Dupilumab in Inflammatory Skin Diseases: A Systematic Review

Dupilumab was first approved for the treatment of atopic dermatitis (AD) and blocks the signaling of interleukin (IL)-4 and -13. Several other chronic skin conditions share mechanistic overlaps with AD in their pathophysiology, i.e., are linked to type 2 inflammation. Most recently, dupilumab was approved by the U.S. Food and Drug Administration for prurigo nodularis (PN). Given its relatively good safety profile, effective off-label use of dupilumab has been reported for a multitude of dermatologic diseases and several clinical trials for dermatologic skin conditions are currently ongoing. We conducted a systematic review of applications of dupilumab in dermatology other than AD and PN by searching the databases PubMed/Medline, Scopus, Web of Science and Cochrane Library as well as the clinical trial registry ClinicalTrials.gov. We found several reports for effective treatment of bullous autoimmune diseases, eczema, prurigo, alopecia areata, chronic spontaneous urticaria, Netherton syndrome and a variety of other chronic inflammatory skin diseases.


Introduction
Dupilumab is a human monoclonal IgG4 antibody directed against the interleukin (IL)-4 receptor alpha chain (IL4Rα) and inhibits signaling of both IL-4 and -13. These cytokines are key mediators of type 2 helper T cell (Th2)-related immune responses that drive atopic and many other inflammatory skin diseases. Th2-responses are associated with eosinophilia, basophil and mast cell recruitment and production of IgE. Dupilumab was first approved by the European Medicines Agency and the U.S. Food and Drug Administration in 2017 for the management of moderate-to-severe atopic dermatitis (AD) in adults, and more recently, in adolescents and children from the age of 6 months. Clinical trials showed long-term improvement of AD-signs and symptoms including pruritus, size and severity of skin lesions and overall quality of life, as well as lower rates of skin infections compared with placebo treatment [1][2][3]. Patient skin samples revealed downregulation of Th2 molecular markers, reduction of cellular infiltrate and an improved skin barrier function [4,5]. Beyond dermatology, dupilumab is also effective and approved for moderate-to-severe asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP) [6] and eosinophilic esophagitis. In addition, efficacy of dupilumab in prurigo nodularis (PN) and other forms of chronic prurigo was previously shown in several reports . The phase 3 clinical trials LIBERTY-PN PRIME and PRIME2 showed significantly reduced itch, amelioration of skin lesions, sleep, pain and quality of life compared to placebo treatment in a total of 153 treated patients (NCT04202679, NCT04183335). These findings led to the approval of dupilumab for PN in adults in September of 2022 [33].
Adverse events reported most frequently are nasopharyngitis, upper respiratory tract infections, headache, injection-site reactions and conjunctivitis [2]; further, facial and neck Nonscarring patchy hair loss on the scalp in a patient with alopecia areata. Progression can lead to total hair loss of the head (alopecia totalis, AT) or even the entire body (alopecia universalis, AU). (E) Chronic urticaria presenting with recurrent wheals that form and fade in rapid succession and can be accompanied with itch. (F) A pediatric patient with Netherton syndrome presenting with severe itchy chronic infiltration, lichenification and papulation of the skin resembling atopic dermatitis. (G) Mycosis fungoides in an elderly patient with localized dark patches on the trunk that are highly pruritic.

Methods
The databases PubMed/Medline, Scopus, Web of Science and Cochrane Library were queried for the terms ("dermatology" OR "skin" OR "dermatitis") AND "dupilumab" and reports published before 15 January 2023 were collected. Spelling variants of the query terms were included. Further, the registry ClinicalTrials.gov was queried for "dupilumab" as specialty specifications were frequently not denoted. The search strategy Progression can lead to total hair loss of the head (alopecia totalis, AT) or even the entire body (alopecia universalis, AU). (E) Chronic urticaria presenting with recurrent wheals that form and fade in rapid succession and can be accompanied with itch. (F) A pediatric patient with Netherton syndrome presenting with severe itchy chronic infiltration, lichenification and papulation of the skin resembling atopic dermatitis. (G) Mycosis fungoides in an elderly patient with localized dark patches on the trunk that are highly pruritic. This systematic review addresses clinical outcomes and potential future use of dupilumab in chronic inflammatory skin conditions.

Methods
The databases PubMed/Medline, Scopus, Web of Science and Cochrane Library were queried for the terms ("dermatology" OR "skin" OR "dermatitis") AND "dupilumab" and reports published before 15 January 2023 were collected. Spelling variants of the query terms were included. Further, the registry ClinicalTrials.gov was queried for "dupilumab" as specialty specifications were frequently not denoted. The search strategy was represented in a flow chart according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [38] (Figure 2).  Duplicate reports were identified automatically by PubMed or ClinicalTrials.gov identifiers (PMID or NCT registry numbers) and excluded. By screening based on titles and abstracts performed by hand, we then excluded duplicate reports not identified previously, articles in languages other than English, all review articles and meeting abstracts. Further, we excluded reports unrelated to the field of dermatology, reports on other drugs than dupilumab, or reports of sole in-label treatment with dupilumab (including treatment for AD or PN in adults), as well as reports of adverse events of inlabel dupilumab treatment.
The search was refined by full-text review after excluding articles that could not be retrieved. Here, we excluded reports other than case reports, case series, retrospective clinical studies or randomized controlled trials (RCT), reports that did not clarify clinical responses, and studies that had not yet reported. Further, reports of adult patients with chronic prurigo were excluded if the subtype of prurigo was not elucidated in order to Duplicate reports were identified automatically by PubMed or ClinicalTrials.gov identifiers (PMID or NCT registry numbers) and excluded. By screening based on titles and abstracts performed by hand, we then excluded duplicate reports not identified previously, articles in languages other than English, all review articles and meeting abstracts. Further, we excluded reports unrelated to the field of dermatology, reports on other drugs than dupilumab, or reports of sole in-label treatment with dupilumab (including treatment for AD or PN in adults), as well as reports of adverse events of in-label dupilumab treatment.
The search was refined by full-text review after excluding articles that could not be retrieved. Here, we excluded reports other than case reports, case series, retrospective clinical studies or randomized controlled trials (RCT), reports that did not clarify clinical responses, and studies that had not yet reported. Further, reports of adult patients with chronic prurigo were excluded if the subtype of prurigo was not elucidated in order to avoid repeated reporting of PN. The levels of evidence were categorized for each report adapting the Oxford Centre for Evidence-Based Medicine (OCEBM) levels of evidence table [39]: Level 5-singular case reports; level 4-case series or uncontrolled retrospective studies; level 3-prospective and interventional studies as well as controlled retrospective studies; level 2-randomized controlled trials and level 1-meta-analyses.

Eczema
Pruritus is often a prime symptom of eczema and hence, eczematous skin lesions frequently show signs of scratching and excoriation ( Figure 1A). A variety of eczema entities including atopic hand eczema (HE)/hand dermatitis or nummular eczema (NE) can have clinical and functional overlaps with AD. Still, hand and nummular eczema/dermatitis can develop in non-atopic individuals and without fulfilling diagnostic criteria for AD (e.g., Hanifin's and Rajka's criteria), thus, treatment with dupilumab in these conditions is currently off-label, or can be offered to patients with concomitant AD.
NE is characterized by coin-shaped eczematous plaques and was typically associated with skin microbial disbalance; yet, pathogenesis is highly heterogeneous. We identified retrospective case series with a total of 36 patients with NE treated with dupilumab. However, the majority of patients (30/36) had concomitant AD. Significant improvement of skin manifestations measured by the eczema area and severity index (EASI) or affected body surface area (BSA) as well as improvement in pruritus and quality of life was found in all treated patients, including 6 patients without AD. The responses were sustained in all but one patient during a follow-up period of up to 2 years (Table 1) [40,41]. The phase 2 placebo-controlled RCT DUPINUM (NCT04600362) investigating efficacy and safety of dupilumab in adults with NE is currently recruiting.
Contact dermatitis is frequently associated with the patient's occupation and can be caused by irritants (irritant-toxic contact dermatitis, ICD) or type-IV allergens (allergic contact dermatitis, ACD). ACD is found more frequently in patients with AD, suggesting a susceptibility to type-IV sensitivities possibly by a defective skin barrier. ACD mechanisms are highly variable and allergen-specific with, e.g., a strong Th1/Th17-polarization found for nickel while fragrances and rubber showed a Th2-bias [42]. Records found for a total of 67 patients with or without concomitant AD that were refractory to topical and systemic steroids as well as other systemic immunosuppressants and subsequently treated with dupilumab showed complete or partial responses in 65/67 patients (Table 1) [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]. In two cases, no effects of dupilumab were reported [60,61]. Interestingly, some reports demonstrated clinical remissions under dupilumab when allergen or irritant avoidance was not feasible. Other studies performed patch-testing before and after treatment with dupilumab and found that for most type-IV allergens except for fragrance and balsam of Peru, testing results remained positive despite overall clinical improvement [62]. Thus, larger studies considering allergen specificities and concomitant atopy are needed. Currently, two open-label phase 4 clinical trials evaluating dupilumab in ACD are recruiting (NCT05535738, NCT03935971).     Reports of eczema other than AD treated with dupilumab were identified via database search. Evidence levels 1 through 5 were assigned to each report according to the Oxford Centre for Evidence Based Medicine and denoted in parentheses after the study type. AD, atopic dermatitis; BSA, body surface area; CHE, chronic hand eczema; CVID, common variable immunodeficiency; DLQI, dermatology life quality index; EASI, eczema area and severity index; HE, hand eczema; HECSI, hand eczema severity index; MMF, mycophenolate mofetil; mo, month; MTX, methotrexate; NRS, numerical rating scale; q2w, biweekly; s.c., subcutaneous; SD, standard deviation; wk, week.
Chronic hand eczema, also known as dermatitis (CHE), can be a clinical form of AD (atopic HE), ACD or ICD, but unrelated etiologies are found as well. Frequent clinical phenotypes include chronic hyperkeratotic/fissured and recurrent dyshidrotic/vesicular HE among others. Reports of a total of 162 patients demonstrated clinical effectiveness of dupilumab in various subtypes of CHE for patients that had failed various topical and systemic therapies including most frequently topical and systemic steroids, topical calcineurin inhibitors, retinoids, ciclosporin A and phototherapy (Table 1) [63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78]. A prospective study following 72 patients with chronic fissured or vesicular HE for 52 weeks showed a mean reduction of 89% of the hand eczema severity index (HECSI, 95%; confidence interval 93.1-84.5%) and a 90% improvement of HECSI met by 62.9% with no difference between clinical subtypes [66]. Another retrospective study of 19 patients indicated significantly smaller effects of dupilumab in patients with hyperkeratotic CHE compared to all other investigated subtypes (p = 0.033) [65]. Likewise, a lack of response to dupilumab or even deterioration was reported in a total of 6 cases, all of which had hyperkeratotic CHE [65,67]. Two phase 2 placebo-controlled RCTs evaluating effects of dupilumab were found with one being currently active with patients with severe CHE (DUPSHE, NCT04512339) and one currently recruiting patients with moderate to severe CHE (DUPECZEMAIN, NCT03861455).
Localized or generalized eczema can develop in response to drugs in the form of druginduced eczematous eruption (EE) typically described for TNFα-inhibitors. Dupilumab treatment of EE induced by anti-IL-17 or -23 agents (tildrakizumab, brodalumab, ixekizumab and ustekinumab) given for underlying psoriasis or Crohn's disease led to complete clearance within months in all 4 reported patients [79,80]. EE of aging is an exclusion diagnosis and was treated with dupilumab leading to sustained improvement of skin lesions and itch in a total of 16 patients without a history of AD or atopic diathesis (Table 1) [81,82]. Furthermore, one record of a patient with EE associated with a common variable immunodeficiency (CVID) demonstrated complete resolution of skin manifestations within 8 weeks [83]. Secondary generalized eczematization in a patient with underlying chronic venous stasis dermatitis was treated with dupilumab which led to significant improvement of itch; however, new psoriasiform lesions developed subsequently and dupilumab was discontinued [84].

Chronic Pruritus and Prurigo
Chronic pruritus imposes a high disease burden and can be refractory to multiple treatment regimens including topical and systemic steroids as well as systemic antipruritic medications such as antihistamines, antidepressants, antiemetics, opioid-antagonists, cannabinoids and anticonvulsants. Etiologies are diverse and include AD and atopy as well as other dermatologic, systemic/metabolic or mental diseases. Th2-mediated inflammation with complex interactions between neurons, keratinocytes and immune cells via chemokines, neuropeptides, alarmins and proteases are described. This includes direct effects on sensory neurons by IL-4 and -13 [85]. Itch-scratch cycles can sustain pruritus and induce skin lesions ( Figure 1B). most notably, dupilumab was approved for prurigo nodularis (PN) in adults. Additionally, two case reports showed efficient use of dupilumab in weight-adjusted dosing schemes in pediatric patients with PN (Table 2) [86,87].
Chronic pruritus of unknown origin (CPUO) or chronic idiopathic pruritus refers to itch lasting more than 6 weeks without an underlying medical condition and can be accompanied by skin lesions. Opposed to skin lesions found in prurigo, CPUO manifestations are secondary. Several reports demonstrated efficient itch control by dupilumab measured by numerical scales, including a case series of 15 cases with a mean itch numerical rating scale (NRS)-reduction of 7 points (SD 1.9) as well as a series of 4 cases with a mean reduction of 8.75 points (SD 1.26). Notably, 26 out of 27 reported patients had no AD. In two cases, dupilumab was withdrawn after only 4 weeks and a sustained response was reported for a 20 weeks follow-up period (Table 2) [8,[88][89][90]. Currently, the placebo-controlled RCT LIBERTY-CPUO-CHIC (NCT05263206) is ongoing and recruiting.   Dupilumab further demonstrated efficiency in pruritus with various defined etiologies. This included 6 cases with uremic pruritus [8,91] and one case with cholestatic pruritus (Table 2) [92]. A clinical exploratory study evaluating dupilumab in cholestatic pruritus is currently recruiting (NCT04256759). Efficient treatment of localized pruritus was reported for a case of neuropathic brachioradial pruritus [93] and a case of anal and genital pruritus ( Table 2) [94].
Reactive perforating collagenosis (RPC) is characterized by umbilicated nodules with a central keratotic plug and is frequently associated with chronic kidney disease. Reports of six cases showed partial improvement of itch NRS as well as resolution of skin lesions under dupilumab treatment. Notably, three patients had no history of AD or atopy (

Bullous and Acantholytic Dermatoses
Dermatoses with sub-or intraepidermal cleft formation and blistering can be caused by autoantibody deposition and subsequent recruitment of effector cells [100], or by inherited defects of structural proteins of the dermoepidermal junction (DEJ) or the epidermis [101].
The most frequent acquired bullous dermatosis is bullous pemphigoid (BP) caused by IgG autoantibodies against BP180 and/or BP230 [102,103]. Autoantibody binding at the DEJ leads to complement fixation and, most prominently, the activation of neutrophils and eosinophils inducing itch and the formation of plaques and tense blisters ( Figure 1C). IL-4 and -13 as well as other Th2-cytokines were found in higher concentrations in sera of patients with BP, as well as in blister fluid [103]. Peripheral eosinophilia is often seen in blood and in inflamed skin. Further, total IgE concentrations in BP sera are frequently increased and correlate with disease severity [104]. Thus, therapeutic efficacy of dupilumab was hypothesized due to inhibition of eosinophil chemotaxis and activation directed by Th2-associated chemokines as well as reduction of IgG and IgE synthesis by B cells stimulated by Th2-responses.
Several case reports showed successful treatment of BP-patients that were resistant to previous standard of care treatments or had contraindications for high-dose systemic steroids or immunosuppressants leading to complete clinical remissions defined by resolution of skin lesions and pruritus (Table 3) [105][106][107][108][109][110][111][112][113][114][115][116]. This included one pediatric patient [117]. Efficient dupilumab mono-therapy inducing clinical remission was reported in 3 cases [118][119][120]. However, some reports showed only partial or no response [114]. In addition, 4 cases of checkpoint inhibitor-induced BP were treated efficiently with dupilumab, a favorable medication as strong immunosuppression needs to be avoided due to the underlying malignancy [121][122][123][124]. Two patients with BP presumably triggered by COVID-19 vaccinations were also treated efficiently with dupilumab [120,125]. most noticeably, two retrospective cohort studies compared co-therapy of dupilumab with conventional therapy against conventional therapy alone (comprised of systemic high-dose steroids and immunosuppressants) and found shorter median time to disease control, more rapid decline of itch measured by NRS and disease activity (measured by the BP disease activity index, BPDAI), higher quality of life (measured by the dermatology life quality index, DLQI) as well as lower cumulative doses of steroids and immunosuppressants in a total of 28 patients [126,127]. A large retrospective study (NCT05649579) and a placebo-controlled RCT evaluating dupilumab in BP (LIBERTY-BP, NCT04206553) are currently recruiting.
By contrast, pemphigus vulgaris (PV), the most frequent intraepidermal autoimmune blistering disease [135], is caused by autoantibodies against desmoglein-3 (Dsg-3), and eosinophilia is seen far less frequently than in BP. Two reports, however, showed efficiency of dupilumab as mono-therapy or as an add-on therapy to strong immunosuppression in a recalcitrant PV case (Table 3) [136,137]. This could be attributed to the finding of Dsg-3 reactive Th2-cells in PV-patients that might stimulate Dsg-3 autoantibody production by B lymphocytes [138]. However, data regarding dupilumab in pemphigus diseases is limited.        Dystrophic epidermolysis bullosa (DEB) is a hereditary subepidermal blistering disease caused by mutations in the gene for collagen 7 (COL7A1). DEB can be associated with intense pruritus highly refractory to anti-inflammatory (steroids, phototherapy) and antipruritic treatments and is termed epidermolysis bullosa pruriginosa (DEB-Pr). Dupilumab showed efficient reduction of itch measured by NAS and despite the hereditary origin of the disease also led to improvement of the skin findings in 6 patients with DEB-Pr that were resistant to extensive previous therapy regimes (Table 3) [139][140][141][142][143]. This reflects a putative Th2-mediated component of the disease and the role of itch-scratch cycles possibly similar to PN.
The most frequent hereditary intraepidermal blistering disease is Hailey-Hailey disease (HHD) often caused by mutations in ATP2C1 that lead to disrupted development of desmosomes of the epidermis and subsequent acantholysis. A total of seven patients were treated with dupilumab after extensive ineffective previous therapies including immunosuppressants, retinoids, antipruritic medications or dermabrasion with significant improvement of skin lesions, itch and quality of life in six patients (Table 3) [144][145][146]. One patient did not respond to dupilumab. HHD-caused skin barrier defects might give rise to secondary Th2-mediated local inflammation possibly inhibited by treatment with dupilumab.
Grover's disease (GD) is characterized histologically by acantholysis; yet, no disease mechanism is known. A total of five patients were reported with complete resolution of skin lesions and pruritus by dupilumab, including one patient with concomitant BP [124,[147][148][149].

Alopecia Areata
Despite being one of the most common forms of nonscarring hair loss, treatment options for alopecia areata (AA, Figure 1D) are still limited. Topical immunosuppression or immunomodulation (including topical steroids, diphenylcyclopropenone, squaric acid, photodynamic therapy), minoxidil as well as systemic immunosuppression, are used with varying effects. Recently, the JAK1/2-inhibitor baricitinib was approved for severe AA in adults. Disease mechanisms in AA are not fully elucidated and possibly heterogeneous: multiple studies suggested a major role of interferon (IFN)-γ-mediated Th1-responses, while others highlighted Th2-mediated effects and regulatory T cell (Treg) deficiency [150]. Notably, patients with AD have a high susceptibility to develop AA, with one study finding a 26-fold increased chance compared to healthy individuals [151], underlining the role of Th2-skewed responses in AA.
Additionally, a phase 2 randomized clinical trial (NCT03359356) [179] compared weekly injections of 300 mg dupilumab versus placebo and showed improvement in SALT at week 24 (p = 0.049) and week 48 (p < 0.0001) as well as 30% improvement in SALT (SALT30) at week 48 reached by 32.5% versus 20% (p = 0.067) and a 50% improvement in SALT (SALT50) at week 48 reached by 22.5% versus 15% (p = 0.02). Interestingly, high serum levels of IgE (>200 U/mL) as well as a medical history of AD or family history of atopy predicted a better outcome.
Conversely, several reports showed novel development of AA after commencing therapy with dupilumab for AD (exemplarily, [180]). Possible predictors of clinical outcomes (IgE serum levels, disease severity, concomitant atopy, age at onset, sex) have to be considered. Currently, a multicenter RCT is registered and not yet recruiting (NCT05551793).

Chronic Urticaria
Urticaria that lasts for more than 6 weeks is defined as chronic urticaria and can have a broad spectrum of etiologies and provocation factors causing recurrent urticae and swellings ( Figure 1E). Dupilumab may exert an inhibitory effect on mast cells by hindering IL-4 driven proliferation and chemotaxis, IL-4 regulated expression of FcεRI and by lowering IgE-production from B cells; also, IL-4 blockade can desensitize vascular structures towards histamine and decrease mast cell-mediated anaphylaxis [181].
Chronic spontaneous urticaria (CSU) entails the absence of identified causes of urticaria and can be highly debilitating and recalcitrant to standard treatments. A total of 14 patients were reported that had failed standard therapies with antihistamines, omalizumab and/or ciclosporin and were subsequently treated with dupilumab (12/14) or a combination of dupilumab and omalizumab (2/14) ( Table 5) [182][183][184][185][186][187][188][189]. Complete sustained resolutions were reported in 10/14 patients by clinical evaluation and the 7-day urticaria activity score (UAS7) or urticaria control test (UCT); a UAS7 of 0 was reported in 5 of these cases. In total, 3/14 patients had a partial response; one patient ended therapy due to financial reasons. Notably, 9/14 patients had AD or other signs of atopy. The placebo-controlled phase 3 clinical trial LIBERTY-CSU CUPID Study A investigated 138 patients with antihistamine-refractory CSU and found an 8.5 points-higher reduction of UAS7 in the dupilumab-treated cohort (p = 0.0003) as well as significantly reduced itch and hives at week 24; strikingly, the effects of dupilumab were independent of baseline serum IgE (NCT04180488) [190,191]. The phase 3 LIBERTY-CSU CUPID Study B enrolled 83 omalizumab-refractory CSU patients and was closed after interim analysis due to the lack of significant differences (NCT04180488). The phase 2 clinical trial DUPICSU (NCT03749135) has not published results, yet. Complete remission (2/2) after 8 wk, sustained at latest follow-up (5 or 23 mo) [185]  Besides CSU, dupilumab treatment in cases with chronic inducible urticaria with identified triggers were reported. A patient with cold urticaria experienced complete remission and tolerance to cold water under therapy with dupilumab [192]; one patient with exercise-induced cholinergic urticaria had a complete remission after 8 weeks with dupilumab [193]; further, a patient with adrenergic urticaria was efficiently treated with a combination of propranolol and dupilumab [194]. Three placebo-controlled RCTs are registered for evaluation of dupilumab in chronic inducible urticaria: A phase 2 RCT is recruiting adults with cholinergic urticaria (CHED, NCT03749148) and a phase 3 RCT for adults with cold urticaria is currently active (LIBERTY-CINDU CUrIADS, NCT04681729). Furthermore, a phase 3 RCT is currently recruiting children (2-12 years) with cold urticaria or CSU (LIBERTY-CSU/CINDU CUPIDKids, NCT05526521).

Netherton Syndrome and Other Hereditary Skin Diseases
Mutations in the gene SPINK5 in patients with Netherton syndrome causes dysfunction of the skin-expressed serine protease LEKTI that can lead to severe pruritus, skin inflammation and increased IgE. Subsequent epidermal remodeling makes patients susceptible to atopic manifestations resembling AD ( Figure 1F) as well as skin infections. Other typical findings are ichthyosis (type linearis circumflexa) and hair abnormalities (trichorrhexis invaginata). Dupilumab treatment for patients with Netherton syndrome was reported in a total of 16 cases (Table 6) [195][196][197][198][199][200][201][202][203][204][205]. All cases showed prompt resolution of itch measured by NRS and an improvement of skin lesions evaluated by EASI or BSA within 3 months. In patients with hair abnormalities, three cases reported improved hair growth while two reported no effect. The response was sustained in 14/16 cases for various follow-up periods, while two patients experienced a relapse after 8 or 20 weeks that was not sufficiently controlled by a dose increase and led to withdrawal of dupilumab [195,202]. Currently, a placebo-controlled RCT is recruiting (NS-DUPI, NCT04244006).Other congenital ichthyoses can lead to skin findings similar to AD by impaired skin barrier functions. Clinical improvement of ichthyosis in patients with concomitant AD treated with dupilumab was reported in a case of lamellar ichthyosis [206] and erythrodermic ichthyosis [207]. A partial response to dupilumab with improved skin findings but persistent itch was reported in one case of peeling skin syndrome 1 [208]. A case of ichthyosiform erythroderma caused by trichothiodystrophy with ERCC2-mutation experienced complete remission of skin lesions and pruritus with dupilumab [209]. An exploratory study in children with congenital ichthyoses compares effects of dupilumab and other biologicals to symptomatic treatment and is currently recruiting (NCT04996485).   Reports of patients with various hereditary primary skin diseases including Netherton syndrome and ichthyoses were collected from databases. Evidence levels 1 through 5 were assigned to each report according to the Oxford Centre for Evidence Based Medicine and denoted in parentheses after the study type. AD, atopic dermatitis; BSA, body surface area; DLQI, dermatology life quality index; EASI, eczema area and severity index; IVIG, intravenous immunoglobulins; mo, month; MTX, methotrexate; NRS, numerical rating scale; q2w, biweekly; q4w, every 4 weeks; s.c., subcutaneous; wk, weeks.
One report of a patient with neurofibromatosis type 1 treated with dupilumab for concomitant AD showed a size reduction of preexisting neurofibromas and stable size and number of neurofibromas for a follow-up of 1.5 years [210].
TTC7A deficiency is a rare congenital disease that leads to intestinal atresia and various immune defects; one patient with pruritic eczema and ichthyosis as well as immunologic findings suggesting vancomycin-induced linear IgA-dermatosis was treated efficiently with dupilumab and experienced complete sustained resolution of itch and skin findings [211].
Mutations in FOXP3 lead to dysfunction of Tregs and severe clinical findings termed IPEX syndrome often associated with various inflammatory skin diseases. One case of a patient with pruritic eczema due to IPEX syndrome was treated efficiently with dupilumab with sustained resolution of skin findings after a range of ineffective aggressive immunosuppressive therapies as well as bone marrow transplantation [212].
A patient with X-linked agammaglobulinemia that resulted in frequent skin infections and AD-like eczema experienced complete remission with dupilumab [213].

Eosinophilic Dermatoses
Peripheral and tissue eosinophilia is known to be promoted by IL-4, -5 and -13 by stimulating eosinophil trafficking and inducing other eosinophil chemoattractants [214]. Several dermatoses are specifically characterized by eosinophilic skin infiltrates or result from systemic eosinophilia.
Hypereosinophilic syndrome (HES) is a difficult to treat hematologic disease characterized by idiopathic blood eosinophilia that can present with pruritic eczema and other organ manifestations. A total of 11 patients with HES, 7 of which had skin manifestations, were treated with dupilumab after failure of systemic steroids. Of note, 2/7 patients reported a history of atopy. Improvement of skin lesions to various degrees was reported in 5/7 patients, one non-atopic individual experienced complete remission (Table 7) [215][216][217].
Hematologic malignancies can be associated with pruritic rashes with skin eosinophilia, a condition termed eosinophilic dermatosis of hematological malignancy (EDHM). We found records of four patients with EDHM treated with dupilumab after failure of systemic steroids, three of which had underlying chronic lymphatic leukemia and one small lymphocytic lymphoma. In two of the reported patients, strikingly, no eosinophilia was found in the blood. All four patients reported rapid complete clearance of skin manifestations within 4-6 weeks (Table 7) [8,[218][219][220].
Hyper-IgE syndromes can be caused by a variety of mutations and patients typically present with generalized eczema and peripheral eosinophilia. Clinically and mechanistically, eczema in hyper-IgE syndromes have a large overlap with AD. We found records of a total of 12 patients with hyper-IgE syndrome presenting with generalized pruritic eczema that was treated with dupilumab. Of those, seven patients had a mutation of STAT3, three of DOCK8 and one of ZNF341. A complete remission of pruritus and skin findings were reported in 10/12 patients andtwo patients showed partial remissions (Table 7) [221][222][223][224][225][226][227][228][229][230][231].
Further reports were found for Kimura's disease with 4 patients treated with dupilumab and 3/4 experiencing complete and one partial remission [232][233][234][235]. Four cases of steroidrefractory papuloerythroderma Ofuji treated with dupilumab all reported complete resolution of skin lesions and pruritus [236][237][238]. Two cases of highly steroid-and immunosuppressantrefractory Well's syndrome reported complete resolutions [239,240], as did two cases of the related erythema annulare eosinophilicum [241,242]. One case of eosinophilic fasciitis reported resolution of skin induration clinically and in MRI-studies under dupilumab treatment [243]. Further, one case of angiolymphoid hyperplasia with eosinophilia refractory to IL-5 inhibitors treated with dupilumab reported sustained resolution of pruritic skin lesions even after discontinuation of the therapy [244].

Connective Tissue Disorders
Several systemic or localized connective tissue inflammatory diseases are accompanied by pruritus. Th2-associated inflammation has been found in some diseases, but Th1pathways are more prominent in systemic collagenoses such as lupus erythematosus.
Dupilumab showed reduction of skin lesions and pruritus in one case of extragenital lichen sclerosus (Table 8) [245]; further, a phase 2 placebo-controlled study is recruiting patients for evaluating dupilumab in localized scleroderma (DupiMorph, NCT04200755).
No effects have, however, been shown for systemic collagenoses, e.g., in a case of dermatomyositis with severe pruritus, dupilumab was ineffective [246]. Notably, some reports showed newly developed lupus erythematosus in AD patients treated with dupilumab. In contrast, a case of steroid-refractory IgG4-related disease and concomitant AD with retroperitoneal fibrosis and pruritic skin manifestations showed resolution of fibrosis and skin lesions on dupilumab [247].
One report showed increased expression of Th2-associated transcripts (IL-4 receptor, IL-13) in keloid tissue in an individual with severe AD. Dupilumab was evaluated in a total of 12 reported cases with keloids (Table 8). One case showed size reduction of the keloid [248], one case with a highly pruritic keloid reported reduction of itch [249]; however, the remaining 10 cases did not report any effects of dupilumab or deterioration [250,251]. Two clinical trials evaluating dupilumab in keloids are currently recruiting (NCT04988022, NCT05128383).
Graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation can show clinical and histologic features of AD; a case series of 4 pediatric patients showed complete resolution of GVHD under treatment with dupilumab, while one patient did not respond [260].
One case found complete resolution of a severe palmoplantar pustulosis with dupilumab after lacking disease control with secukinumab in a non-atopic individual [261]. Psoriasiform dermatoses, however, have been implicated as adverse effects of dupilumab in other reports.
Lichen planus was treated efficiently with dupilumab in three cases, leading to resolution of skin manifestations and pruritus (Table 8) [8,262,263]. Conversely, also lichenoid dermatoses were reported as adverse effects of dupilumab.
Three cases of patients with hidradenitis suppurativa (HS) and concomitant AD showed remission of the previously uncontrolled HS after having failed systemic antibiotics and in one case adalimumab (Table 8) [264][265][266]. High AD-disease activity might impose an additional trigger to flares of HS, however, HS itself is mainly associated with Th1/Th17-responses.
One case of generalized granuloma annulare refractory to adalimumab showed a sustained partial response [267], however, emergence of granulomatous drug reactions was also reported under dupilumab therapy.    NCT 03793608 Records of patients with inflammatory connective tissue disorders or other inflammatory skin diseases not classified before were acquired from clinicaltrials.gov and databases. Evidence levels 1 through 5 were assigned to each report according to the Oxford Centre for Evidence Based Medicine and denoted in parentheses after the study type. AD, atopic dermatitis; CAD, chronic actinic dermatosis; DLQI, dermatology life quality index; GVHD, graft versus host disease; HiSCR, hidradenitis suppurativa clinical response; HS, hidradenitis suppurativa; IGA, investigator global assessment; IHS4, International Hidradenitis Suppurativa Severity Score System; LA, lichen amyloidosis; MMF, mycophenolate mofetil; mo, month; MTX, methotrexate; NRS, numerical rating scale; q2w, biweekly; q3w, every 3 weeks; q4w, every 4 weeks; s.c., subcutaneous; wk, weeks.
Lichen amyloidosus is characterized by extracellular deposits of amyloid proteins in the dermis with often intense pruritus. Reports of 4 patients with lichen amyloidosus and concomitant AD treated with dupilumab showed flattening of dermal papules and reduction of itch (Table 8) [268,269], a partial resolution was also observed in one non-atopic individual after failure of therapy with benralizumab [270].
Food allergies can be associated with AD. One case report of a patient that had suffered an anaphylactic shock after ingestion of corn and had detection of specific IgE against corn extract showed no reaction in a later oral provocation after 12 weeks of dupilumab therapy for AD [271]. A phase 2 clinical trial evaluating dupilumab in 24 patients with peanut allergy showed a tolerance to oral challenge after 24 weeks of therapy in 8.3% (NCT03793608). Another phase 2 study in patients with peanut allergy is completed and has not yet reported (NCT03682770); one was terminated due to COVID-19 (NCT04462055). Currently, a phase 2 study for patients with milk allergy is recruiting (NCT04148352).

Cutaneous Lymphoma
Cutaneous T cell lymphoma (CTCL), including mycosis fungoides and Sézary syndrome, is frequently accompanied by highly refractory pruritus that drastically affects quality of life, especially in palliative settings ( Figure 1G). Dupilumab showed reduction of itch as a supportive care treatment in 10 patients (Table 9) [272][273][274][275][276]. However, 7 of those experienced disease progression with two reported deaths; an average length of initial improvement of 1.9 months was reported for 6 patients. Other reports of 8 patients showed no response, primary worsening or new development of CTCL under dupilumab [274][275][276][277][278][279][280][281][282]. Possible mechanisms could be increased binding of IL-13 to IL-13RA2 expressed on lymphoma cells that is not inhibited by dupilumab. Thus, dupilumab could merely be considered a supportive care strategy for symptom control.
One patient with cutaneous B cell pseudolymphoma showed complete remission with dupilumab [283].
Further, one patient with a treatment-refractory generalized lichenoid drug eruption associated with mogamulizumab given for treatment of underlying MF reported complete resolution of the drug rash with dupilumab [284].

Discussion
This systematic review summarizes the existing evidence for treatment with dupilumab in other dermatologic conditions than atopic dermatitis and prurigo nodularis.
A high level of evidence (level 2 according to the OCEBM) was found for alopecia areata with a phase 2 RCT reporting significant improvement of the disease score SALT at week 24 and 48; however, conflicting case reports showed paradoxical reactions or lack of effects (15/66 reported patients).
Further, a high level of evidence (level 2) was found for antihistamine-refractory chronic spontaneous urticaria with a phase 3 RCT showing a significantly higher reduction of the disease score UAS7 compared with placebo in 138 treated patients. Anecdotal evidence was found for other forms of chronic urticaria.
For bullous pemphigoid, a medium level of evidence (level 3) was found based on multiple cohort studies. Dupilumab could become more relevant in checkpoint inhibitorinduced BP for patients with underlying malignancy.
A medium level of evidence (level 3) was also found for chronic hand eczema with a large prospective study showing an average 89% reduction of the disease score HECSI at 52 weeks. Numerous reports also showed efficacy of dupilumab in allergic contact dermatitis; however, the culprit allergen seemed to affect responses. Lower levels of evidence (level 4) were found for nummular eczema, chronic pruritus of unknown origin and Netherton syndrome. Anecdotal evidence (level 5) based on individual reports was shown for eczematous eruptions, cholestatic or uremic pruritus, perforating collagenosis, other pemphigoid diseases than BP and pemphigus diseases, epidermolysis bullosa dystrophica, Hailey-Hailey disease, Grover's disease, congenital ichthyoses and other genodermatoses, eosinophilic dermatoses such as Kimura's disease, chronic photodermatoses, graft-versus-host disease and food allergies.
For symptomatic treatment of cutaneous lymphoma, the reports were ambivalent and some showed progression or novel development of the underlying disease.
Strengths of this systemic review are the multifaceted comprehensive evaluation of dupilumab effects in a range of heterogeneous dermatologic conditions in order to give a broad overview. However, the evidence found was scarce or conflicting for many diseases and mainly based on individual reports; statistical meta-analysis was thus not feasible and larger cohort sizes are needed. In addition, many of the reported conditions can be considered multicausal with unidentified factors confounding the responses to dupilumab. In addition, dupilumab was frequently given as second-or third-line treatment in refractory patients.
As a drug with favorable safety profile as well as established and efficient clinical use for a broad range of patient populations [285], dupilumab holds significant promise for amending treatment options for a plethora of dermatologic conditions. With numerous clinical trials ongoing, we expect future expansion of the use of dupilumab in dermatology.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest:
All authors have read the journal's policy and the authors of this manuscript have the following competing interests: D.T. received honoraria and lecture fees from AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, Roche-Posay, Sanofi, Target-Solution and UCB. All other authors declare no conflict of interest.