pigtail hairs is highly suggestive.

Discerning between AAI and DAA relies on pull test and trichoscopy. DAA entails acute diffuse anagen effluvium with dystrophic hair roots on the pull test and distinctive exclamation mark hairs and broken hair patterns on trichoscopy. DAA potentially extends to other regions like the eyebrows and often progresses to alopecia totalis, whereas AAI does not [22]. Alessandrini et al. reported DAA's predilection for parietal and anterior-temporal regions. Common trichoscopic features shared between AAI and DAA include empty yellow dots, yellow dots with vellus hairs, and small regrowing hairs. However, black dots and dystrophic hairs are more common in DAA [8]. Histopathology is similar between the two entities. Nonetheless, a greater number of telogen hairs, smaller number of terminal follicles in anagen, and lower number of miniaturized follicles have been reported in DAA. The typical swarm of bees infiltrate might be present, as it is a manifestation of acute disease [8].

As previously mentioned, ULBP3 can also be a useful marker for the diagnosis of AAI [7].

Treatment and Prognosis

Presently, there is no consensus on AAI-specific treatments. Nonetheless, evidence suggests AAI's favorable prognosis due to a limited progression to alopecia universalis or totalis and positive responses to potent topical steroids [4, 8]. High-potency topical steroids, particularly clobetasol 0.05% cream under occlusion three times weekly, represent a first-line intervention, yielding a 73.8% improvement rate within 4 months [8, 23]. Intralesional steroids, administered at a dose of 5 mg/ml, have been shown to be another valuable therapy, particularly in women [10]. In severe cases, pulse systemic steroids (40 mg intramuscular triamcinolone acetonide monthly) with a gradual taper over a 6-month period may be used [4, 8]. Supplementary topical or low-dose oral minoxidil may stimulate hair regrowth [1, 7]. Recently, skin patting and iontophoresis in combination with triamcinolone acetonide gel has been reported as an additional effective and safe treatment option [24]. Although benign in its course, certain AAI cases may be recalcitrant to standard therapy. In such circumstances, squaric acid dibutyl ester (SADBE) topical immunotherapy may offer promise [1] (Fig. 3). A recent study showed complete regrowth in up to 66.7% of subjects who failed other first-line treatments like steroid therapy [1]. There is scarce evidence regarding the efficacy of Janus kinase (JAK) inhibitors on AAI, but in the authors' experience they are effective. A recent report described successful use of oral tofacitinib (5 mg twice daily) in relapsing circumscribed AAI. [14]. Future studies evaluating the efficacy of oral JAK inhibitors in less severe forms of AA are needed, as they may be a potential therapy for AAI patients who have failed conventional treatment. However, these patients might be difficult to include in clinical trials because of challenges in establishing a severity score and possible association with AGA.

Fig. 3.

Proposed treatment algorithm for AAI

Conclusion

AAI is a variant of AA that mimics ATE. Dermatologists should be aware of this condition when patients present with sudden diffuse hair loss and severe thinning. Timely intervention is crucial, as untreated AAI may progress to chronicity. Prevalent among females aged 20 to 40, AAI's trichoscopy findings of numerous yellow dots, pigtail hairs, and short regrowing hairs aid in diagnosis. Although histopathologic features might be subtle, a dermoscopy-guided biopsy is mandatory as it solidifies diagnosis. Providing sufficient clinical data to the dermatopathologist is necessary to properly asses AAI histologic findings. While generally benign, AAI often displays a favorable response to topical steroids.

Author Contribution

Giselle Rodriguez Tamez and Antonella Tosti conceived the review idea. Giselle Rodrigues Tamez and Narges Maskan Bermudez performed the literature search and collected the data. Antonella Tosti supervised the project. All authors contributed in writing the manuscript. All authors provided critical feedback and helped reviewing and editing the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article.

Declarations

Conflicts of interest

Antonella Tosti is a consultant for DS Laboratories, Almirall, Thirty Madison, Eli Lilly, Bristol Myers Squibb, P&G, Pfizer, Myovant, Ortho Dermatologics and Sun Pharmaceuticals. Antonella Tosti is an Editorial Board member of Dermatology and Therapy. Antonella Tosti was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Giselle Rodriguez Tamaz and Narges Maskan Bermudez have no conflicts to declare.

Ethical approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Ethical approval was not required.