Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(1):e2024006 1 Retrospective Analysis of the Effect of Comorbid Atopic Dermatitis on the Treatment Response to Topical Immunotherapy in Pediatric Alopecia Areata Patients Ayşe Mine Gök1, Özge Aşkın2, Server Serdaroğlu2, Zekayi Kutlubay2 1 Şırnak State Hospital Dermatology Department, Şırnak, Turkey 2 Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Dermatology Department, Istanbul, Turkey Key words: alopecia areata, atopic dermatitis, topical immunotherapy Citation: Gok AM, Aşkın Ö, Serdaroglu S, Kutlubay Z. Retrospective Analysis of the Effect of Comorbid Atopic Dermatitis on the Treatment Response to Topical Immunotherapy in Pediatric Alopecia Areata Patients. Dermatol Pract Concept. 2024;14(1):e2024006. DOI: https://doi.org/10.5826/dpc.1401a6 Accepted: July 30, 2023; Published: January 2024 Copyright: ©2024 Gok et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Ayşe Mine Gök, Cizre Street Şırnak State Hospital, Şırnak, Turkey. E-mail: draysebayazit@gmail.com Introduction: Alopecia areata is an organ-specific autoimmune disease. In addition, treatment options are limited in pediatric patients. Topical immunotherapy treatment may be preferred, especially in pediatric patients with severe and/or refractory alopecia areata. Objectives: In this study, it was aimed to examine the effect of atopic dermatitis, which is one of the poor prognostic factors in pediatric alopecia areata, on topical immunotherapy treatment. Methods: The data of patients aged 18 years and younger who received at least 20 sessions of topical immunotherapy with the diagnosis of alopecia areata in our clinic between January 2018 and Decem- ber 2020 were analyzed. Results: A total of 139 patients were included in the study. The mean age of the patients was 10.29 years, 67 (48.20%) of the patients were female, 72 (51.80%) were male, 24 (17.26%) of the patients had mild disease, 115 of them (82.73%) had severe disease. Atopic dermatitis accompanying alopecia areata was detected in 38 of the patients. Inadequate response was obtained in 60 (43.17%) patients and adequate response was obtained in 79 (56.83%) patients with topical immunotherapy treatment. In addition, the presence of atopic dermatitis in the patient group with inadequate response to treatment was found to be statistically significantly higher than the patient group with adequate response to treatment. Conclusions: Topical immunotherapy treatment was found to be effective in 56.83% of pediatric alopecia areata patients included in the study. Our study showed that questioning pediatric alopecia areata patients for atopic dermatitis before topical immunotherapy treatment can predict the response to treatment. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2024;14(1):e2024006 Introduction Alopecia areata is an autoimmune disease characterized by non-cicatricial alopecia of the scalp and/or body with an un- predictable course [1]. Alopecia areata affects approximately 2% of the general population throughout life [2]. The epide- miology, clinical features and treatment of childhood alope- cia areata have been less studied [3]. Although the pathogenesis of alopecia areata is still un- known, the common theory in the pathogenesis is the loss of immune privilege in the hair follicle caused by immune mechanisms [4]. Alopecia areata is accepted as a tissue- specific autoimmune disease that occurs with an environmental trig- gering factor on the basis of genetic predisposition [5-7]. Relationships have been reported between alopecia areata and autoimmune diseases such as autoimmune thyroid dis- eases, vitiligo, type 1 diabetes mellitus and celiac disease [8]. It has also been reported that atopic conditions such as atopic dermatitis, allergic rhinitis, and asthma are common comorbid diseases in alopecia areata [9]. Treatment decision in alopecia areata; it is given by eval- uating factors such as the age of the patient, the severity of the disease, the duration of the disease, access to treatment and the cost of treatment [10]. However, there is currently no curative treatment. Topical treatments used in pediatric al- opecia areata include contact immunotherapy, cryotherapy, topical minoxidil, topical calcineurin inhibitors, topical and intralesional steroids, and topical prostaglandins. Systemic treatments used include systemic steroids, methotrexate, sul- fasalazine, hydroxychloroquine and jack inhibitors. The use of systemic steroids is limited due to significant side effects, while the use of systemic JAK inhibitors is limited due to their safety profile and cost [11]. Topical immunotherapy offers the best efficacy and safety in long-term treatment in patients with treatment-resistant alopecia areata [12]. Agents used in topical immunotherapy; contact sen- sitizing agents such as diphenylcyclopropenone (DPCP), dinitrochlorobenzene (DNCB), squaric acid dibutylester (SADBE). Although the mechanism of action is not fully known, it is thought that they act by reducing the CD4+/ CD8+ lymphocyte ratio around the follicle, directing T lym- phocytes from the perifollicular area to the interfollicular area and dermis, and attracting new T lymphocytes to the treated area, which eliminates the antigenic stimulus [13]. Objectives The search for effective and safe treatment in alopecia areata, especially in severe and treatment-resistant pediatric patients, is still ongoing. Topical immunotherapy treatment is frequently preferred in this patient group. In this study, we aimed to retrospectively evaluate the effect of atopic dermatitis accompanying alopecia areata on the treat- ment of pediatric alopecia areata patients receiving topical immunotherapy. Methods Patient Selection In our study, the clinical data of patients aged 18 years and younger who received at least 20 sessions of topical immu- notherapy (SADBE/DPCP) treatment with the diagnosis of alopecia areata in our clinic between January 2018 and De- cember 2020 were retrospectively analyzed. Patients with a follow-up period of less than 6 months and receiving addi- tional treatment were excluded from the study. Patient Evaluation Pre-treatment hair loss severity was evaluated according to the criteria defined in the alopecia areata research evaluation guidelines: S0: no hair loss, S1:<25%, S2:25-49%, S3:50- 74%, S4:75%-99, S5:100% hair loss as classified. S1 and S2 were considered mild disease and S3, S4 and S5 were consid- ered severe disease. The patients response to treatment was evaluated ac- cording to the improvement in the percentage of baseline SALT score. Accordingly, good response ≥50% improve- ment, moderate response 25%-49% improvement, poor re- sponse 1%-24%, and the same SALT score before and after treatment were considered as non-response. Good and mod- erate responders were graded as adequate response, poor response, and non-responders as inadequate response, and statistics were made accordingly. In addition, the presence of atopic dermatitis, which was determined using Hanifin Rajka diagnostic criteria, was re- corded in the patients before treatment. In patients with atopic dermatitis, atopic dermatitis disease severity was graded using the SCORing Atopic Dermatitis (SCORAD) scoring system. This study was approved by the tertiary hospital ethics committee (No. 154281; August 6, 2021). Written informed consent was obtained from all participants. Statistical Methods Statistical analyses in the study were made with the NCSS (Number Cruncher Statistical System) 2007 Statistical Soft- ware package program. In the evaluation of the data, besides descriptive statistical methods (mean, standard deviation [sd], median, etc), the distribution of variables was examined with the Shapiro-Wilk test of normality. Binary groups of normally distributed variables independent t-test was used for comparison and Mann-Whitney U test was used for com- parison of binary groups of variables that did not show nor- mal distribution. Chi-square test was used in the comparison Original Article | Dermatol Pract Concept. 2024;14(1):e2024006 3 of qualitative data and logistic regression analysis was used to determine the factors affecting response to treatment. The results were evaluated at the significance level of P < 0.05. Results A total of 139 patients, 69 of whom received SADBE and 70 of whom received DPCP treatment, were included in the study. Sixty-seven (48.20%) of the patients were female and 72 (51.80%) were male. The mean age was 10.29 years (sd: 3.77 years) and the mean disease duration was 4.02 years (sd: 2.84 years). In addition, 44 (31.65%) patients had nail involvement (due to alopecia areata), 31 (22.3%) had a family history of alopecia areata, 31 (22.3%) had a family history of atopic disease. The mean value of the total IgE level of the patients before the treatment was 283.87 IU/ml (sd:864.28 IU/ml), and the lowest value was 0 and the high- est value was 9024 IU/ml (normal value:0-100 IU/ml). However, 38 (27.34%) patients had atopic dermatitis. When the data of 38 patients with atopic dermatitis were compared with the data of 101 patients without atopic der- matitis; no significant difference was observed between the two groups in terms of gender distribution, mean age, dis- ease duration (years), and the presence of a family history of alopecia areata (P values, respectively: 0.378, 0.329, 0.780, 0.810). In the patient group with atopic dermatitis, the mean of total IgE values, the presence of nail involvement (due to alopecia areata), and the presence of a family history of atopy were found to be statistically significantly higher than the patient group without atopic dermatitis (P values, re- spectively: 0,0001, 0,036, 0,001). When the severity of the disease was evaluated according to the pre-treatment SALT scores; in the group with atopic dermatitis, mild disease was detected in 4 patients (10.53%), while severe disease was de- tected in 34 patients (84.47%), in the group without atopic dermatitis, mild disease was found in 20 patients (19.80%) and severe disease was found in 81 patients (80.20%). How- ever, these evaluations were not found suitable for statistical interpretation in terms of their distribution (Table 1). When the response to topical immunotherapy treat- ment was evaluated according to the improvement in the percentage of baseline SALT score, 37 (26.62%) of the pa- tients had no response, 23 (16.55%) had a poor response, and 14 (10.07%) moderate response was obtained, and 65 (46.76%) had good response. When the conditions affecting the response to treatment were examined; when the data of 60 patients who responded inadequately to treatment with topical immunotherapy treatment and 79 patients who re- sponded adequately to treatment were compared. There was no statistically significant difference between the two groups in terms of: gender distribution, mean age, distribu- tion of treatment type (SADBE/DPCP), mean duration of disease (years), presence of nail involvement (due to alope- cia areata), presence of family history of alopecia areata and mean total IgE (P values respectively: 0.092, 0.123, 0.448, 0.798, 0.271, 0.281, 0.170). The presence of family history Table 1. Comparison of the data of the patient group with atopic dermatitis and the patient group without atopic dermatitis. Atopic Dermatitis (-) N = 101 Atopic Dermatitis (+) N = 38 P Age (Years) Mean±Standard Deviation 10.49±3.90 9.79±3.38 0.333 Gender Male 50 49.50% 22 57.89% 0.378 Female 51 50.50% 16 42.11% Disease duration (years) Mean±Standard Deviation 4.08±2.92 3.84±2.67 0.780 Median (IQR) 4 (2-6) 3 (2-5.25) Nail involvement (due to alopecia areata) ( - ) 37 36.63% 7 18.42% 0.04 ( + ) 64 63.37% 31 81.58% Family history of alopecia areata ( - ) 79 78.22% 29 76.32% 0.810 ( + ) 22 21.78 9 23.68% Family history of atopy ( - ) 89 88.12% 24 63.16% 0.001 ( + ) 12 11.88% 14 36.84% Total IgE (IU/ml) Mean±Standard Deviation 133.46±310.21 683.63±1516.59 0.0001 Median (IQR) 43.32 (15.7-91.77) 251.5 (36.92-617.55) IQR = interquartile range. 4 Original Article | Dermatol Pract Concept. 2024;14(1):e2024006 In addition, many diseases that accompany alopecia areata and can determine the prognosis of the disease have been re- ported. Considering the accompanying diseases [15] it was determined that the risk of atopic dermatitis increased espe- cially in patients with alopecia areata younger than 10 years of age [16]. In addition, treatment options are limited in pedi- atric alopecia areata patients due to concerns about treatment tolerance. Topical immunotherapy treatments are one of the most frequently applied treatment methods, especially in treat- ment-resistant and severe pediatric alopecia areata cases. In a study, diseases that may accompany alopecia areata in patients with pediatric alopecia areata were examined, and atopic dermatitis was detected in 17.4% of alopecia areata patients and in 2.2% of controls, and it was determined as the most common disease accompanying pediatric alopecia areata [17]. On the contrary, there is a study in the literature reporting that no difference was found between the adult and pediatric alopecia areata patients and the control group in terms of the frequency of atopic disease [18]. We found the of atopy, the presence of atopy history in the patient, the presence of atopic dermatitis in the patient group with inade- quate response to the treatment were found to be statistically significantly higher than the patient group with adequate re- sponse to the treatment (P values respectively: 0.036, 0.002, 0.032). In addition, the SCORAD score averages calculated in the patients with atopic dermatitis in the patient group with inadequate response to the treatment were found to be statistically significantly higher than the patient group with adequate response to the treatment (P 0.0001) (Table 2). Ad- ditionally, photographs of patients with and without atopic dermatitis before and after topical immunotherapy treat- ment are shown in Figures 1 and 2. (Figure 1 and Figure 2) Conclusions Alopecia areata is a chronic, autoimmune disease [1,3]. Al- though alopecia areata can occur at any age, the majority of cases appear before the age of 40 [14]. Table 2. Distribution of factors affecting treatment response. Inadequate response to treatment N = 60 Adequate response to treatment N = 79 P Age (years) 9.73±3.25 10.72±4.08 0.123 Gender Male 36 60.00% 36 45.57% 0.092 Female 24 40.00% 43 54.43% Type of treatment SADBE Treatment 32 %3.33% 37 46.84% 0.448 DPCP Treatment 28 46.67% 42 53.16% Disease duration (years) Mean±Standard Deviation 3.88±2.63 4.12±3.01 0.798 Median (IQR) 3 (2-6) 3 (2-6) Nail involvement (due to alopecia areata) ( - ) 16 26.67% 28 35.44% 0.271 ( + ) 44 73.33% 51 64.56% Family history of alopecia areata ( - ) 44 73.33% 64 81.01% 0.281 ( + ) 16 26.67% 15 18.99% Patient’s history of atopy ( - ) 39 65.00% 69 87.34% 0.002 ( + ) 21 35.00% 10 12.66% Family history of atopy ( - ) 44 73.33% 69 87.34% 0.036 ( + ) 16 26.67% 10 12.66% Total IgE (IU/ml) Mean±Standard Deviation 491.33±1267.14 126.3±220.89 0.170 Median (IQR) 65.82 (11.97-395.5) 43.32 (22.11-135.7) Atopic Dermatitis ( - ) 38 63.33% 63 79.75% 0.032 ( + ) 22 36.67% 16 20.25% SCORAD Score Mean±Standard Deviation 45.43±16.61 23.48±13.95 0.0001 Median (IQR) 44.98 (36.58-57.13) 22.20 (12.8-30.55) DPCP = diphenylcyclopropenone; IQR = interquartile range SADBE = squaric acid dibutylester. Original Article | Dermatol Pract Concept. 2024;14(1):e2024006 5 the presence of nail involvement (due to alopecia areata), the presence of a family history of atopy, and the total IgE aver- ages statistically significantly higher in the group of patients with alopecia areata with atopic dermatitis compared to the patient group without atopic dermatitis. In addition, there are many studies in the literature ex- amining the factors affecting the responses obtained with topical immunotherapy, but the data are conflicting in terms of situations that can predict treatment responses and be used as prognostic factors. In a retrospective study, disease severity, disease duration, atopy history (especially eczema), and early development of contact dermatitis in the area where the topical immunotherapy agent applied for sensi- tization was applied were identified as the main factors af- fecting treatment responses [21]. In addition, there are very few studies evaluating the response to topical immunother- apy treatment, especially in pediatric patients, and examin- ing the factors that may affect these treatment responses. In our study, we investigated the factors that may affect the treatment response in pediatric patients receiving topical im- munotherapy treatment. And finally, the presence of atopy in the family, the presence of atopy in the patient, and the presence of atopic dermatitis in 27.34% of pediatric alopecia areata patients included in our study. However, since there was no control group in our study, this value could not be compared with the control group. While Th1 cell-mediated pathways are thought to be effective in the pathogenesis of alopecia areata, especially Th2 cell-mediated pathways are thought to be effective in the pathogenesis of atopic derma- titis. Recently, it has been shown that Th1 and Th17 cell- mediated pathways are also effective in the pathogenesis of atopic dermatitis, especially in the chronic period. The fre- quently reported association of alopecia areata and atopic dermatitis in the literature can be explained by these overlap- ping immunological pathways [19]. In many studies in the literature, the relationship between atopy and alopecia areata has been examined, but atopic diseases have been customized and their relationship with alopecia areata has not been men- tioned much. Addressing this, one study found that patients with alopecia areata with atopic dermatitis and/or a family history of atopic dermatitis were statistically significantly more likely to have severe forms of alopecia areata, such as alopecia totalis and alopecia universalis, than patients with- out a history of atopic dermatitis [20]. In our study, we found Figure 1. (A,B) Before (A) and after (B) topical immunotherapy treatment of a patient without atopic dermatitis Figure 2. (A,B) Before (A) and after (B) topical immunotherapy treatment of a patient with atopic dermatitis 6 Original Article | Dermatol Pract Concept. 2024;14(1):e2024006 7. Simakou T, Butcher JP, Reid S, Henriquez FL. Alopecia areata: A multifactorial autoimmune condition. J Autoimmun. 2019;98:74- 85. DOI: 10.1016/j.jaut.2018.12.001. PMID: 30558963. 8. Chanprapaph K, Mahasaksiri T, Kositkuljorn C, Leerunyakul K, Suchonwanit P. Prevalence and Risk Factors Associated with the Occurrence of Autoimmune Diseases in Patients with Alopecia Areata. J Inflamm Res. 2021;14:4881-4891. DOI: 10.2147/JIR .S331579. PMID: 34588794. PMCID: PMC8473714. 9. Harries M, Macbeth AE, Holmes S, et al. Epidemiology, manage- ment and the associated burden of mental health illness, atopic and autoimmune conditions, and common infections in alopecia areata: protocol for an observational study series. BMJ Open. 2021;11(11):e045718. DOI: 10.1136/bmjopen-2020-045718. PMID: 34785540. PMCID: PMC8596050. 10. Hordinsky MK. Current Treatments for Alopecia Areata. J Investig Dermatol Symp Proc. 2015;17(2):44-46. DOI: 10.1038/jidsymp .2015.41. PMID: 26551946. 11. Barton VR, Toussi A, Awasthi S, Kiuru M. Treatment of pedi- atric alopecia areata: A systematic review. J Am Acad Derma- tol. 2022;86(6):1318-1334. DOI: 10.1016/j.jaad.2021.04.077. PMID: 33940103. PMCID: PMC8556406. 12. Rattananukrom T, Suchonwanit P. Are drug treatment strategies re- ally effective against alopecia areata? Expert Opin Pharmacother. 2021;22(3):257-260. DOI: 10.1080/14656566.2020.1854728. PMID: 33280456. 13. Boztepe G, Demirgüneş E, Gündüz Ö, Erkin G, Şahin S. Di- phencyprone immunotherapy for alopecia areata: prospective clinical study. Turkderm-Turk Arch Dermatol Venereol. 2006; 40(1):11-16. 14. Cranwell WC, Lai VW, Photiou L, et al. Treatment of alopecia areata: An Australian expert consensus statement. Australas J Dermatol. 2019;60(2):163-170. DOI: 10.1111/ajd.12941. PMID: 30411329. 15. Tan E, Tay YK, Goh CL, Chin Giam Y. The pattern and pro- file of alopecia areata in Singapore--a study of 219 Asians. Int J Dermatol. 2002;41(11):748-753. DOI: 10.1046/j.1365-4362 .2002.01357.x. PMID: 12452996. 16. Trüeb RM, Dias MFRG. Alopecia Areata: a Comprehensive Review of Pathogenesis and Management. Clin Rev Allergy Im- munol. 2018;54(1):68-87. DOI: 10.1007/s12016-017-8620-9. PMID: 28717940. 17. Conic RZ, Tamashunas NL, Damiani G, et al. Comorbidities in pediatric alopecia areata. J Eur Acad Dermatol Venereol. 2020; 34(12):2898-2901. DOI: 10.1111/jdv.16727. PMID: 32531131. 18. Serarslan G, Savaş N, Yenin JZ. Is atopy and autoimmunity more prevalent in patients with alopecia areata? A comparative study. J Eur Acad Dermatol Venereol. 2012;26(6):720-723. DOI: 10.1111/j.1468-3083.2011.04152.x. PMID: 21692870. 19. Lee HJ, Hong NS, Kim SH, Jang YH. Association between Alo- pecia Areata and Comorbid Allergies: Implications for Its Clini- cal Course. Ann Dermatol. 2020;32(6):523-525. DOI: 10.5021 /ad.2020.32.6.523. PMID: 33911798. PMCID: PMC7875230. 20. Goh C, Finkel M, Christos PJ, Sinha AA. Profile of 513 patients with alopecia areata: associations of disease subtypes with at- opy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol. 2006;20(9):1055-1060. DOI: 10.1111 /j.1468-3083.2006.01676.x. PMID: 16987257. 21. Zerbinati N, Esposito C, D’Este E, Calligaro A, Valsecchi R. Topical Immunotherapy of Alopecia Areata: A Large Retrospective Study. Dermatol Ther (Heidelb). 2018;8(1):101-110. DOI: 10.1007/ s13555-018-0226-5. PMID: 29442292. PMCID: PMC5825331. presence of atopic dermatitis were found to be statistically significantly higher in the patient group who responded in- adequately to the treatment. In addition, the SCORAD score averages calculated in the patients with atopic dermatitis in the patient group with inadequate response to the treatment were found to be statistically significantly higher than the av- erage SCORAD score calculated in the patients with atopic dermatitis in the patient group with adequate response to the treatment. The most important limitation of our study is the ab- sence of a control group. The effect of the presence of atopic dermatitis on topical immunotherapy treatment in pediatric alopecia areata patients will be better understood with stud- ies with a higher number of cases and control groups. In conclusion, with the data we obtained in our study, we determined that atopic dermatitis, which is a disease often accompanying alopecia areata in pediatric patients, and the presence of a family history of atopy associated with it and the presence of atopy in the patient were more common in patient groups who did not respond to topical immunother- apy treatment, and these conditions were observed before topical immunotherapy treatment was started. We thought that investigating the presence of atopic dermatitis that may accompany in pediatric alopecia areata patients, and the presence of atopy in the family and in the patient may help predict the response to treatment, and that it is more difficult to obtain a good response in the treatment of these patients with topical immunotherapy, and perhaps it would be a better choice to try other treatment methods in these patients. References 1. Juárez-Rendón KJ, Rivera Sánchez G, Reyes-López MÁ, et al. Alopecia Areata. 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