The emerging role of dupilumab in dermatological indications.
Napolitano Maddalena,Di Guida Adriana,Nocerino Mariateresa,Fabbrocini Gabriella,Patruno Cataldo
Expert opinion on biological therapy
INTRODUCTION:Dupilumab represents a breakthrough in the management of atopic dermatitis (AD), thanks to its powerful T-helper (Th)2-mediated immunity modulating activity. It can reduce the atopic skin molecular signature and induce a significant decrease in the clinical signs and symptoms of AD patients. AREAS COVERED:Th2 activation has been confirmed or suspected in skin diseases other than AD, and several reports about the treatment with dupilumab in these conditions have been published. In order to review the new indications of dupilumab in dermatology, we performed a search on PubMed, Embase, Cochrane Skin databases, and clinicaltrials.gov. EXPERT OPINION:The analysis of available literature suggests that dupilumab may have a large application in dermatology, besides AD. Clinical trials are underway on some widespread disease (i.e. chronic urticaria, bullous pemphigoid, alopecia areata, or allergic contact dermatitis). The data are still partial, but they seem to indicate that dupilumab is efficacious and safe. On the other hand, the dupilumab use in some rare skin diseases remains only hypothetical or linked to few case reports. Dupilumab could have a prominent position in the therapeutic algorithm of chronic skin diseases that significantly affect the quality of life of patients, require long-term treatment, or lacking effective therapies.
Immunological Properties of Atopic Dermatitis-Associated Alopecia Areata.
Kageyama Reiko,Ito Taisuke,Hanai Shiho,Morishita Naomi,Nakazawa Shinsuke,Fujiyama Toshiharu,Honda Tetsuya,Tokura Yoshiki
International journal of molecular sciences
Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4IL-4 cells and CD4IFN-γ cells to CD4IL-13 cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8IFN-γ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4 cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3 cells had no remarkable change while the number of CCR4 cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.
Evaluation of the level of serum Interleukins (IL-2, IL-4, IL-15 andIL-17) and its relationship with disease severity in patients with alopecia areata.
Aşkın Özge,Yücesoy Sera Nur,Coşkun Erkam,Engin Burhan,Serdaroğlu Server
Anais brasileiros de dermatologia
BACKGROUND:Alopecia areata (AA) is a hair disease that causes hair loss without scarring. The etiopathogenesis of AA has not been fully understood yet. OBJECTIVE:To determine serum interleukin levels (IL-2, IL-4, IL-15, and IL-17) in patients diagnosed with alopecia areata and to investigate the relationship of IL levels with the duration and severity of alopecia areata and the response to tofacitinib therapy. METHODS:Patients (≥16 years old) diagnosed with alopecia areata and healthy individuals as a control group was enrolled. Baseline serum interleukin levels of the patients and controls were measured. In the patient group receiving tofacitinib therapy, serum interleukin levels were measured again after 6 months. Disease severity for alopecia areata was assessed using the Severity of Alopecia Tool. RESULTS:Sixty-one AA patients and 30 healthy individuals were included; they were comparable regarding age and sex. The mean disease duration for AA was 7 ± 6 years and the baseline mean Severity of Alopecia Tool score was 71 ± 30 (range, 20-100). Baseline IL-2, IL-4 and IL-15 levels were significantly higher in the patient group than those in the control group (p < 0.001 for each). No significant correlation was found between the baseline interleukin levels and either disease duration or disease severity (baseline Severity of Alopecia Tool score). Among the patients receiving tofacitinib (n = 22), all interleukin levels significantly decreased after treatment. However, no significant relationship between the change in interleukin levels and the change in the Severity of Alopecia Tool scores was observed after tofacitinib treatment. STUDY LIMITATIONS:This is a monocentric study conducted in a single university hospital. CONCLUSION:High interleukin levels in alopecia areata patients and the significant decrease with treatment support the idea that interleukins have a role in pathogenesis. Nevertheless, no relationship could be demonstrated between IL levels and disease duration or severity.
Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients.
BACKGROUND:Treatments for alopecia areata (AA) patients with extensive scalp hair loss are limited, and recent evidence supports a role for type 2 T-cell (Th2)-immune response in AA. Dupilumab, a monoclonal antibody inhibiting Th2 signaling, approved for type 2 diseases including atopic dermatitis, was evaluated in AA patients. METHODS:Alopecia areata patients with and without concomitant atopic dermatitis were randomized 2:1 to receive weekly subcutaneous dupilumab (300 mg) or placebo for 24 weeks, followed by another 24-week dupilumab open-label phase. The primary outcome was change from baseline in the Severity of Alopecia Tool (SALT) score at week 24; secondary outcomes included a range of measures of hair regrowth. RESULTS:Forty and 20 patients were assigned to the dupilumab and placebo arms, respectively. At week 24, disease worsening was documented in the placebo arm, with a least-squares mean change in the SALT score of -6.5 (95% confidence-interval [CI], -10.4 to -2.6), versus a change of 2.2 (95% CI, -0.6 to 4.94) in the dupilumab arm (p < .05). After 48 weeks of dupilumab treatment, 32.5%, 22.5% and 15% of patients achieved SALT /SALT /SALT improvement, respectively, while in patients with baseline IgE ≥ 200 IU/ml response rates increased to 53.8%, 46.2%, and 38.5%, respectively. Moreover, baseline IgE predicts treatment response with 83% accuracy. No new safety signals were detected. CONCLUSIONS:This hypothesis-driven trial is the first to indicate the possible pathogenic role of the Th2 axis and Th2 targeting in AA patients. Patient selection based on baseline serum IgE levels may improve treatment results (Clinicaltrials.gov number, NCT03359356).
The Role of Serum Th1, Th2, and Th17 Cytokines in Patients with Alopecia Areata: Clinical Implications.
Waśkiel-Burnat Anna,Osińska Marta,Salińska Anna,Blicharz Leszek,Goldust Mohamad,Olszewska Małgorzata,Rudnicka Lidia
Alopecia areata is a type of non-scarring hair loss. The dysregulation of numerous systemic Th1 (IL-2, IFN-γ, TNF, IL-12, and IL-18), Th2 (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17E, IL-31 and IL-33) and Th17 (IL-17, IL-17F, IL-21, IL-22, IL-23 and TGF-β) cytokines was observed in patients with alopecia areata. Positive correlations between the severity of alopecia areata and an increased serum level of various cytokines including IL-2, TNF, IL-12, IL-17, and IL-17E were reported in the literature. An increased serum level of numerous cytokines, such as IL-2, IL-6, TNF, IL-12, IL-17E, and IL-22, was described as positively correlated with the duration of the disease. Moreover, it was shown that increased pre-treatment serum level of IL-12 was a positive, while increased serum levels of IL-4 and IL-13 were negative prognostic markers for the efficacy of diphenylcyclopropenone. In conclusion, alopecia areata is associated with the dysregulation of systemic Th1, Th2 and Th17 cytokines with their role in the pathogenesis, clinical manifestations and prognosis of the disease. Available data indicate the most significant role of serum IL-2, TNF, IL-12, IL-17, and IL-17E as markers of disease activity. The serum levels IL-4, IL-12 and IL-13 may be useful as potential predictors of diphenylcyclopropenone efficacy.
[Dermatology - Latest developments in targeted therapies for atopic dermatitis, alopecia areata and chronic spontaneous urticaria].
Piletta-Zanin Aurélie,Hsieh Aurélie,Mühlstädt Michael,Andenmatten-Trigona Béatrice
Revue medicale suisse
In recent years, a lot of targeted therapies have appeared on the market. The huge choice and rapid development make it sometimes difficult to stay up to date. This article reviews the latest therapies in the field of atopic dermatitis, alopecia areata and chronic spontaneous urticaria. Anti-IL-4 and anti-IL-13 antibodies and, more recently, JAK inhibitors have been proven to be effective for moderate to severe atopic dermatitis. JAK inhibitors seem promising for the treatment of severe alopecia areata. Ligelizumab and nemoli zumab will provide therapeutical options for chronic spontaneous urticaria and prurigo respectively. These breakthroughs will improve the quality of life of people suffering from invalidating dermatitis, at a certain price.
Remission of Alopecia Universalis after 1 Year of Treatment with Dupilumab in a Patient with Severe Atopic Dermatitis.
Romagnuolo Maurizio,Barbareschi Mauro,Tavecchio Simona,Angileri Luisa,Ferrucci Silvia Mariel
Skin appendage disorders
Alopecia areata (AA), an autoimmune disease with a relapsing-remitting course, represents the second cause of non-scarring alopecia worldwide and is associated with several comorbidities, notably atopic dermatitis (AD). In particular, AD is related to its more severe forms alopecia totalis (AT) and alopecia universalis (AU) [Nat Rev Dis Primers. 2017;3:17011]. Considering that AA has been classified as T helper 1-driven disease, whereas AD is the prototypical T helper 2 (Th2)-driven skin disorder, recent studies suggest that these forms may underlie a different chemokine expression resulting in a Th2 skewing as a key pathomechanism that could explain this association [JAMA Dermatol. 2015 May;151(5):522-8]. Several reports showed that dupilumab, a fully human monoclonal antibody targeting the interleukin 4α receptor and thus downregulating Th2 response, led to an improvement of AA associated with AD; most of these patients were females with AT or AU, early-onset AD, and atopic comorbidities [Exp Dermatol. 2020 Aug;29(8):726-32]. We report here a case to further support this hypothesis.
Dupilumab for alopecia areata treatment: A double-edged sword?
Journal of cosmetic dermatology
Alopecia areata (AA), which is a common and inflammatory hair loss and one of the most frequent dermatological conditions with higher incidence worldwide, the complex interplay involved multiple factors was contributed to the pathogenesis that consists of immune privilege losing and destruction with autoimmune-mediated in hair follicle also the abnormal regulation of inflammatory pathways was highlighted, although it was remained unclear to date.(J Am Acad Dermatol, 78, 2018, 1) Some treatment options for AA were proposed with great advances in recent years, but the options and efficacy were limited, such as platelet-rich plasma, JAK-STAT inhibitor, PDE4 inhibitor, and others, also the good response with regrow hair of cytokine-targeted therapy like dupilumab, ustekinumab was shown.(Clin Exp Med, 21, 2021, 215; Drugs, 80, 2020, 635) Here, we present a case with onset of AA following dupilumab treatment, the chronological relationship between the AA onset and dupilumab use should be known and emphasized.