Peculiarities of clinical course and diagnostic of alopecia areata with comorbidity. Clinical observations

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INTRODUCTION
The main cause of hair loss is alopecia, most often (86% of cases) they are recorded at the age of 6-15 years, while alopecia areata accounts for 89% of cases. Alopecia areata (GA) in the general structure of skin pathology is from 0.7 to 3.8% (in the population, the indicators are 1: 1000) with the risk of developing the disease during life in 1.7%. It is possible that the true incidence of the disease is higher, because mild cases of baldness can go unnoticed, or (relatively quickly) end in spontaneous healing [1-7]. There are no gender differences in the incidence of GA in men and women, most often baldness develops at the age of 15-30 and less often in older age categories [1, 4, 6, 7]. Alopecia areata (alopecia areata) is an acquired non-scarring alopecia that often begins with (mostly) rounded patches of alopecia on the scalp and affects any other area of ​​the skin. Morphologically, in GA, formed peribulbar lymphocytic infiltrates are determined [1]. In accordance with the ICD of the 10th revision, there are 4 forms of GA: total alopecia (L 63.0), universal (L 63.1), alopecia areata (ribbon-like) (L 63.2), other alopecia areata (L 63.8), unspecified alopecia areata (L 63.9) [4.7]. The manifestations of GA depend on the clinical forms: local - one or more foci of alopecia appear; subtotal - more than 40% of hair is missing; total - characterized by a complete lack of hair. They also distinguish: multifocal alopecia, ophiasis (ribbon-like lesion along the hairline in the occipital and temporal regions), inverse ophiasis-sicapho (spreading along the hair growth zone to the fronto-parietal and temporal regions), diffuse alopecia (with partial or complete hair thinning scalp), total baldness (with complete loss of terminal hairs on the scalp), universal shape (no hair on the scalp, in the eyebrows, eyelashes and trunk skin). Severe forms of HA include baldness with a lesion of 50% or more of the area of ​​the scalp - a total and universal variety. During GA, there are 3 stages: active (progressive or progressive), stationary and regressive. In the active stage, there are no subjective symptoms (rarely - itching, burning or pain in the foci), areas of non-scarring baldness of rounded or oval outlines appear, with unchanged skin (rarely - in the foci, the skin is pink-red or peach in color). Characterized by the presence of proximally narrowed and distally located "wide" hair in the form of an exclamation mark, located in the focus or along its periphery. At the borders of HA foci the test for "hair tension" is positive, and along the periphery, a zone of "loose" hair 0.5 - 1 cm wide is determined. At the initial stage, only pigmented hair is affected. In the stationary stage, the skin in the focus is of normal color, the area of ​​"loose" hair is not determined. In the regressive stage, the growth of velus (depigmented vellus hair) and partial growth of terminal (pigmented) hair are noted in the HA focus. In dynamics, their gradual pigmentation occurs: from hypopigmentation at the beginning of the process, to complete restoration of color during clinical cure [1-9].
With GA, degenerative changes in the nail plates can be observed (in 7 - 66% of patients, according to other sources - in 35% of children): point dystrophy, "BO lines", onychorexis, thinning or thickening of the nail plates, onychomadesis, koilonychia, point and transverse leukonychia , red spotted lunulae [1-7.9]. The large scatter of data on the frequency of occurrence and clinical forms of altered nail plates casts doubt on the specificity of these lesions [1-7, 10], but indicates a combination of GA and onychodystrophy. The course of GA is more often chronic, recurrent (more than one episode of GA was found in 85% of patients), but spontaneous remission without treatment is possible in 50% of patients. With manifestations of GA before puberty, there is a high probability of developing a total form of the disease (up to 50%). The probability of a complete cure in severe forms of alopecia is less than 10% of cases. The risks of an unfavorable course and prognosis include: a burdened family history, an early onset of the disease, a prolonged course of HA, a large lesion area, changes in the nail plates, the presence of concomitant atopy and other autoimmune conditions [1-7].
The study of the reasons for the development and mechanisms of the pathogenesis of HA indicate a pronounced role of neurotrophic disorders, autoimmune and genetic factors, endocrine diseases and injuries. In this regard, it is of great interest to study the correlation between the quantitative level of vitamin D and the occurrence of HA, with the inclusion of autoimmune mechanisms [1-4]. There was a high correlation (10-42%) between alopecia areata and a burdened family history [1-3, 5, 10].At the same time, human leukocyte antigen-DR (HLA-DR) on chromosome 6 is the main risk factor for the development of HA, and the HLA class II genes are closely associated with CD4 + and CD8 + T cells, which play a significant role in the development of the disease. This mechanism also involves BCL2-like protein 11 (also known as BIM), which is involved in the regulation of autophagy processes. Genes encoding natural killer T cell receptor ligands and downstream JAK effector pathways also influence the development of HA [1-4, 6, 7, 9, 11-15]. The data obtained made it possible to formulate the definition of alopecia areata, taking into account the mechanisms of pathogenesis - it is a chronic organ-specific autoimmune inflammatory disease with a genetic predisposition, characterized by damage to hair follicles and sometimes nail plates (in 7 -66% of patients), persistent or temporary non-scarring hair loss [1, 2] ... Patients with GA have a high level of mental (more often anxiety-depressive) disorders, thyroid diseases occur in 8-28% of patients (without a correlation between the severity of baldness and the level of thyroid antibodies). Combinations with various forms of anemia (pernicious and hemolytic), rheumatoid arthritis, Cronkite-Canada syndromes (lentiginosis with gastrointestinal polyposis, alopecia and nail dystrophy), Down and Shereshevsky-Turner (appearance of the "small nails" sign), celiac disease, vitamin D deficiency are described [1-5, 14, 16-23]. Celiac disease in patients with autoimmune diseases (occurs 3-10 times more often than in the population) may be associated with the common genotype HLA-DQ2 (DQA1 * 0501 and DQB1 * 0201) [22, 23]. The most common cause of the onset of alopecia areata is stress [5, 6, 10, 21]. Elevated levels of adrenocorticotropic hormone and cortisol correlate with high levels of proinflammatory cytokines in the skin, which may play a potential role in psychological and physiological stress triggers in the onset of HA. Other provoking factors include: vaccination, past viral infections (including HIV infection, and more recently the new coronavirus infection SARS-CoV2), as well as hypoparathyroidism and diabetes mellitus [2, 4, 6, 17, 18, 21, 24-26].
With GA, comorbid conditions on the skin associated with the presence of other diseases are possible: systemic lupus erythematosus - in 3.5%, psoriasis - in 1.8%, vitiligo, atopic dermatitis, etc. population, so, with vitiligo occurs in 3-8% of patients, and with atopy - 2 times more often (3.5%) [2, 4, 6, 7, 9, 16, 17, 19, 25, 26]. It is known that comorbid conditions will complicate the diagnosis and treatment of the underlying disease and concomitant dermatoses. This determines the need for a clear delineation of treatment and diagnostic approaches, based on their reliable significance, which will eliminate unnecessary or outdated measures [1, 2, 4, 6, 7, 16, 25-30].

Description of clinical cases.
We present 2 clinical cases of alopecia areata in patients with anemia and celiac disease, as well as the development of GA after coronavirus infection (SARS - CoV2) in a patient with iron deficiency anemia and autoimmune thyroiditis.
Clinical case 1.
We observed a child from the age of 1 year, with a diagnosis of alopecia areata, progressive stage, subtotal form, onychodystrophy. Concomitant diagnoses: grade I iron deficiency anemia. Celiac disease, typical form. Chronic gastritis, atrophic duodenitis. Reactive pancreatitis.
Medical history. A woman with child “A” at the age of 1 year applied to the pediatrician of the Tver Regional Children's Hospital (CSTO), complaining of slow growth of the child, the appearance of frequent and profuse bowel movements, bloating, and during the last 2 months - hair loss ... The first to appear was a focus of alopecia in the temporal region, after 2-3 weeks the process acquired a multiple character. At the beginning of the disease, the foci rapidly increased in size, and after 2-3 weeks, the growth slowed down. After a clinical examination by a pediatrician, a gastroenterologist at the Tver Regional Children's Clinical Hospital and employees of the Department of Dermatovenereology with a course of cosmetology at the Tver State Medical University (head of the department, Professor Dubensky V.V.), as well as a number of laboratory, functional and morphological studies (clinical analysis of peripheral blood, genetic and serological tests, EGDS, ultrasound, dermatoscopy of the skin and nail plates, histological examination of a biopsy specimen of the duodenal mucosa) diagnosed with alopecia areata (subtotal form, progressive stage). Onychodystrophy. Concomitant diagnoses: iron deficiency anemia, I degree. Celiac disease, typical form. Chronic gastritis, atrophic duodenitis. Reactive pancreatitis.
Dermatological status. The skin is pale, with an earthy tinge. The process is localized on the surface of the entire scalp, captures the temporal, parietal, occipital regions, while preserving hair along the zone of their growth on the skin of the frontal and temporal regions. The skin in the lesions is not changed, flesh-colored, in the absence of the pink component, it corresponds to the general skin color of the face (Fig. 1-a). A positive test for "hair tension" is noted, along the periphery, with a width of 0.5 to 1 cm, an area of ​​loose hair is placed. The nail plates of all fingers of both hands are pink, with a strip-like longitudinal striation and pronounced “thimble-like” impressions. Minor subungual hyperkeratosis.
Results of physical, laboratory and instrumental research. The clinical blood test met the diagnostic criteria for iron deficiency anemia (IDA) in children (CP <0.85; MCH <26 pg / cell, erythrocyte microcytosis - MCV <80 fl; normoregeneration). Conclusion: WA I degree. Serological tests for the diagnosis of celiac disease were negative (IgA, IgG to tissue transglutaminase, IgA, IgG to gliadin). Based on HLA typing, genes for celiac disease susceptibility were found - locus DQ2, DQ8. Ultrasound of the abdominal organs: dyscholia, reactive changes in the pancreas, pancreatopathy. According to EGDS: superficial gastritis, atrophic duodenitis. Histological examination of the duodenal mucosa: the mucosa is thinned, the crypts are expanded and flattened; the villi are shortened, the epithelium is mature, the number of mucus-forming cells is reduced; edematous lamina propria with diffuse infiltration of lymphocytes. Conclusion: Chronic gastritis, duodenitis. Celiac disease, typical form.
Dermatoscopy: in the foci of alopecia on the scalp, there are “black dots” and hair in the form of an “exclamation mark” (Fig. 1-b). When examining the nail plates of the fingers of the hands, dystrophic changes of the "thimble" type were found. Fungi were not detected during cultural examination of fragments of the nail plates.
Treatment. Taking into account the presence of combined diseases of the internal organs, hematopoietic system and skin of the child, the treatment was prescribed by a commission, at an interdisciplinary council: a dermatologist, a gastroenterologist and a pediatrician. For alopecia areata, external use of a topical steroid (Methylprednisolone aceponate) was prescribed, in the form of an ointment of 0.1% (registration number: P013 563/03 from 06.07.11. Date of re-registration: 18.08.20) until complete hair regrowth. In the treatment of celiac disease, anemia and gastrointestinal diseases, a gluten-free diet was used, and the intake of iron preparations, probiotics, enzymes, and vitamins was used in accordance with clinical guidelines [22, 23].
Exodus. During the 2nd year of life, hair growth in the foci of baldness was fully restored. Initially, the hair was non-pigmented (velus), then gradual repigmentation took place. Observations during 2-3 years of life confirmed a stable clinical cure (Fig. 1-c). However, the changes in the nail plates of the fingers of the hands of the “thimble” type were preserved (Fig. 1-d). Against the background of a gluten-free diet (in the first 2-4 months), clinical symptoms of celiac disease were arrested, and by the end of 2 years of life - clinical and laboratory.

Clinical case 2.
Patient I, 24 years old, has been under our supervision since November 2020. Main diagnosis: Alopecia areata, progressive stage, universal form. Concomitant diagnosis: grade I iron deficiency anemia. Autoimmune thyroiditis. Condition after suffering coronavirus infection SARS-Co V2, hypovitaminosis D.
Medical history.
For the first time with complaints of hair loss (up to 300-400 per day) (Fig. 2-a) she turned to a dermatovenerologist in December 2020, then the disease progressed and within 1 month there was a complete loss of hair on the scalp, trunk, limbs , armpits, pubis, as well as loss of eyelashes and part of the eyebrows. 1 month before that there was a period with severe headaches and muscle pains, weakness, malaise, a slight increase in body temperature. During the same period, the patient's husband suffered from SARS-CoV2 coronavirus infection (laboratory confirmed). The patient herself was not examined for infection. For several years, patient "I" has been suffering from autoimmune thyroiditis and is receiving treatment prescribed by an endocrinologist.
Dermatological status. The skin is pale, there is no pink component in its color. The balding process covers the entire scalp, completely eyelashes, there is a diffuse thinning of the eyebrows, hair in the armpits on the skin of the trunk, upper and lower extremities and in the pubic area is completely absent (Fig. 2-b). The nail plates of the fingers of the hands have a cyanotic shade, are somewhat thinned, brittle, a pronounced longitudinal striation is determined on the surface. There are three white superficial transverse grooves (Bo lines) on the nail plates of the toes. The surface of the plates is tuberous, the distal edge is uneven.
The results of physical, laboratory and instrumental studies (11.2020 g). Clinical blood test: l - 12.6 × 109 / l, e - 4.85 × 1012 / l, HB -9.7 g / dl, lymph. - 12.9% (1.64x109 / l), m - 2.9% (0.37x109 / l), ESR - 23 mm / hour. Biochemical studies: glucose - 5.87 mmol / l; AST - 64.90 units / l; ALT - 109.1 units / l; total protein - 56.07 mg / l; T3 light - 3.34 pmol / l; T4 St. - 8.32 pmol / l; TSH - 0.07 μIU / ml. Antinuclear factor on HEp-2 cells is positive (titer 640), IgG antibodies to RBD domain S 1 of the SARS-CoV2 coronavirus protein (201.6 BAU / ml) were detected. Abdominal ultrasound: signs of a slight sediment in the gallbladder. Deformation of the gallbladder. Right-sided nephroptosis. Ultrasound of the thyroid gland: signs of chronic autoimmune thyroiditis. EGDS: gastroesophageal reflux disease, catarrhal esophagitis. Erosive gastritis. Superficial bulbitis, exacerbation. Endocrinologist: autoimmune thyroiditis. Therapist: Gastroesophageal reflux. Esophagitis. Iron deficiency anemia, stage I Transferred SARS CoV2.
Dermatoscopy: "yellow" and "black dots", hair in the form of an exclamation mark were found in the foci of alopecia in the area of ​​the scalp, forearms, armpits and pubis. The nail plates of the fingers of the hands have a degenerative character with thinning, cyanotic color and longitudinal striation. On the nail plates of the toes, there are three superficial transverse grooves, white, with bumpy edges (Bo lines). During the cultural study of fragments of the nail plates, there is no growth of fungi.
Treatment. Based on the results of a consultation with a therapist, endocrinologist and dermatologist, therapy was prescribed for thyroid diseases and anemia. Treatment of alopecia areata was carried out according to the Federal Clinical Recommendations: prednisolone at a dosage of 40 mg / day with a gradual decrease in the daily dose as it improves, external anti-inflammatory therapy with 0.05% clobetasol propionate cream in combination with 5% minoxidil twice a day for three months. It is recommended to use 5% minoxidil as a stimulant until hair regrowth [4, 7].
Exodus. During 3 months of systemic hormone therapy with corticosteroids, active hair growth was noted, at the beginning - unpigmented, later pigmented, with complete restoration of the hairline in all areas. A certain sequence of hair regrowth is noted: at the beginning - on the scalp, then - in the armpits and pubis, and later - on the eyebrows and eyelashes (Fig. 2-c). The color of the nail plates of the fingers of the hands changed to pink, the fragility of the nail plates decreased, but the longitudinal striation on the hands and Bo's lines on the feet remained (Fig. 2- d 1.2). By the 6th month from the start of treatment, it was possible to achieve a correction of the hematological parameters of anemia and a decrease in the activity of thyroiditis; against this background, the hairline was completely restored (Fig. 2-e).

Discussion. In the literature, there is a significant divergence of opinions on the causes of occurrence, factors of pathogenesis and even on the frequency of occurrence of HA, as well as a number of its clinical manifestations (in particular, damage to the nail plates). At the same time, data on the frequency and age of onset do not meet the requirements of evidence-based medicine and are based, as a rule, on individual clinical cases and observations [1, 2, 4-7]. If the views of the researchers coincide with respect to the clinical forms and the main manifestations of HA, then regarding the lesion of the nail plates there are completely different opinions: "... are affected in all," "... some of the patients" or "... sometimes" the incidence of damage varies from 6 to 77%, which is indicated in the definition of the disease in the Federal clinical guidelines [4, 7]. In the available literature, various clinical forms of damage to the nail plates in HA are given without statistical data and correlations. On this basis, we can conclude about the combination of onychodystrophy and GA, but not about the specificity of the pathology of the nail plates, because there are about ten types of degenerative changes.
With regard to trigger factors or comorbid conditions in GA, there are also various data [1, 2, 4-7, 9, 14, 17-21, 23-26]. The results of our own observations of 6 patients with GA (2 - children, 4 - adults -1 man and 3 women), revealed the presence of iron deficiency anemia and thyroiditis in all patients. Of the other diseases, they were also diagnosed with celiac disease, chronic gastrointestinal diseases, and postcoid syndrome. Treatment of concomitant pathology and GA leads to the restoration of the hairline with the normalization of hematological parameters and the state of the thyroid gland. There is a certain analogy in the incidence of anemia in patients receiving chemotherapy for malignant neoplasms and their subsequent development of total or subtotal diffuse toxic alopecia. In these cases, anemia is more often of a transient nature; completion of chemotherapy and correction of hematological parameters correlate with hair regrowth.
There are also different views on the diagnosis of GA. So, in the Federal clinical guidelines, rather extensive clinical and laboratory studies are proposed concerning both the direct process of baldness and the general condition of organs and systems. However, there are other opinions, in particular foreign experts, who believe that the diagnosis of HA can be made by a competent dermatologist on the basis of characteristic data of anamnesis and clinical manifestations (including symptoms). Additional objective studies, for example, a diagnostic biopsy, are required in 1 patient out of 400. Trichograms, consultations with other specialists, biochemical and hormonal studies are also considered superfluous. This is justified by their inconclusiveness, when the requirements of evidence-based medicine are applied to them [1, 2].
We believe it is important for the diagnosis of GA to clearly distinguish between the main diagnostic methods and additional ones. At the same time, the main methods include: data from anamnesis, objective clinical examination, dermatoscopy of hair and nail plates. Additional - morphological examination of biopsy, clinical and biochemical blood tests, including enzymatic activity of the liver, levels of vitamin D, serum iron, ferritin, thyroid hormones; determination of antinuclear factor, serological reactions to syphilis, microscopic and cultural methods for the diagnosis of dermatophytosis. The amount of additional research is determined individually. At the same time, morphological studies confirm the main diagnosis, studies for syphilis - for differential diagnosis with syphilitic baldness, for fungi - with dermatophytosis, morphological - to exclude cicatricial alopecia; hematological parameters are necessary to identify concomitant comorbid conditions and when prescribing immunosuppressive therapy for GA.
Conclusion. The presented literature data and the results of our own observations of GA indicate possible comorbid conditions: anemia, thyroiditis, chronic gastrointestinal diseases, celiac disease, postcoid syndrome. Proceeding from this, when examining patients with HA, it is necessary to use not only basic, but also additional diagnostic methods, with the help of which it is possible to identify concomitant diseases and to reasonably safely prescribe immunosuppressive therapy. The main manifestations of GA are described quite fully in the literature and are objectively regulated by clinical and statistical classifications. However, the frequency of occurrence and features of damage to the nail plates in HA raise doubts about the reliability of the available data. The existing variety of forms of onychodystrophies does not allow identifying specific lesions of the nail plates in HA, and statistically does not meet the criteria of evidence-based medicine and requires further study.
Contribution of authors. Dubensky Valery Viktorovich - creation of a concept for the study and design of clinical cases, writing an article and making amendments to the manuscript in order to increase the scientific value of the article, approving the final manuscript, agreeing to be responsible for all aspects of the work. Elizaveta Georgievna Nekrasova - obtaining, analyzing data, interpreting the results, writing one of the sections of the article, approving the final manuscript, agreeing to be responsible for all aspects of the work.
Patient consent. Patients voluntarily signed an informed consent for the publication of personal medical information in anonymized form in the Russian Journal of Skin and Venereal Diseases.

Captions under the drawings to the article

Pig. 1.

a - patient A., 10 months. Alopecia areata, subtotal form, progressive stage. Hair loss on the scalp. Thinning of eyebrows.

b -the same patient. Dermatoscopy: presence of «black dots» and hair in the form of an "exclamation mark" within the hair follicles.

c- the same patient. Clinical recovery. Restoration of hair growth on the scalp, eyebrows, eyelashes at the age of 3 years.

d -the same patient. Deformation of the finger nail plates in the form of a "thimble" at the age of 3 years.

Pig. 2.

a - patient I., 24 years old. Alopecia areata, progressive stage, universal form. Hair loss every day.

b - the same patient. Total hair loss in the scalp, eyebrows, eyelashes, armpits.

c - the same patient. Restoration of hair growth on the scalp and eyebrows after 3 months.

d-1- the same patient. Longitudinal grooves on the nail plate of the second finger of the left hand.

d-2- the same patient. Transverse grooves (Bo lines) of the nail plate of the first toe of the left foot.

e - the same patient. Restoration of hair growth on the scalp, in the area of ​​eyebrows and eyelashes after 6 months.

About the authors

Valeriy V. Dubenskiy

Tver State Medical University

Author for correspondence.
Email: valerydubensky@yandex.ru
ORCID iD: 0000-0002-1671-461X
SPIN-code: 3577-7335

MD, Dr. Sci. (Med.), Professor

Russian Federation, 4, Sovetskaya st., Tver’, 170642

Elizaveta G. Nekrasova

Tver State Medical University

Email: nekrasova-7@mail.ru
ORCID iD: 0000-0002-2805-6749
SPIN-code: 5831-5824

MD, Cand. Sci. (Med.), Associate Professor

Russian Federation, 4, Sovetskaya st., Tver’, 170642

References

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