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ORIGINAL ARTICLE
Year : 2021 | Volume
: 41
| Issue : 2 | Page : 83-90
Serum level of interleukin-17A in patients with alopecia areata and its relationship to age of patients and disease recurrence
Khaled Gharib, Ayman Elsayed
Department of Dermatology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
Correspondence Address:
MD Khaled Gharib
Department of Dermatology, Faculty of Medicine, Zagazig University, Zagazig, 44681
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ejdv.ejdv_24_20
Introduction Alopecia areata (AA) is a relatively common reversible patchy hair loss of the scalp. It is usually manifested as patchy areas of complete hair loss on the scalp and sometimes with or without other body parts that can progress to complete loss of all body hair. This disorder affects all age groups, with a higher incidence in children and adolescents. AA is an autoimmune disorder characterized by hair cycle dysfunction with peribulbar and perifollicular mononuclear cell infiltrates.
Aim To estimate interleukin-17A (IL-17A) serum level in patients with AA as well as study its relationship with the age of the patients, severity, and recurrence of disease.
Patients and method s The study was carried out in Outpatient Clinic of Dermatology, Venerology, and Andrology Department, Zagazig University Hospitals, on 45 patients with AA of both sexes. Results were compared with 45 healthy participants with matched age (5–50 years).
Results The present study included two groups: patient group included 45 patients diagnosed clinically with AA and control group included 45 age-matched and sex-matched healthy individuals.
Conclusion The significantly higher levels of serum IL-17A in patients with AA suggest a possible role of IL-17A as a proinflammatory cytokine in the pathogenesis of AA and that IL-17A level may be influenced by age and disease recurrence in patients with AA.
Keywords: alopecia areata, interleukin-17A, patchy hair loss
Alopecia areata (AA) is a relatively common reversible hair loss disorder. It is usually manifested as patchy areas of complete hair loss on the scalp and other body parts that can progress to complete body hair loss. All age groups could be affected, with a higher prevalence in children and adolescents. The etiology of AA is an autoimmune disorder characterized by hair cycle dysfunction and presence of peribulbar and perifollicular mononuclear cell infiltrates [1].
Many theories have postulated in the pathogenesis of AA. So AA is a multifactorial disorder, sometimes associated with other autoimmune diseases, for example, vitiligo, atopic dermatitis, and autoimmune thyroid disease [2].
Interleukin-17A (IL-17A) is called cytotoxic T-lymphocyte-associated protein 8. It was identified as a cytokine expressed by T cells, exerting effects on epithelial, endothelial, and fibroblast cells [3].
IL-17A is a Th17 proinflammatory cytokine that has been linked to the pathogenesis of diverse autoimmune and inflammatory diseases [4].
IL-17 is the key product of Th17 cells; thus, findings confirm an upregulated Th17 profile in patients with AA. Th17 cells are considered to be pathogenic forms of CD4+ T cells driven by IL-23. In addition to IL-17, Th17 cells produce IL-6 and tumor necrosis factor upon antigen-specific stimulation. These cytokines are essential for the establishment of organ-specific inflammation associated with autoimmunity [4].
AimThe aim was to measure serum IL-17A level in patients with AA and study its relationship with the age of the patients, the severity, and the recurrence of the disease.
Patients and methodsThe study was carried out in the outpatient clinic of the Department of Dermatology, Venerology, and Andrology, Zagazig University Hospitals. A total of 90 participants of both sexes were included: 45 patients with AA and 45 healthy participants as a control group; both groups were matched regarding ages, which ranged between 5 and 50 years.
This was a case–control study done during the period from March 2017 to March 2018 after approval of Institutional Review Board (IRB) (Zu-IRB-3317-22-1-207), and a written informed consent was taken from all patients and controls or from their parents before start of the study.
The patients with AA were classified into two subgroups:
Nonrecurrent cases: 23 patients with AA who did not receive any treatment before.Recurrent cases: 22 patients with recurrent AA after treatment.Acute disease was considered if the duration of AA was less than 6 months and chronic disease if the duration of AA was more than or equal to 6 months [5].
Patients aged less than 16 years at the time of disease onset are considered to have juvenile-onset AA, and those aged more than or equal to 16 years at disease onset are considered to have maturity-onset AA [5].
Inclusion criteria
The following were the inclusion criteria:
Patients with AA not receiving any treatment before.Age ranging from 5 to 50 years.Both sexes.Patients with recurrent alopecia after treatment.Exclusion criteria
The following were the exclusion criteria:
Associated autoimmune, inflammatory, or allergic diseases and asthma.Immunosuppressive drug intake.All patients were subjected to the following:
Complete history taking, which included the following:
Personal history: name, age, sex, and residence.Family history of AA or related autoimmune, inflammatory, or allergic diseases and asthma.Complaint: lesion(s) of hair loss.History of the present illness: analysis of the complaint; onset, duration, and course, as well as location and number.Past history: it included history of surgery, fever, illness, stress, anemia, and autoimmune diseases.History of drug intake, irradiation, chemotherapy, history of previous treatment (e.g. Minoxidil hydrochloride), or history of allergy to previous treatment.General examination
General and medical examinations of the body systems were done to discover predisposing factors and associated medical conditions.
Detailed dermatological examination included the following:
Dermatological examination of the lesion(s) of hair loss: site, size, and number (solitary or multiple).Dermatological examination of scalp skin, eye brows, eye lashes, as well as facial and body hair.Clinical assessment of the degree of alopecia areata
National Alopecia Areata Foundation working committee has devised ‘Severity of Alopecia Tool score’ (SALT score). Scalp is divided into four areas, namely, vertex − 40% (0.4) of scalp surface area; right profile of scalp − 18% (0.18) of scalp surface area; left profile of scalp − 18% (0.18) of scalp surface area; and posterior aspect of scalp − 24% (0.24) of scalp surface area. Percentage of hair loss in any of these areas is the percentage of hair loss multiplied by percent surface area of the scalp in that area. SALT score is the sum of percentage of hair loss in all aforementioned areas.
The extent of scalp hair loss was determined by alopecia SALT score as follows:
S, scalp hair loss.S0, no hair loss.S1, less than or equal to 25% hair loss.S2, 25–49% hair loss.S3, 50–74% hair loss.S4, 75–99% hair loss.S4a, 75–95% hair loss.S4b, 96–99% hair loss and S5, 100% hair loss.Classifications of patients
Patients were classified regarding the severity of AA according to SALT score into the following:
Mild AA: patients who were S1 (<25% hair loss).Moderate AA: patients who were S2 (25–49% hair loss).Severe AA: patients who were S3, S4, and S5 (>50% hair loss).Measurement of serum interleukin-17A
Blood samples of 3 ml were collected in BD Vacutainer Plus plastic blood collection tubes (Becton Dickinson & Co., Franklin Lakes, New Jersey, USA). Samples were left to clot for 30 min at room temperature before they were centrifuged for 15 min at ∼1000 g. Serum was then separated using a sterile pipette and stored at −20°C until the time of assay.
Repeated freeze–thaw cycles were avoided. On the day of assay, samples and reagents were brought to room temperature, and concentrations of IL-17A were assayed in patients and controls using the Human IL-17A ELISA Kit. Samples were assayed according to the manufacturer’s protocol. Absorbance was measured at 450 nm. A standard curve was prepared from seven human IL-17A standard dilutions, and serum IL-17A concentrations in samples were determined.
ResultsA total of 45 patients complaining of AA of the scalp with body involvement in one case and 45 healthy controls of matched age and sex were included in the two groups of the present study.
The patient group was subdivided into two groups according to the recurrence of the disease: recurrent cases and nonrecurrent cases. Their ages ranged from 5 to 50 years. The mean±SD ages of patients and controls were 30.11±9.79 and 24.71±10.65 years, respectively. There was no significant difference between the groups regarding age (P=0.075).
According to SALT score, the severity of AA was as follows: 25 (55.6%) patients had S1 (hair loss<25%), 18 (40%) patients had moderate disease, one (2.2%) patient presented with alopecia universalis, and one (2.2%) patient presented with ophiasis, as shown in [Table 1].
Of 45 patients with AA, 28 (62.2%) were male and 17 (37.8%) were female, whereas 34 (75.6%) individuals of the control group were male and 11 (24.4%) were female. There was no statistically significant difference between the groups regarding sex (P=0.17), as shown in [Table 2] and [Figure 1].
Cases had significantly higher IL-17A levels than control group, where the mean IL-17A level of patients was 230.2±154.5 pg/ml compared with 154.08± 49.75 pg/ml for the control group ((P=0.047), as shown in [Table 3].
There was no significant difference between nonrecurrent cases and control regarding IL-17A level, as nonrecurrent cases had mean IL-17A level of 142.6±33.79 pg/ml compared with 154±49.75 pg/ml in the control group (P=0.097) ([Table 4]).
[Table 4] shows that recurrent cases were significantly higher than control group regarding IL-17A, as recurrent cases had mean IL-17A level of 328.1±140.8 pg/ml compared with 154.08±49.75 pg/ml in the control group (P=0.00).
[Table 5] show that recurrent cases were significantly younger than nonrecurrent cases, as the mean±SD age of nonrecurrent cases was 40.56±7.45 years, whereas in recurrent cases was 19.18±9.46 years (P=0.00).
The study included 45 patients, comprising 28 (62.2%) males and 17 (37.8%) females. At the time of disease onset, 11 of the patients with AA were aged less than 16 years (juvenile-onset AA) (24.4%) and 43 patients were aged more than or equal to 16 years (maturity-onset AA) (75.6%). According to age class, 20 patients were aged less than 30 (44.4%) and 25 (55.6%) patients were aged more than 30 years. Moreover, our study included 15 (33.3%) patients with acute disease and 30 patients with chronic disease. Recurrence was significantly associated with age less than 30 years, noticed in patients aged less than 16 years (juvenile-onset AA), and in cases with acute disease (P=0.00), but there was no statistically significant association between recurrence and sex (P=0.098), as shown in [Table 6].
The recurrent cases had significantly higher IL-17A levels than nonrecurrent cases, where recurrent cases had mean IL-17A level of 328.1±140.8 pg/ml, whereas nonrecurrent cases had mean IL-17A level of 142.6±33.79 pg/ml (P=0.00), as shown in [Table 7].
IL-17A was significantly higher in patients with age less than 30 years (mean±SD: 349.59±164.1 pg/ml), early onset (mean±SD: 422.43±177.96 pg/ml), and acute disease (mean±SD: 369.78±191.5 pg/ml) (P=0.00), as shown in [Table 8].
DiscussionAA is an unpredictable disease. It is usually a patchy nonscarring hair loss condition that may affect any hair-bearing area. It is an organ-specific autoimmune disease against hair follicles. Anagen hair follicles are immunoprivileged sites with down-regulation of major histocompatibility complex class I antigens [6],[7].
Disturbance of immune function and complex interactions between predisposing genetic and environmental factors act as triggers for disease progression. Viruses, trace element alterations, endocrine disorders, and thyroid dysfunction also have been hypothesized. The multiple factors involved in its pathogenesis may lead to consider it as a psychosomatic illness [8].
IL-17A is the founding and best characterized member of the IL-17 cytokine family, which has been linked to the pathogenesis of a range of diverse autoimmune and inflammatory diseases and is also essential for host defense against many microbes, particularly extracellular bacteria and fungi [9].
In the present study, to gain a better understanding of the proinflammatory process in AA and the autoimmune basis, we aimed to determine whether AA is associated with alterations in serum IL-17A as a member of circulating Th17 cytokines. Two other studies showed dense infiltrations of IL-17-producing cells around the hair follicles and interstitial areas of the dermis. However, the details of the participation of Th17 cells in the pathogenesis of AA are not known [10].
Our study was carried out on 90 participants of both sexes: 45 patients with AA and 45 healthy participants. Analysis of family history of the studied cases has revealed that family history of AA was negative. This is in contrary to the study of Esfandiarpour et al. [11] who found positive family history of AA in 26.5%, and the study of Wani and Jan [12], which found a positive family history of AA and atopy in 20 and 16% of the patients, respectively. However, in another study, Manzoor and Masood [13] found that the family history of AA was low (1.5%). The discrepancy between the results may be attributable to difference in the number of cases and ethnic differences.
Our study denoted that AA is more common in male (62.2%) than in females (37.8%) and most patients were less than 40 years of age. This was in agreement with the findings of El-Morsy et al. [14] whose study on patients with AA included 60.0% males and 40.0% females, with patients’ age ranging from 9.0 to 46.0 years, and most patients being less than 30 years of age. Moreover, the study done by Al-Mutairi and Eldin [15] on patients with AA included 65.02% males and 34.97% females, and most patients were between 21 and 40 years of age. Bhat et al. [6] reported also increased incidence of AA in men (68%) compared with women (32%), and most patients were in the third decade of life.
Our results also support the results of the study by El-Morsy et al. [14], which included 71.8% male and 28.2% female. The study reported increased incidence of AA in men compared with women.
On the contrary, a study by Manolache and Benea [16] reported a female predominance, as they found that in the AA adult group, there were 27 (60%) female and 18 (40%)male participants.
In the current study, cases had significantly higher IL-17A levels than control group, as patients had mean IL-17A level of 230.2±154.5 pg/ml, whereas the control group had mean IL-17A level of 154.08±49.75 pg/ml. This was in agreement with the study done by El-Morsy et al. [14] who found that serum IL-17A level in patients was significantly higher than control group, as patients had mean IL-17A of 3.07±1.51 pg/ml, whereas the control group had mean IL-17A level of 2.43±1.15 pg/ml.
Similar results denoted that patients with AA were found to have higher serum IL-17A levels than controls, as patients had mean IL-17A level of 16.63±10.89 pg/ml and controls had mean IL-17A level of 16.50±5.02 pg/ml, but this increase in serum IL-17A levels was not statistically significant (P=0.271) [14].
Moreover, in an attempt to assess the role of Th17 in the pathogenesis of AA, Tembhre and Sharma [17] found that cases had significantly higher IL-17A level than control group, as serum levels of IL-17A in patients with AA ranged from 2.71 to 20.77 pg/ml, whereas in the control group ranged from 4 to 43.67 pg/ml and also demonstrated that IL-17A levels were varied among AA phenotypes, but the difference was of borderline significance.
The high serum levels of IL-17A among patients with AA may highlight a functional role of this proinflammatory cytokines in the pathogenesis of this important and common skin disease and may provide another valuable insight into the mechanisms underlying the pathogenesis of AA. However, more studies are needed on more patients to investigate different Th17 cytokines in serum and skin of patients with AA. Our results also may support the trial of therapeutic approaches targeting IL-17A in patients with AA and may open a new channel for its treatment.
In our study, age was significantly positively correlated with IL-17A in control but was significantly negatively correlated with IL-17A in cases, as patients aged less than 30 years had mean IL-17A level of 349.5±164.1 pg/ml and patients aged more than 30 had mean IL-17A level of 134.76±32.79 pg/ml. This was in agreement with El-Morsy et al. [14] whose study denoted that serum IL-17A levels were significantly higher in patients aged less than 30 years than in patients aged more than 30 years, as mean serum level of IL-17A in patients aged less than 30 years was 3.47±1.82 pg/ml and in patients aged more than 30 years was 2.50±0.59 pg/ml.
AA can be triggered by psychological stress. It has been shown that both innate and adaptive cutaneous immune responses are affected by psychological stress and that chronic stress can shift activated lymphocytes toward a Th17 response [18].
Hence, the negative correlation between age and serum IL-17A levels in AA may be attributable to the greater vulnerability of children to the effect of psychological stresses: as people mature, they become better able to adopt a range of behavioral, cognitive, and emotional strategies to cope with stressful life events [19].
According to the SALT scores obtained, our study revealed that the correlation between clinical disease severity and IL-17A levels was nonsignificant (r’s=0.152, P=0.643). However, Kubo et al. [20] reported a positive correlation between the severity and progression of alopecia and the increase in the number of interferon-γ-producing Th1 cells or IL-17-producing Th17 cells.
Moreover, a study published by Morsy et al. [21] reported that there was no statistically significant correlation detected between disease severity and IL-17A level whereas reported negative correlation between severity of AA and IL-17A level after NB-UVB treatment (r=0.448, P=0.047). This could be attributed to the immunomodulatory effect of NB-UVB.
To the best of our knowledge, our study was the only one that detected the relation between serum level of IL-17A and recurrence of AA and demonstrated that recurrent cases had significantly higher IL-17A level than nonrecurrent cases, as recurrent cases had mean IL-17A level of 328.1±140.8 pg/ml, whereas nonrecurrent cases had mean IL-17A level of 142.6±33.79 pg/ml (P=0.00), denoting that recurrent cases were younger than nonrecurrent cases and recurrence was significantly associated with age less than 30, less than 16 onset, and acute disease (P=0.00).
In this study, we found that IL-17A was significantly higher in patients with juvenile-onset AA (mean±SD: 422.43±177.96 pg/ml) than in patients with maturity-onset AA. This was in agreement with the study by El-Morsy et al. [14], which found that serum IL-17A levels in patients with juvenile-onset AA (mean±SD: 3.84±2.18 pg/ml) were significantly higher than in patients with maturity-onset AA (mean±SD: 2.68±0.85 pg/ml), which may explain why patients with juvenile-onset AA tend to have a less favorable prognosis than those with maturity-onset AA.
In our study, serum IL-17a was significantly higher in patients with acute disease (mean±SD: 369.78±191.5 pg/ml) than in those with chronic disease (mean±SD: 160.46±58.35 pg/ml) (P=0.001). This was in contrary to the study of El-Morsy et al. [14], which found that the correlation between the difference in serum IL-17A levels between patients with acute disease and patients with chronic disease was nonsignificant (P=0.211).
Hordinsky [22] revealed that IL-17A represents a possible therapeutic target for autoimmune and immunoinflammatory diseases. Several biologic drugs targeting the IL-17A pathway in AA were found to be generally well tolerated, raising the possibility of targeting IL-17 as a potential therapeutic modality in AA.
The significantly higher levels of serum IL-17A in patients with AA suggest a possible role of IL-17A as a proinflammatory cytokine in the pathogenesis of AA and that IL-17A level may be influenced by age and disease recurrence in patients with AA.
On the basis of the conclusions that have been reached in this study, further studies with larger numbers of patients to verify the relationship between age and IL-17A and to evaluate the expression of IL-17R in hair follicles are recommended. In addition, therapeutic manipulations targeting IL-17 should be evaluated as a source of possible therapeutic modalities for the treatment of recalcitrant AA.
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Conflicts of interest
There are no conflicts of interest.
References
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