Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2025;15(2):5143 1 Eosinophilic Annular Erythema: Clinicopathologic Analysis and Therapeutic Outcomes from a Multicenter Cohort Luca Bettolini1,2, Vincenzo Maione1, Stefano Bighetti1,2, Marina Venturini1,2, Paolo Incardona3, Piergiacomo Calzavara-Pinton1,2, Antonio Podo Brunetti4,5, Giorgio Stabile4,5, Franco Rongioletti4,5 1 Dermatology Department, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy 2 Faculty of Medicine and Surgery, University of Brescia, Brescia, Italy 3 Pathology Department, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy 4 Department of Clinical Dermatology, Vita-Salute San Raffaele University, Milan, Italy 5 Unit of Dermatology, IRCCS San Raffaele Hospital, Milan, Italy Key words: Eosinophilic Annular Erythema, Dupilumab, Figurate Lesions, Targeted Therapies, Biologics, Multicenter Study Citation: Bettolini L, Maione V, Bighetti S, et al. Eosinophilic Annular Erythema: Eosinophilic Annular Erythema: Clinicopathologic Analysis and Therapeutic Outcomes from a Multicenter Cohort. Dermatol Pract Concept. 2025;15(2):5143. DOI: https://DOI.org /10.5826/dpc.1502a5143 Accepted: March 6, 2024; Published: April 2025 Copyright: ©2025 Bettolini 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. Ethics Statement: The patients in this manuscript provided written informed consent to the publication of their case details. Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. Corresponding Author: Luca Bettolini, MD. Department of Dermatology, Spedali Civili, University of Brescia, Brescia, Italy. ORCID ID: 0000-0003-4374-802X. E-mail: l.bettolini@unibs.it Introduction: Eosinophilic annular erythema (EAE) is a rare dermatosis characterized by persistent pruritic erythematous annular plaques with dermal eosinophilic infiltrates. It typically has a chronic, relapsing course with variable treatment responses and frequent refractory cases. Objectives: This retrospective multicenter study reports the clinical and histopathological features of EAE and the treatment outcomes in a case series of 10 patients. Methods: Ten patients with a confirmed clinical and histopathological diagnosis of EAE were referred to the Dermatology Departments of the University of Brescia and the University San Raffaele of Milan for evaluation and treatment. Results: The cohort included six females and four males, all Caucasian, with a median age of 56 years. Time from lesion onset to diagnosis ranged from two days to seven years. Patients exhibited annular, ABSTRACT 2 Original Article | Dermatol Pract Concept. 2025;15(2):5143 Introduction Eosinophilic annular erythema (EAE) is a rare condition of unknown etiology and pathogenesis characterized by per- sistent, pruritic, erythematous, annular, and gyrate plaques [1]. Histopathology shows inflammatory infiltrates with eosin- ophils in the dermis [2]. The course is usually chronic and relapsing. Several drug treatments are available, but the ther- apeutic response in individual patients is largely unpredict- able, and refractory cases to one or more treatment options are common [1]. Objectives In the present retrospective multicenter study, we report the clinical and histopathological features and the clinical out- come of various treatment approaches in a case series of ten individuals. Methods We reviewed medical records of 10 EAE patients referred to the outpatient clinics of the Dermatology Departments of the affiliated universities from January 2011 to December 2020. All patients had itching figurate or annular plaques and un- derwent a skin biopsy, which revealed dermal infiltrates with eosinophils. We looked at the medical files for information on age, sex, comorbidities, disease duration, clinical fea- tures, symptoms, prior treatments and their outcome, blood count with formula, and routine biochemistries. Histological samples were always available and were reviewed by expert dermopathologists. The study was approved by the local ethics committee (protocol number: 4017), and all partici- pants provided written informed consent. It was conducted in strict adherence to the principles outlined in the Declara- tion of Helsinki, ensuring the confidentiality of participants’ data and their absolute right to withdraw from the study at any point. Results All enrolled patients (six females and four males) were Cau- casian. The median age was 56 years (range: 35–85 years). The main personal, clinical, and histopathologic features are reported in Table 1. The duration from lesion onset to EAE diagnosis varied from between two days and 84 months (median: 10 months). All patients were suffering from annu- lar, figurate, or polycyclic plaques with slightly elevated ery- thematous borders (Figures 1–3). The borders were dashed in eight (80%) patients, and lesions had a central pigmen- tation in seven (70%) patients. Lesions were located on the trunk (80%), lower limbs (70%), and upper limbs (60%). Chronically sun-exposed body areas, i.e., the face, neck, and hands, were never affected. All patients reported itching, which was intense in nine (90%). The histopathological ex- amination revealed normal epidermis in eight patients and spongiosis in two (Table 2). All biopsies revealed a dermal infiltrate primarily composed of lymphocytes with various numbers of eosinophils, ranging from scattered (10%) to abundant (40%) and numerous (50%). Mucin deposits were found in three patients (33%). Flame Figures were detected only in the second biopsy of one patient. Skin samples from four patients were investigated with direct immunofluores- cence, and granular C3 deposits at the dermal-epidermal junction were seen in one case (10%). Blood eosinophilia was observed in only two patients (20%). Regarding ther- apeutic approaches, the most common first-line treatment was oral corticosteroids alone (seven patients; 70%) or in combination with hydroxychloroquine (two; 20%). Among the patients treated with oral corticosteroids alone, three (30%) did not exhibit any clinical improvement. An addi- tional three patients (30%) experienced relapses during follow-up, necessitating multiple treatment cycles. Only one patient (10%) achieved complete remission after a single course of corticosteroid therapy. Of the two patients who re- ceived the combination of oral corticosteroids and hydroxy- chloroquine, one required further treatment cycles due to figurate, or polycyclic plaques with erythematous borders—dashed in 80% and centrally pigmented in 70% of cases. Intense itching was reported by 90%. Histopathology displayed dermal infiltrate pri- marily composed of lymphocytes with various numbers of eosinophils, ranging from scattered (10%) to abundant (40%) and numerous (50%). Treatment responses were variable, oral corticosteroids, either alone or in combination with hydroxychloroquine, being the most used therapies. However, flares frequently occurred following discontinuation of treatment. Dupilumab has shown promise in achieving long-term remission. Conclusion: Most patients exhibited pruritic lesions with dashed borders and central pigmentation, strongly suggesting a diagnosis of EAE. The positive response to dupilumab in refractory cases, along with long-term follow-up, reinforces the growing body of scientific evidence from case reports docu- mented in the literature. Original Article | Dermatol Pract Concept. 2025;15(2):5143 3 T ab le 1 . B as el in e C ha ra ct er is ti cs , P re vi ou s T he ra pi es , a nd T re at m en t O ut co m es o f th e 10 P at ie nt s W it h E os in op hi lic A nn ul ar E ry th em a (E A E ). C as e Se x, A ge C lin ic al L es io n D as he d B or de rs C en tr al Pi gm en ta ti on In vo lv ed S it e C om or bi di ti es A ss oc ia te d Sy m pt om s E os in op hi lia O ns et Pr ev io us T re at m en ts O ng oi ng T re at m en t, O ut co m e 1 F, 5 6 E ry th em at ou s, an nu la r pl aq ue s + + T ru nk a nd ex tr em it ie s Pr io r he pa ti ti s B Pr ur it us no 7 y C yc lo sp or in e, hy dr ox yc hl or oq ui ne , da ps on e, m et ho tr ex at e, th al id om id e, U V A 1 ph ot ot he ra py , in tr av en ou s st er oi ds + in do m et ha ci n, a nd or al s te ro id s D up ilu m ab C om pl et e re m is si on , no r el ap se 2 F, 6 8 A nn ul ar , po ly cy cl ic , a nd gy ra te d le si on s + + T ru nk a nd lo w er ex tr em it ie s M aj or de pr es si ve di so rd er Pr ur it us an d lim b ar th ra lg ia no 2 d no ne O ra l s te ro id s C om pl et e re m is si on , no r el ap se 3 F, 7 8 E ry th em at ou s, an nu la r pl aq ue s + + L ow er ex tr em it ie s C hr on ic ly m ph oc yt ic le uk em ia , ar te ri al hy pe rt en si on , ty pe 2 d ia be te s, pr io r he pa ti ti s B Pr ur it us no 5 m Fu si di c ac id c re am , te rb in afi ne g el , a nd to pi ca l a nd o ra l st er oi ds D up ilu m ab C om pl et e re m is si on , no r el ap se s 4 F, 3 8 A nn ul ar , po ly cy cl ic , a nd gy ra te d le si on s + - T ru nk N on e Pr ur it us an d bu rn in g se ns at io n no 10 m U V A 1 ph ot ot he ra py , ce ti ri zi ne , a nd t op ic al st er oi ds O ra l s te ro id s C om pl et e re m is si on , ne w fl ar es a ft er di sc on ti nu at io n 5 M , 3 5 A nn ul ar , po ly cy cl ic , a nd gy ra te d le si on s - + T ru nk a nd ex tr em it ie s N on e Pr ur it us no 4 m N on e In do m et ha ci n Pa rt ia lly e ff ec ti ve , ne w fl ar es a ft er di sc on ti nu at io n 6 M , 5 6 E ry th em at ou s, an nu la r pl aq ue s + - E xt re m it ie s N on e Pr ur it us no 8 m PU V A p ho to th er ap y O ra l s te ro id s an d hy dr ox yc hl or oq ui ne C om pl et e re m is si on , ne w fl ar es a ft er di sc on ti nu at io n T ab le 1 co nt in ue s 4 Original Article | Dermatol Pract Concept. 2025;15(2):5143 C as e Se x, A ge C lin ic al L es io n D as he d B or de rs C en tr al Pi gm en ta ti on In vo lv ed S it e C om or bi di ti es A ss oc ia te d Sy m pt om s E os in op hi lia O ns et Pr ev io us T re at m en ts O ng oi ng T re at m en t, O ut co m e 7 M , 8 5 E ry th em at ou s, an nu la r pl aq ue s - + T ru nk a nd lo w er ex tr em it ie s C le ar c el l ca rc in om a Pr ur it us no 6 m N on e O ra l s te ro id s C om pl et e re m is si on , ne w fl ar es a ft er di sc on ti nu at io n 8 M , 4 9 A nn ul ar , po ly cy cl ic , a nd gy ra te d le si on s + + T ru nk a nd u pp er ex tr em it ie s N on e N on e no 1 y N on e H yd ro xy ch lo ro qu in e C om pl et e re m is si on , ne w fl ar es a ft er di sc on ti nu at io n 9 F, 6 1 A nn ul ar , po ly cy cl ic , a nd gy ra te d le si on s + + T ru nk a nd u pp er ex tr em it ie s N on e Pr ur it us ye s 1 y O ra l s te ro id s O ra l s te ro id s an d hy dr ox yc hl or oq ui ne C om pl et e re m is si on , no r el ap se 10 F, 4 9 A nn ul ar p la qu es an d gy ra te d le si on s + - T ru nk a nd up pe r an d lo w er ex tr em it ie s N on e Pr ur it us ye s 1 y N on e O ra l s te ro id s C om pl et e re m is si on , ne w fl ar es a ft er di sc on ti nu at io n y: y ea rs ; m : m on th s; d : d ay s T ab le 1 . B as el in e C ha ra ct er is ti cs , P re vi ou s T he ra pi es , a nd T re at m en t O ut co m es o f th e 10 P at ie nt s W it h E os in op hi lic A nn ul ar E ry th em a (E A E ). (c on ti nu ed ) Original Article | Dermatol Pract Concept. 2025;15(2):5143 5 Figure 1. (A) Clinical eosinophilic annular erythema (EAE) with (B) corresponding histopathology (right side, H&E) of three patients on the left thigh, with superficial-deep, perivascular, and interstitial mixed infiltrate of lymphocytes with numerous eosinophils. Figure 2. (A) annular plaques on the trunk and the upper arms and (B) histopathology displaying abundant eosinophilic infiltrate. Figure 3. (A) EAE lesion of the trunk with dashed borders and central pigmentation, characterized with superficial-deep, perivascular, and (B) interstitial mixed infiltrate of lymphocytes and abundant eosinophils. relapse, while the other experienced long-lasting remission following the discontinuation of therapy. UVA1 photother- apy and PUVA treatment were administered to one patient each, without any improvement. Indomethacin was partially effective in one patient, and hydroxychloroquine alone was completely effective in another, but relapses occurred after discontinuation in both patients, and continuous treatment cycles were administered. Two patients were treated with an initial subcutaneous dose of dupilumab (600 mg), fol- lowed by a maintenance dose of 300 mg every two weeks for 12 months. Subsequently, the dosing regimen was adjusted to 300 mg every month. Both patients achieved complete clinical 6 Original Article | Dermatol Pract Concept. 2025;15(2):5143 T ab le 2 . H is to pa th ol og ic al C ha ra ct er is ti cs o f th e 10 P at ie nt s W it h E os in op hi lic A nn ul ar E ry th em a (E A E ). C as e Se x, A ge Sp on gi os is In fla m m at or y In fil tr at e an d Pa tt er n of E os in op hi lic I nfi lt ra ti on D ir ec t Im m un ofl uo re sc en ce Fl am e Fi gu re s M uc in D ep os it 1 F, 5 6 - Su pe rfi ci al -d ee p, p er iv as cu la r, an d in te rs ti ti al m ix ed in fil tr at e of ly m ph oc yt es w it h nu m er ou s eo si no ph ils N ot T es te d - + 2 F, 6 8 - Su pe rfi ci al , p er iv as cu la r, an d in te rs ti ti al m ix ed in fil tr at e of ly m ph oc yt es w it h nu m er ou s eo si no ph ils N ot t es te d - - 3 F, 7 8 + Su pe rfi ci al , p er iv as cu la r, an d in te rs ti ti al m ix ed in fil tr at e of ly m ph oc yt es w it h sc at te re d eo si no ph ils N ot t es te d - - 4 F, 3 8 - Su pe rfi ci al -d ee p, p er iv as cu la r, an d in te rs ti ti al m ix ed in fil tr at e of ly m ph oc yt es w it h ab un da nt e os in op hi ls N ot t es te d - - 5 M , 3 5 - D en se d er m al in fil tr at e w it h ly m ph oc yt es a nd a bu nd an t eo si no ph ils N ot t es te d - + 6 M , 5 6 - D en se d er m al in fil tr at e of ly m ph oc yt es , a nd n um er ou s eo si no ph ils - - + 6 M , 5 6 - D en se d er m al in fil tr at e of ly m ph oc yt es , a nd n um er ou s eo si no ph ils - + + 7 M , 8 5 - D en se d er m al in fil tr at e of ly m ph oc yt es , a nd n um er ou s eo si no ph ils G ra nu la r C 3 de po si ts a t th e de rm al -e pi de rm al ju nc ti on - - 8 M , 4 9 - D en se d er m al e os in op hi lic in fil tr at e w it h ly m ph oc yt es , a nd h is ti oc yt es N ot t es te d - - 9 F, 6 1 + Pe ri va sc ul ar a nd in te rs ti ti al in fil tr at e w it h ly m ph oc yt es a nd a bu nd an t eo si no ph ils - - - 10 F, 4 9 - Pe ri va sc ul ar a nd in te rs ti ti al in fil tr at e w it h ly m ph oc yt es a nd a bu nd an t eo si no ph ils N ot t es te d - - Original Article | Dermatol Pract Concept. 2025;15(2):5143 7 previously reported in two cases [9,10] and in two patients of the present case series. Moreover, we report the cases of EAE treated with dupilumab with the longest follow-up pe- riod free of relapses. Furthermore, a maintenance dose of 300 mg every month post-remission did not demonstrate any flare. Additional studies are necessary to confirm and vali- date these findings. Beyond its efficacy in atopic dermatitis, dupilumab has been successfully used in other eosinophilic disorders, such as eosinophilic esophagitis [11] and chronic rhinosinusitis with nasal polyps [12]. The response of EAE to dupilumab observed in our case series is consistent with its efficacy in these conditions, suggesting a broader role of IL-4/IL-13 inhibition in eosinophil-mediated skin disorders. The relationship between Wells syndrome (WS) and EAE remains debated [2,13]. WS is most often characterized by cellulitis-like erythematous plaques accompanied by blood eosinophilia, and at histologic examination, dermal edema, eosinophilic dermal infiltration, and free eosinophilic gran- ules coating collagen bundles (flame Figures) are seen. EAE presents with annular and figurate lesions with central pig- mentation, normal blood level of eosinophils, and eosino- philic infiltrates without flame Figures. However, the clinical presentation of WS and EAE may be heterogeneous, and the differentiation may be difficult. In fact, both our study and the existing literature have reported the presence of flame Figures and blood eosinophilia in cases of EAE. It is noteworthy that, in our case series, the vast majority of the figurate lesions exhibited interrupted margins, defined as “dashed borders”. Managing EAE is challenging due to the lack of standardized treatment guidelines1. The therapy typ- ically begins with topical corticosteroids such as betameth- asone or clobetasol, achieving none to partial and complete responses. For more severe or resistant cases, systemic cor- ticosteroids and antimalarial drugs like hydroxychloroquine are effective. Dapsone serves as a second-line treatment, and combination therapies of systemic corticosteroids with hydroxychloroquine can be used for refractory patients. In cases associated with hematologic malignancies, appropri- ate cancer therapy combined with corticosteroids has been successful. Methotrexate and thalidomide have been used in anecdotal cases, with varying success [1]. Last-resort options include advanced biologics and JAK inhibitors, while some patients may experience spontaneous improvement without aggressive treatment. This study has several limitations. First, its retrospective design may have introduced selection and reporting biases. Second, the small sample size limits the generalizability of our findings and precludes robust statistical analysis. Finally, the lack of standardized treatment protocols across centers may have influenced therapeutic outcomes. In conclusion, EAE presents as a chronic, relapsing derma- tologic condition characterized by pruritic lesions with central response without any reported adverse events. Notably, no relapse was observed during a 4-year follow-up period. Conclusion EAE is a rare clinical disorder, and the delay before diag- nosis is considerable up to seven years in the present case series. Clinically, it manifests as annular plaques, which can sometimes be polycyclic or exhibit dashed borders or central pigmentation. Histologically, despite differences in clinical presentation, an inflammatory infiltrate composed of lym- phocytes and variable numbers of eosinophils is observed. Mucin deposits may also be present at times. In one case, flame Figures were noted, although immunofluorescence findings were inconsistent. Regarding therapy, there is cur- rently no established treatment approach for EAE. Several drugs, i.e., oral corticosteroids, cyclosporine, indomethacin, doxycycline, hydroxychloroquine, thalidomide, methotrex- ate, dapsone and nicotinamide, and phototherapies have been used, with variable outcomes in isolated case reports or small case series, ranging from none/partial to complete re- sponse [1]. Notably, relapse of EAE has been reported upon discontinuation of most of these therapies [1]. The broad range of treatments with very different mechanisms of action suggests a largely empirical therapeutic approach, given that the pathogenesis of EAE has not yet been clarified. Indeed, only recently has it been emphasized that eosinophils’ dermal infiltration plays a key role [3]. The upregulation of the Th-2 response, triggered by unidentified stimuli, releases interleu- kin (IL)-5, prompting the migration of eosinophils from the bone marrow into the bloodstream. These mechanisms could explain why two cases showed complete resolution of EAE with the administration of anti-IL-5 mepolizumab [4] and benralizumab [5], respectively. Nakazato and colleagues [6] demonstrateed that central pigmentation reflects basal melanosis. Melanocytes express IL-5 at a low level, and it is conceivable that IL-5, which attracts eosinophils to the dermis, may also exert an effect on melanocytes, supporting the idea that dysregulated tissue eosinophilia act as a pivotal factor. Additionally, IL-4 and IL-13 contribute to their re- cruitment into tissues, sustaining the activation of the Th-2 response. However, these mechanisms remain unclear, war- ranting further research to improve therapies. Dupilumab is a fully human monoclonal antibody that has been approved for treating moderate-to-severe atopic dermatitis. It works by blocking the α subunit of the IL-4 receptor, which in turn prevents the signaling cascade of IL-4 and IL-13. This ul- timately leads to a reduction in the Th2 immune response. Additionally, dupilumab prevents the migration of eosino- phils into tissues by blocking the production of eotaxins and vascular cell adhesion molecules mediated by IL-4 and IL-13 [7,8]. This mechanism could be helpful in treating EAE, as 8 Original Article | Dermatol Pract Concept. 2025;15(2):5143 study of 10 cases. J Eur Acad Dermatol Venereol. 2017;31(11): 1916-1923. DOI: 10.1111/jdv.14350. PMID: 28543605. 7. Wechsler ME, Klion AD, Paggiaro P, Nair P, Staumont-Salle D, Radwan A, et al. Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis.  J Allergy Clin Immunol Pract. 2022;10(10):2695-2709. DOI: 10.1016/j.jaip.2022.05.019. PMID: 35636689. 8. Rossi M, Bettolini L, Artelli GL, Fraghì A, Tomasi C, Calzavara-Pinton P. Dupilumab Treatment Efficacy and Impact on Clinical Scores, Serum Biomarkers, and Itch in Adult Patients with Atopic Dermatitis: A Retrospective Analysis.  J Asthma Allergy. 2023;16:1233-1240. DOI: 10.2147/JAA.S433515. PMID: 37965272. 9. Maione V, Caravello S, Cozzi C, Venturini M, Incardona P, Frassi M, et al. Refractory eosinophilic annular erythema treated suc- cessfully with dupilumab.  J Dtsch Dermatol Ges. 2020;18(9): 1031-1032. DOI: 10.1111/ddg.14254. PMID: 32909389. 10. Gordon SC, Robinson SN, Abudu M, Her M, Deverapalli S, Levin A, et al. Eosinophilic annular erythema treated with dupi- lumab. Pediatr Dermatol. 2018;35(4):e255-e256. DOI: 10.1111 /pde.13533. PMID: 29790187. 11. Dellon ES, Rothenberg ME, Collins MH, Hirano I, Chehade M, Bredenoord AJ, et al. Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis.  N Engl J Med. 2022;387(25): 2317-2330. DOI: 10.1056/NEJMoa2205982. PMID: 3654 6624. 12. Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials [published correction appears in Lancet. 2019 Nov 2;394(10209):1618. DOI: 10.1016/S0140-6736(19)32218-4.].  Lancet. 2019;394(10209):1638-1650. DOI:10.1016/S0140 -6736(19)31881-1. PMID: 31543428. 13. Eljazouly M, Chahboun F, Alj M, Oqbani K, Chiheb S. Eosino- philic Annular Erythema: A New Entity of Eosinophilic Derma- tosis. Cureus. 2022;14(2):e22657. DOI: 10.7759/cureus.22657. PMID: 35371819. pigmentation and dashed borders, which strongly raise sus- picion for the diagnosis. Standard treatments, such as corti- costeroids and hydroxychloroquine, often result in relapses upon discontinuation. However, dupilumab has demonstrated significant promise in refractory cases, achieving long-term remission with no relapse during extended follow-up. These findings support the growing evidence for dupilumab as an effective treatment for EAE, emphasizing the need for further studies to validate its long-term efficacy and safety. References 1. Chastagner M, Shourik J, Jachiet M, Battistella M, Lefevre G, Gibier JB, et al. Treatment of Eosinophilic Annular Erythema: Retrospective multicenter study and literature review. Ann Der- matol Venereol. 2022;149(2):123-127. DOI: 10.1016/j.annder .2021.07.007. PMID: 34716028. 2. Rongioletti F, Fausti V, Kempf W, Rebora A, Parodi A. 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Eo- sinophilic annular erythema is clinically characterized by central pigmentation reflecting basal melanosis: a clinicopathological