Alopecia areata (AA) is a relatively common autoimmune disorder typically characterized by nonscarring alopecic patches on the scalp.1 The etiology of AA has not been fully elucidated. However, increased risks of AA in patients with allergic diseases has been reported in several studies.2,3 In particular, concomitant atopic dermatitis (AD) has been considered to be one of the poor prognostic factors of AA.2 Established therapeutic options for AA, including intralesional corticosteroid injection, can be unsuccessful in AA cases with AD (AD-AA cases).1 Recently, significant improvement of both AD and AA in refractory AD-AA cases treated with dupilumab, an interleukin (IL)- 4 receptor α-antagonist, has been reported.4–6 In contrast, exacerbation or new onset of AA has also been described,7 implicating two-sided nature of influence of dupilumab on AA in AD-AA cases. To date, trajectories of AA in association with AD in dupilumab-treated AD-AA cases have been insufficiently described. Herein, we elaborately depicted clinical courses and laboratory medicine findings of AD and AA in four dulpilumab-treated AD-AA cases. The literature review was additionally conducted to further elucidate a bona fide effect of dupilumab on AA in AD-AA cases.
PATIENT DEMOGRAPHICS AND CLINICAL MANIFESTATIONSFour AD-AA cases are analyzed in this study with IRB approval (Kyorin Univ. No. H30-104). The representative patients’ demographics are summarized in Table.1. All cases were female and the average age was 46.8 ± 6.8 years, ranging from 40 to 54. All cases had a past history of AA. Cases 1 and 3 individually had asthma and allergic rhinitis. Case 4 had a medical history of Basedow's disease. Case 2 had a two-year history of secondary adrenocortical insufficiency, which had been well controlled by oral corticosteroid. All cases had suffered from AD since childhood and had been on topical corticosteroid and/or tacrolimus without successful response.
TABLE 1 Summary of patient demographics at initial visit. Summary of clinical demographics of the cases analyzed in this study.
Patient | Sex | Age | Past history | EASI | SALT score | TARC (pg/ml) | IgE (IU/ml) |
1 | F | 40 | AA, Asthma | 58.2 | 22 | 452 | 30,358 |
2 | F | 51 | AA, Secondary adrenocortical insufficiency | 48.5 | 30 | >30,000 | 537 |
3 | F | 54 | AA, Allergic rhinitis | 22.6 | 10 | 1225 | 8210 |
4 | F | 42 | AA, Basedow's disease | 43.5 | 0 | 3794 | 19,683 |
Abbreviations: AA, alopecia areata; EASI, eczema area and severity index; SALT, severity of alopecia tool; TARC, thymus and activation-regulated chemokine.
The eczema area and severity index (EASI) in each case prior to dupilumab administration was 58.2, 48.5, 22.6, and 43.5, respectively. Several patchy alopecic lesions were observed in case 1, 2, and 3, with respective the severity of alopecia tool (SALT) score of 22, 30, and 10. Cases 2 and 3 had been receiving intralesional corticosteroid injection before dupilumab therapy with minimal response. In contrast, no alopecic lesion was noted in case 4 at the initiation of dupilumab.
CLINICAL COURSE OFAfter the initiation of dupilumab, cases 1–3 achieved 90% improvement of the EASI scores within 3 months (Figure 1). In cases 1–3, alopecic patches simultaneously recovered, resulting in full hair regrowth without any specific treatment for AA within 28 weeks (Figure 1). In contrast, the response to dupilumab was moderate in case 4 after achieving 72% improvement in EASI score within the first 3 months (Figure 1). Eight months after the administration of dupilumab, she developed acute and diffuse hair loss, which eventually led to total hair loss (Figure 1). Hair pull test and trichoscopic sings supported the diagnosis of rapidly progressive AA. Dupilumab was discontinued and intravenous corticosteroid pulse therapy (the pulse therapy) was performed. AD was exacerbated 2 months after the pulse therapy (EASI: 10.9 → 28.9) and dupilumab was restarted because no JAK inhibitor had been approved in Japan at that time. After the restart of dupilumab, AD remained to be moderate and the criteria for JAK inhibitor administration was not satisfied. Two years after the reintroduction of dupilumab, AD condition got worsened again in this case and satisfied the criteria for JAK inhibitor initiation, and therefore upadacitinib was administered. After the initiation of upadacitinib, AD quickly improved and AA has been gradually improving.
FIGURE 1. The clinical courses of atopic dermatitis and alopecia areata in four cases. Cases 1–3 achieved 90% improvement of EASI score with proportional decrease of serum TARC levels and achieved full hair regrowth. In contrast, case 4 failed to achieve 75% improvement of EASI score. TARC level did not correlate with AD severity. Rapidly progressive alopecia areata developed 1 year after the initiation of dupilumab. * The period when dupilumab was temporarily interrupted.
Before the initiation of dupilumab, serum levels of thymus and activation-regulated chemokine (TARC) were high in all cases to varying degrees, ranging from 452 to >30,000 pg/ml (Table 1). After dupilumab administration, cases 1–3 showed marked decrease in serum TARC levels, while serum TARC level increased in case 4, despite partial improvement of AD (Figure 1).
REVIEW OF PREVIOUS REPORTSThe published work search using the PubMed database with following keywords, “alopecia areata,” “atopic dermatitis,” and “dupilumab,” was conducted to find those reporting the efficacy of dupilumab on adult AD-AA cases with the detailed description of clinical courses sufficient for the evaluation of AA responses. The literature review found 39 dupilumab-treated AD-AA cases; 24 cases with AA improvement (improved group), 15 cases with AA exacerbation or new onset (exacerbated group) during dupilumab treatment (Table 2). The differences in gender and age between both groups were not obvious. Serum IgE and TARC levels before dupilumab initiation tended to be higher in the improved group than in the exacerbated group. Without exception, 19 improved-group cases with detail description of AD clinical course showed AD improvement. Majority of the improved cases (15/24) achieved more than 90% of improvement of AA with hair regrowth within approximately 1 year after the initiation of dupilumab. Improvement rate of SALT score was 73.6 ± 31.2% on average (n = 19). On the other hand, one case in the exacerbated group demonstrated the parallel exacerbation of AA and AD similarly to case 4.7 The duration from the initiation of dupilumab to AA exacerbation ranged from 2 days to 1 year (n = 7).
TABLE 2 Summary of literature review of AD-AA cases treated with dupilumab
Improved group | Exacerbated group | |
Number of patients | 24 |
Worsened group: 5 New onset group: 6 Undefined: 4 |
Sex |
Male: 16 Female: 8 |
Male: 9 Female: 6 |
Age | 21–61 (Average: 38.3 ± 8.9) | 23–53 (Average: 34.9 ± 11.1) |
Serum IgE level before treatment (IU/ml) | 2129–58,737 (n = 13, Average: 16328.7 ± 16980.5) | 122–433.3 (n = 2) |
Serum TARC level before treatment (pg/ml) | 2366–23,339 (n = 3) | 737 (n = 1) |
EASI score before treatment | 13–59.4 (n = 17, Average: 35.1 ± 13.0) | 5.2–35 (n = 4) |
Clinical response of AD | Improved (n = 19) |
Improved (n = 10) Worsen (n = 1) |
Improvement rate of EASI score (%) | 46.5–98.7 (n = 11, Average: 82.8 ± 18.7) | 97.1 (n = 1) |
Duration from AA onset to dupilumab initiation | 0.5–27 years (n = 16, Average: 7.9 ± 9.1) | 2–5 years (n = 5) |
Duration from dupilumab initiation to hair regrowth or exacerbation | 2–13.5 months (n = 23, Average: 6.0 ± 3.0) | 2 days-1 year (n = 7) |
Improvement rate of SALT score | 4–100 (n = 19, Average: 73.6 ± 31.2) | - |
Abbreviations: AA, alopecia areata; EASI, eczema area and severity index; SALT, severity of alopecia tool; TARC, thymus and activation-regulated chemokine.
DISCUSSIONAA has been recognized as a type 1 autoimmune hair loss disorder; however, recent studies suggested possible involvement of type 2 immunity in the pathogenesis of AA,1,8-11 implicating the advantage of using dupilumab for AA. In line with this, a recent phase 2a randomized clinical trial demonstrated that dupilumab-treated AA patients with or without AD achieved SALT score improvement in 48 weeks, while placebo-treated group tended to have worsened SALT score.12 As this study enrolled AA patients irrespective of the presence of AD, it is debatable whether improvement of AA was achieved directly by the bioactivity of dupilumab or secondarily to immune modulation subsequent to withdrawal of AD. In accordance with the previous study investigating AA cases with intrinsic or extrinsic AD,8 our literature review suggested that AD-AA patients with high serum IgE levels (extrinsic AD) were inclined to show AA improvement and those with low IgE levels were prone to worsen/develop AA.
Case 4 is exceptional but educational because the clinical course clearly depicts the difficulty in the management of intractable AD-AA cases. Her AD only partially responded to dupilumab, as indicated by unexpected fluctuation of TARC level. Given that TARC level was elevated even during moderation of EASI score in this case, dupilumab could have been insufficient to suppress type 2 immunity involved in AA and AD, leading to the failure of controlling AA. Another possibility is that her AA was deviated to type 1 immunity which could be relatively upregulated by the suppression of type 2 immunity by dupilumab. Recent studies suggested that the pathophysiology underlying AD is rather complicated; consisting of type 1 and 2 immunity, IL-17/22 activation, impairment of epidermal barrier and intercellular lipid abnormality.13 The exact pathomechanism accounting for AA exacerbation and moderate improvement of AD in case 4 remains elusive; however, the observation may imply the complexity of AD pathophysiology in this case. The result of our literature review elucidated that 10 of 29 AD-AA cases have experienced worsening/development of AA despite AD improvement.4,8,14-21 Accordingly, early detection of AA exacerbation and switching to alternative therapeutic modalities is crucial in such cases. Considering possible involvement of immunological skewing to type 1 immunity in those cases,4 JAK inhibitors might be plausible substitutes.7 Indeed, one case listed in our review experienced simultaneous worsening of AD and AA on dupilumab. However, this case improved after the therapy was switched to oral cyclosporine and tofacitinib.7
It should be noted that dupilumab is currently approved for moderate to severe AD, bronchial asthma and chronic sinusitis with nasal polyp by FDA and Japanese health insurance system and not for AA. Furthermore, how dupilumab modulate AA pathophysiology has been ill-dissected. The findings of our cases as well as literature review alert physicians that use of dupilumab in expectation of AA improvement in AD-AA cases would not always be fruitful and could lead to unexpected exacerbation of AA in some patients.
CONFLICT OF INTERESTM.F. serves as an investigator of research project conducted by Eli Lilly Japan K.K. not related to this study and receives honorarium. M.K.I serves as an investigator for clinical trials conducted by Eli Lilly Japan K.K. and Pfizer Japan Inc. Y.M. declares no conflict of interest. M.O. receives advisory fee from Eli Lilly Japan K.K., Pfizer Japan Inc., Janssen Pharmaceutical KK., lecture fees from Eli Lilly Japan K.K., and research grants not related to the current work from Maruho Co., Sun Pharma Japan Ltd. and AbbVie G.K.
DATA AVAILABILITY STATEMENTThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
ETHICS STATEMENTApproval of the research protocol: This study was approved by the intramural review board committee of Kyorin University (No. H30-104).
Informed Consent: Informed consent was obtained from all patients in the form of opt-out.
Registry and the Registration No. of the study: N/A.
Animal Studies: N/A.
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Abstract
Objectives
Alopecia areata (AA) often coexists with atopic dermatitis (AD). Recently, several reports suggested that dupilumab, an interleukin 4 receptor α-antagonist, administration could be a promising medication not only for severe AD but also for AA concomitant with AD (AD-AA). At the same time, dupilumab has also been reported to exacerbate AA in AD-AA cases. Thus, the efficacy of dupilumab on AA in AD-AA cases remains controversial.
Methods
In this study, we retrospectively analyzed four AD-AA cases treated with dupilumab to evaluate its influence on AD and AA.
Results
All cases had suffered from severe AD since childhood and their average eczema area and severity index (EASI) scores prior to dupilumab administration was 43.2 ± 15.0. Three of four cases had moderate to severe multifocal AA, which successfully recovered in response to dupilumab, accompanied by the decrease in serum thymus and activation-regulated chemokine (TARC) levels and significant improvement of AD, achieving approximately 90% improvement of EASI scores within 3 months. In contrast, the remaining one case developed rapidly progressive hair loss 8 months after the initiation of dupilumab. In this case, AD was incompletely controlled by dupilumab with the elevation of serum TARC level despite AD improvement. The literature review found 39 dupilumab-treated AD-AA cases with elaborate description of clinical course; 24 cases with AA improvement, 15 cases with AA exacerbation, or new onset.
Conclusions
These findings alert physicians that use of dupilumab in expectation of AA improvement in AD-AA cases can lead to unfortunate consequence in some patients.
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