Dupilumab-induced psoriasiform dermatitis in two pediatric cardiac transplant patients

Dupilumab is an interleukin-4 receptor antagonist important in the treatment of refractory atopic dermatitis (AD), particularly among pediatric patients. Two boys with a history of AD and cardiac transplant who developed psoriasiform dermatitis in response to dupilumab therapy are reported. These patients paradoxically developed an immune-mediated adverse drug reaction despite taking systemic immunosuppressive agents. While the literature suggests possible pathomechanisms for psoriasiform dermatitis despite immunosuppression, further research is necessary to better characterize this unique and unexpected phenomenon.     

生物制剂在特应性皮炎治疗中的进展

特应性皮炎是一种好发于儿童的慢性炎症性皮肤病,其发病机制复杂,免疫学异常是其发病的核心环节.以免疫调节、抗炎、恢复皮肤屏障为基础的传统治疗方案对部分难治性特应性皮炎的疗效欠佳.近年来,有越来越多关于靶向性生物治疗难治性特应性皮炎的疗效报道,其治疗机制包括抑制T/B淋巴细胞活化、抑制相关细胞因子及炎症介质的释放来发挥作用.研究显示,白细胞介素4及CD20拮抗剂治疗难治性特应性皮炎安全性高,且疗效较好.肿瘤坏死因子α及IgE抗体拮抗剂的疗效尚存争议.     

Assessing the need for routine safety testing for patients being treated with dupilumab for moderate-to-severe atopic dermatitis

Atopic dermatitis (also known as AD or eczema) is a common skin disease that can cause intense and persistent itching and rashes. Skin creams or ointments are not suitable or effective for some patients with moderate-to-severe AD. In these patients, oral (taken by mouth) or injected medications may be required. Some of those oral or injected treatments could be toxic and often have unwanted side effects, especially when used for a longer period of time, so patients must be regularly tested to see whether those treatments are harming their blood or organs. Dupilumab is a newer injectable drug for treating moderate-to-severe AD. Dupilumab specifically targets key molecules in the body that cause AD. Dupilumab has been tested for up to one year in more than 2000 patients enroled in placebo-controlled clinical trials. During those trials, patients provided blood and urine samples for laboratory testing while they were being treated with dupilumab or placebo (dummy drug). In this paper, the authors from Germany and the U.S.A, analysed how blood cells, blood chemistry, and urine chemistry changed during treatment, to check whether dupilumab is safe to use without the need for regular laboratory tests. After performing many routine laboratory tests on patients’ blood and urine, they found that there were no clinically important changes in test results that could be linked to dupilumab. They concluded that patients using dupilumab for moderate-to-severe AD do not need routine laboratory testing. This is a summary of the study: Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS)     

Clinical remission of disseminated molluscum contagiosum infection in a patient with atopic dermatitis treated with dupilumab

Atopic dermatitis predisposes to skin infections, and on the other hand, some therapies used for atopic dermatitis may worsen viral infections whose lesions may be more diffuse and resistant to treatment. The authors present a patient with severe atopic dermatitis and disseminated molluscum contagiosum infection. The molluscum contagiosum did not clear with topical treatment, and it worsened her atopic dermatitis even more, so the authors started treatment with dupilumab. After two months, the patient's dermatitis went into clinical remission and there was resolution of the infection with no recurrence at the 12-month follow-up. Dupilumab is nowadays a promising treatment for severe atopic dermatitis. To our knowledge, only four reports of molluscum contagiosum during dupilumab therapy have been reported in the literature, with contrasting effects. According to the authors’ experience, treatment with dupilumab appears to be a safe alternative for patients with severe atopic dermatitis who are also infected with molluscum contagiosum, as opposed to other treatments such as systemic corticosteroids or cyclosporine.     

The effect of topically applied corticosteroids on interleukin 1β levels in patients with atopic dermatitis

Background Atopic dermatitis (AD) is a chronic recurrent disease of childhood. The therapeutics of AD needs to be more tailored given the new cytokine antibodies available. In this scenario we considered interleukin 1 beta (IL‐1β) levels before and after therapy with topical corticosteroids. Objectives To measure the IL‐1β levels before and after treatment in patients with AD after 75% improvement in scoring for atopic dermatitis index. Methods Forty‐five subjects with AD were treated with betamethasone ointment and their IL‐1β level was measured prior to and following treatment. Results The IL‐1β levels were raised during disease activity and following improvement they decreased in a statistically significant manner. Also the IL‐1β levels corresponded with the severity of disease activity. Conclusions Newer modalities of therapy in the form of cytokine monoclonal antibodies should be studied in a larger scale in AD.     

Dupilumab treatment improves quality of life in adult patients with moderate‐to‐severe atopic dermatitis: results from a randomized,placebo‐controlled clinical trial

Atopic dermatitis is a skin disease, commonly known as eczema. It affects up to 1 in 10 adults. Atopic dermatitis is usually very itchy, causing people to wake up at night, and feel “low”. This state of general discomfort is known as reduced quality of life. Dupilumab is a new treatment approved in the U.S.A. for adults with moderate‐to‐severe atopic dermatitis. The treatment blocks some of the mechanisms involved in the disease. In a clinical trial conducted in Europe, researchers observed 109 patients with moderate‐to‐severe atopic dermatitis. The patients received dupilumab over 12 weeks. They found that the treatment improved the eczema and its symptoms, such as itch. The researchers also studied how the treatment affected quality of life in 64 out of 109 patients in the study. These patients had answered a set of questions that measures how atopic dermatitis affects their quality of life (Quality of Life Index for atopic dermatitis [QoLIAD]). Thirty‐two patients received dupilumab 300 mg weekly, by injection under the skin, and 32 received placebo. About 6 out of 10 patients treated with dupilumab had better quality of life over the 12 weeks, whereas only about 1 in 10 placebo‐treated patients improved. The researchers also found a relatively strong link between improvements with dupilumab in QoLIAD score and improvements in the eczema and symptoms. Dupilumab was well‐tolerated by the patients. The authors conclude that dupilumab, a new breakthrough treatment for atopic dermatitis, improves eczema and its symptoms, and in turn, the patients’ quality of life.     

Interleukin-18 is elevated in the horny layer in patients with atopic dermatitis and is associated with Staphylococcus aureus colonization

Background An increase in interleukin (IL)‐18 production from epidermal cells has been reported in an atopic dermatitis (AD) mouse model, and subsequent topical application of Staphylococcus aureus results in severe dermatitis. Objectives To reveal the relationship between S. aureus colonization of skin lesions and keratinocyte IL‐18 production, particularly in AD with relatively low serum IgE levels. We also aimed to establish a simple and noninvasive method of assaying IL‐18 produced by epidermal keratinocytes to evaluate local skin inflammation and therapeutic effects in patients with AD. Methods IL‐18 in the horny layer of the skin was collected via a tape‐stripping method and measured in 95 patients with AD and 40 healthy controls by enzyme‐linked immunosorbent assay (ELISA). Clinical severity, blood data and S. aureus skin colonization were evaluated before and after treatment. Results IL‐18 levels in the horny layer were significantly higher in the skin lesions of patients with AD than in healthy controls and correlated with SCORAD, levels of serum IL‐18, IgE, lactate dehydrogenase, thymus and activation‐regulated chemokine, blood eosinophils and transepidermal water loss. In the AD group with serum IgE < 1500 IU mL^?1, significantly higher IL‐18 levels were observed in the horny layer of patients colonized with S. aureus compared with those who were not. Conclusions Epidermal IL‐18 production was associated with the severity of AD. Staphylococcus aureus colonization seems to contribute to this IL‐18 production, especially in the AD group with relatively low IgE production. Tape stripping provides an easy and noninvasive method to assess epidermal IL‐18 production by ELISA.     

Omalizumab for the treatment of atopic dermatitis

Atopy is almost always associated with an elevated immunoglobulin (Ig) E production. Omalizumab is a monoclonal anti-IgE antibody that is currently indicated for the treatment of cases of asthma that satisfy certain criteria. A number of studies have been published on the usefulness of omalizumab in the treatment of atopic dermatitis, and the results have been variable. We present our experience in the treatment of 9 patients with severe atopic dermatitis refractory to at least 2 systemic drugs. All patients reported a decrease in pruritus and an improvement in quality of life. Good control of the skin disease was achieved with omalizumab in monotherapy in 2 patients, and there was a slight improvement in the eczematous lesions in 4 patients. Those patients who also had asthma achieved good control of their respiratory symptoms and did not require additional therapy. Omalizumab is a well-tolerated and safe drug that can be useful for the treatment of severe atopic dermatitis refractory to other systemic therapies. This monoclonal anti-IgE antibody is a major therapeutic advance as it opens the door to the management of atopic dermatitis using systemic immunomodulating therapies.     

Relationship between serum levels of interleukin-18, IgE and disease severity in patients with atopic dermatitis

Background. Interleukin (IL)‐18 is a pleiotropic cytokine. Synergistically with IL‐12, IL‐18 promotes immune responses of the T helper type, by enhancing synthesis of interferon‐γ and inhibiting IgE production. IL‐18 can also enhance production of IL‐4 and IL‐13 production, and stimulate synthesis of IgE. Moreover, in the presence of IL‐3, IL‐18 can directly stimulate basophils and mast cells to produce their mediators in an IgE‐independent manner. These results indicate a role for IL‐18 in the pathogenesis of atopic dermatitis (AD). Aim. To examine the association of serum IL‐18 with IgE levels and disease severity in patients with AD. Methods. ELISA was used to measure IL‐18 and total IgE levels in the sera of 67 patients with AD and 50 healthy volunteers. The SCORing Atopic Dermatitis (SCORAD) tool was used to determine the severity of this disease. Results. The mean serum level of IL‐18 in study group (155.68 pg/mL) was significantly higher than that of controls. IL‐18 was also significantly higher in the sera of the patients with severe AD than in those with milder disease. There was a correlation with IgE and IL‐18 levels, as patients who had high IgE levels also had high IL‐18 levels, compared with controls. Conclusion. IL‐18 seems to play an important role in the pathogenesis of AD, but this requires further study. IL‐18 could be a useful clinical marker of disease severity in AD.     

Naïve CD4+ T cells from patients with atopic dermatitis show an aberrant maturation towards IL-4-producing skin-homing CLA+ cells

Abstract: Overproduction of interleukin‐4 (IL‐4) has been reported in lesional and in peripheral T cells from patients with atopic dermatitis (AD). It is not clear whether the development of IL‐4‐producing T helper type 2 (Th2) cells from naïve precursors is an intrinsic phenomenon of T cells or whether other, extrinsic factors play a significant role. To analyze these alternatives, we investigated the IL‐4 production of effector T cells generated in vitro from highly purified CD4+ CD45RA+ naïve T cells in the absence of signals derived from antigen‐presenting cells. Effector T cells generated from naïve precursors from both AD and healthy donors produced comparable amounts of IL‐4 after restimulation. Priming in the presence of exogenous IL‐4 enhanced the production of IL‐4 while neutralizing endogenously produced IL‐4 abolished IL‐4 production similarly in atopic and healthy T cells. A subset of effector T cells acquired the expression of the cutaneous lymphocyte antigen (CLA). The frequency of CLA+ T cells was not different between atopic and healthy donors. CLA+ T cells, differentiated from naïve atopic, but not healthy T cells, showed a preferential Th2 cytokine profile as assessed by intracellular cytokine staining. Also effector T cells derived from atopic patients without dermatitis tended to show this imbalance, although it was not significantly different to healthy controls. This Th2 cytokine profile did not develop when naïve T cells were cultured in the presence of IL‐12. In conclusion, high IL‐4 production in developing T cells from AD patients was associated with CLA expression, the net IL‐4 production of all effector CD4+ T cells, however, was similar to IL‐4 production by T cells from healthy donors.     

Interleukin‐4 and interleukin‐13 evoke scratching behaviour in mice

Persistent and relapsing itch commonly manifests in inflammatory skin disorders such as atopic dermatitis (AD). AD pathogenesis is driven by interleukin‐4 (IL‐4) and interleukin‐13 (IL‐13). Dupilumab, a monoclonal antibody blocking the action of IL‐4 and IL‐13 effectively reduces the symptoms of AD and itch. Little is known whether IL‐4 and IL‐13 directly contribute to itch transduction. A recently published study (Oetjen et al, Cell, 2017, 171, 217) found IL‐4 and IL‐13 to directly activate itch‐sensory neurons in vitro. Surprisingly, they found no significant increase in scratching after intradermally injecting high doses (2.5 ug/ml) of IL‐4 and IL‐13 into mice. Similar experiments in our lab, however, suggested that both IL‐4 and IL‐13 contribute to acute itch in vivo. We intradermally injected lower doses (1 ug/ml) of IL‐4 and IL‐13 into mice and found a significant increase of scratching bouts compared to vehicle. Interestingly, the combined treatment of IL‐4 and IL‐13 produced additive increase of scratching and acute pruritus at an earlier time point compared to each cytokine administered alone. In summary, our study shows a rapid and significant increase of scratching after intradermal injection of IL‐4, IL‐13 or combined IL‐4/ IL‐13 compared to vehicle in mice 5‐10 minutes after injection. Our data suggest that IL‐4 and IL‐13 alone and combined directly act as potent acute pruritogens on sensory nerves. This finding expands our understanding of cytokines as pruritogens, how targeted anticytokine medications act in AD, and about neuroimmune communication in the skin.     

Long-term application of extracorporeal photochemotherapy in severe atopic dermatitis

BACKGROUND: Extracorporeal photochemotherapy (ECP) using UVA irradiation of enriched leukocytes in the presence of methoxsalen as a photoactivatable substrate has been employed for the treatment of several immunologically mediated disorders. OBJECTIVE: Our purpose was to determine the efficacy and safety of long-term ECP in the treatment of severe atopic dermatitis. METHODS: Fourteen patients with severe recalcitrant atopic dermatitis were treated with ECP in an open clinical trial at 2-week intervals. Disease activity was scored before each ECP cycle by means of a standardized protocol. RESULTS: A complete clinical remission was achieved in 4 patients (29%). Five patients (36%) experienced a substantial response with reduction of skin inflammation by at least 75%, whereas in one patient (7%) disease activity was reduced by more than 50%. Four patients were withdrawn from the study for unresponsiveness. No clinical signs of immunosuppression or other severe adverse events became evident. CONCLUSION: Long-term ECP may have significant beneficial effects on the course of atopic dermatitis and should therefore be considered as a treatment modality for patients suffering from severe and otherwise refractory atopic skin disease.     

Omalizumab for treatment of refractory severe atopic dermatitis. A pediatric perspective

Omalizumab is a monoclonal antibody, targeting Fc receptor of IgE, approved for the treatment of allergic asthma and chronic spontaneous urticaria. Its utility in atopic dermatitis appears controversial from data in literature since the molecule is well tolerated but it seems less effective than other medications used in adult patients (eg, Dupilumab). At present, the use of Dupilumab is not approved in pediatric patients therefore there are no second level treatments available in this age group. Here we report two clinical cases of patients (15 and 16 years old) suffering from both atopic dermatitis and asthma, treated with Omalizumab. Our experience suggests that atopic eczema of young patients with allergic comorbidities can benefit from asthma treatment with Omalizumab observing improvement on both conditions.     

Soluble E-selectin and eosinophil cationic protein are distinct serum markers that differentially represent clinical features of atopic dermatitis

The serum levels of eosinophil cationic protein (ECP), soluble E-selectin (sE-selectin), soluble CD14 (sCD14) and interleukin (IL)-4 are known to be elevated in patients with atopic dermatitis (AD). However, little is known of the mutual relationship between these factors. To elucidate the clinical and mutual relevance of these markers, we examined the serum levels of ECP, sE-selectin, sCD14 and IL-4 as compared with eruption scores, itch scores, total IgE and numbers of peripheral eosinophils in patients with AD (n = 43), non-atopic eczema (n = 24) and urticaria (n = 13) and in normal individuals (n = 45). In 27 patients with AD the levels of these markers were compared before and after treatment. Levels of ECP were elevated only in the patients with AD, whereas the sE-selectin levels were higher not only in AD but also in non-atopic eczema in a severity-dependent manner. The levels of both markers significantly diminished after treatment. Significant correlations existed between ECP levels and numbers of eosinophils, sE-selectin levels and itch scores, and sE-selectin levels and IgE levels. No significant changes were observed in the sCD14 and IL-4 levels. Taken together, sE-selectin and ECP are good but distinct serum markers that reflect different clinical features of AD.     

[Translated article] Haptens,Proteins, and Atopic Dermatitis

Atopic dermatitis is a chronic inflammatory disease that is multifactorial in nature. Allergic contact dermatitis and protein contact dermatitis are allergic conditions that may occur in the context of atopic dermatitis and be the cause of exacerbations. Although the prevalence of allergic contact dermatitis is similar in atopic patients and the general population, these 2 conditions are frequently associated because atopic inflammation disrupts the skin barrier. Skin tests are therefore recommended in atopic individuals. Dupilumab could be useful for treating allergic contact dermatitis if it is mediated by type 2 helper T cells but could exacerbate inflammation if mediated by T_H1 cells: further study is needed before conclusions can be drawn. Although the mechanism by which exposure to environmental proteins exacerbates atopic dermatitis remains under discussion, such exacerbations are routinely seen in clinical practice. Prick testing is recommended in symptomatic atopic dermatitis. When prick-test findings are positive, patients should be advised to avoid the culprit substances.     

Personalized Immunomodulatory Therapy for Atopic Dermatitis: An Allergist's View

The current standard medical therapy for atopic dermatitis (AD) mainly focuses on symptomatic relief by controlling skin inflammation with topical corticosteroids and/or topical calcineurin inhibitors. However, the clinical efficacy of pharmacological therapy is often disappointing to both patients and physicians. The terminology of AD contains a historical meaning of eczematous dermatitis caused by hypersensitivity reaction to environmental inhalant or food allergen. Complex interrelationships among genetic abnormalities, environmental triggers, skin barrier defects, and immune dysfunction resulting in a vicious domino-circle seem to be involved in the development and maintenance of AD. In the viewpoint of AD as an allergic disease, complete avoidance of clinically relevant allergen or induction of specific immune tolerance through administrations of allergen (allergen immunotherapy) can provide clinical remission by breaking the vicious domino-circle maintaining a chronic disease state. In recent clinical studies, monoclonal antibodies including the anti-interleukin-4 receptor antibody and anti-B cell antibody induced significant clinical improvements in patients with AD. The detailed characteristics of immune dysfunction are heterogeneous among patients with AD. Therefore, a personalized combination of immunomodulatory therapies to reduce hypersensitivity (allergen immunotherapy) and correct immune dysfunction (monoclonal antibody therapy) could be a reasonable therapeutic approach for patients with AD. Future immunomodulatory therapies for AD should be developed to achieve long-term treatment-free clinical remission by induction of immune tolerance.     

Haptenos,proteínas y dermatitis atópica

Atopic dermatitis is a chronic inflammatory disease that is multifactorial in nature. Allergic contact dermatitis and protein contact dermatitis are allergic conditions that may occur in the context of atopic dermatitis and be the cause of exacerbations. Although the prevalence of allergic contact dermatitis is similar in atopic patients and the general population, these 2 conditions are frequently associated because atopic inflammation disrupts the skin barrier. Skin tests are therefore recommended in atopic individuals. Dupilumab could be useful for treating allergic contact dermatitis if it is mediated by type 2 helper T cells but could exacerbate inflammation if mediated by T_H1 cells: further study is needed before conclusions can be drawn. Although the mechanism by which exposure to environmental proteins exacerbates atopic dermatitis remains under discussion, such exacerbations are routinely seen in clinical practice. Prick testing is recommended in symptomatic atopic dermatitis. When prick-test findings are positive, patients should be advised to avoid the culprit substances.     

Increased interleukin‐36γ expression in skin and sera of patients with atopic dermatitis and mycosis fungoides/Sézary syndrome

Interleukin (IL)‐36γ is expressed by keratinocytes and functions as a key initiator of inflammation in the skin. IL‐36γ expression is enhanced by tumor necrosis factor‐α and IL‐17A, having a strong association with psoriasis. In this study, we examined the role of IL‐36γ in atopic dermatitis (AD) and mycosis fungoides (MF)/Sézary syndrome (SS). Serum levels of IL‐36γ in AD patients and MF/SS patients were elevated compared with those of healthy controls. Importantly, serum IL‐36γ levels in AD patients positively correlated with Eczema Area and Severity Index and those of MF/SS patients positively correlated with serum soluble IL‐2 receptor levels. IL‐36γ mRNA levels in AD skin and MF/SS skin were significantly higher than those of normal skin. IL‐36γ mRNA levels in MF/SS skin positively correlated with IL‐17A mRNA levels. Immunohistochemical staining revealed that IL‐36γ was highly expressed in keratinocytes in lesional skin of AD and MF/SS. Taken together, our study demonstrated that IL‐36γ expression was increased in sera and skin of patients with AD and MF/SS as was reported in psoriatic patients.     

Serum eosinophil cationic protein in children with atopic dermatitis

BACKGROUND: Eosinophil cationic protein (ECP) is a cytotoxic agent secreted by activated eosinophils during allergic and inflammatory processes. The aim of the study was to determine the ECP level, absolute and relative eosinophil count and IgE antibodies in children with atopic dermatitis (AD) compared with those of nonatopic children, and to assess the correlation of these laboratory parameters with the clinical severity of AD. METHODS: This prospective study comprised 70 children. There were 49 children with AD aged 3-36 months, and the control group comprised 21 children with a negative personal and family history for atopic diseases. Detailed history, serum ECP levels (UniCAP FEIA), relative and absolute eosinophil counts and total serum IgE antibodies were determined in both groups. In the children with AD, skin involvement was measured by the SCORAD index. RESULTS: The calculated SCORAD index was between 16 and 83. IgE antibodies, relative and absolute eosinophil counts showed a significantly wider range of values and a statistically higher median (P < 0.001) in the patients with AD compared with the control group. These laboratory parameters did not correlate with the severity of AD. The serum ECP median level, in the children with AD, was 16.2 microg/L (range 3.01-65.30) compared with 5.92 microg/L (range 2.76-21.90) in the control group. Correlation of the total SCORAD index and the serum ECP levels was negative, weak (r = -0.065) and statistically not significant (P > 0.05). The same was found for the correlation of serum ECP and intensity of skin changes (r = -0.095) and serum ECP and subjective symptoms (r = -0.045). The correlation was positive, but weak and statistically not significant for the serum ECP and extent of the skin lesions (r = 0.079, P > 0.05). CONCLUSION: Elevated levels of ECP, relative and absolute eosinophil counts, as well as IgE antibodies were determined in the patients with AD. As these laboratory findings did not correlate with the severity of AD, they can be considered only as additional methods in the evaluation of patients with AD.