Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

Dupilumab shows long-term effectiveness in a large cohort of treatment-refractory atopic dermatitis patients in daily practice: 52-Week results from the Dutch BioDay registry.

BACKGROUND: Real-life data on long-term effectiveness and safety of dupilumab in atopic dermatitis patients are limited. OBJECTIVE: To study 52-week effectiveness and safety of dupilumab in a prospective multicenter cohort of adult patients with treatment-refractory atopic dermatitis. METHODS: Patients treated with dupilumab and participating in the Dutch BioDay registry were included. Clinical effectiveness and safety were evaluated. RESULTS: Two hundred ten atopic dermatitis patients were included. Mean percentage change in Eczema Area and Severity Index score after 16 weeks was -70.0% (standard deviation 33.2%) and further decreased to -76.6% (standard deviation 30.6%) by week 52. A greater than or equal to 75% improvement in the score was achieved by 59.9% of individuals by week 16 and by 70.3% by week 52. The most reported adverse effect was conjunctivitis (34%). Limited patients (17; 8.1%) discontinued dupilumab treatment. LIMITATIONS: Because of the lack of a control group and observational design, factors of bias may have been induced. CONCLUSION: Treatment with dupilumab resulted in a rapid improvement in clinical outcome measures, and effectiveness further improved during the 52-week follow-up period.

Management of dupilumab-associated conjunctivitis in atopic dermatitis.

Since September 2017, the monoclonal antibody dupilumab (Dupixent® ) has been approved in the EU for the treatment of moderate-to-severe atopic dermatitis. By blocking IL-4 and IL-13 signaling pathways, dupilumab improves both objective signs and subjective symptoms of the disease. Blocking of the IL-4aRα subunit leads to improvement of the skin's barrier function and reduction in Th2-mediated inflammation. While the rate of adverse events on dupilumab is generally low, mild-to-moderate conjunctivitis associated with redness as well as a burning and foreign body sensation has been reported in up to 28 % of patients. Treatment options include topical corticosteroids and topical calcineurin inhibitors. The present review highlights the clinical presentation of dupilumab-associated conjunctivitis and addresses pharmacological and non-pharmacological options available for the treatment of this clinically highly relevant condition.

Dupilumab in atopic dermatitis: rationale, latest evidence and place in therapy.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. The prevalence of AD is increasing and is currently estimated at 10-20% in adults worldwide. In the majority of patients, AD can be adequately controlled with topical treatment or ultraviolet light therapy, but there is a high unmet need for effective and safe therapeutics in patients with more severe or difficult to treat AD. During the past decade, new advances in the understanding of the underlying immune pathogenesis of AD have led to the development of new, more targeted therapies. Dupilumab, a fully human monoclonal antibody targeting the interleukin (IL)-4 receptor α, thereby blocking the IL-4 and IL-13 pathway, is one of the first biologics that has been developed for AD. Dupilumab has shown promising results in phase III trials and has recently been approved by the US Food and Drug Administration and the European Commission for the treatment of moderate to severe AD. With the approval of dupilumab, we are entering a new era of biological therapeutics in AD management. The place of dupilumab should be established in the current treatment standards. Based on current treatment guidelines and experts' opinions in the management of AD, we have built a proposal for a treatment algorithm for systemic treatment of AD in European countries.

When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council.

BACKGROUND: Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking. OBJECTIVE: To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient. METHODS: A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific literature review, referred to guidelines when available, and provided interpretation and expert opinion. RESULTS: We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy. LIMITATIONS: Our work is a consensus statement, not a systematic review. CONCLUSION: The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies.

Bone mineral density in patients with atopic dermatitis.

In a recent investigation of bone mineral density (BMD) in patients with moderate-to-severe AD, we found that one third of the patients had a low BMD, predominately males. This could be due to the use of topical corticosteroids or due to chronic inflammation. However, neither could be held responsible for the above finding. Low BMD at baseline does not seem to progress quickly, as assessed in a 2-year follow-up study. Treatment of low BMD is questionable as the effect of vitamin D and/or calcium supplementation on low BMD is controversial. We recommend performing long-term follow-up studies to assess the course of BMD over time from onset of AD.

Topical corticosteroids in atopic dermatitis and the risk of glaucoma and cataracts.

INTRODUCTION: There is concern about the development of glaucoma and cataracts associated with topical corticosteroid use in patients with atopic dermatitis (AD). OBJECTIVE: We evaluated glaucoma and cataract development in patients with AD to determine whether they are associated with the cumulative dose of topical steroids and the use of topical corticosteroids on the eyelids and periorbital region. METHODS: In all, 88 patients with AD were recruited from the University Medical Centre Utrecht. Patients were interviewed and completed a questionnaire assessing different factors such as AD involvement of eyelids and periorbital skin. The use of corticosteroids in previous years was obtained from pharmacy records. A complete ophthalmologic examination was performed for the presence of glaucoma and cataracts. RESULTS: Of the 88 patients (41 men and 47 women), with an average age of 37.2 ± 14.3 years (mean ± SD), one patient had transient ocular hypertension and one patient had optic disc cupping without any glaucomatous defects in his visual field. Seven patients were given the diagnosis of cataracts (one AD-related, two corticosteroid-induced, and 4 age-related). Both patients with corticosteroid-induced cataracts had also used systemic corticosteroids. In all, 37 of the 88 patients had used topical corticosteroids (class III and IV) on the eyelids and periorbital region, with an average frequency of 3.9 days per week and 6.4 months per year for 4.8 years. LIMITATIONS: Small sample size, objectiveness of patient recall about the use of topical corticosteroids on the eyelids/periorbital region, overestimation of topical corticosteroid use from pharmacy records, and lack of information on lifetime corticosteroid use were limitations. CONCLUSIONS: In this retrospective study glaucoma was not seen; two patients with AD had corticosteroid-induced cataracts, which were probably caused by the use of systemic corticosteroids. The application of topical corticosteroids to the eyelids and periorbital region, even over longer periods of time, was not related to the development of glaucoma or cataracts in this study population.

Narrowband ultraviolet B and medium-dose ultraviolet A1 are equally effective in the treatment of moderate to severe atopic dermatitis.

BACKGROUND: Phototherapy may be effective in atopic dermatitis (AD). Medium-dose (MD) ultraviolet (UV) A1 was introduced for the treatment of AD. Few immunohistochemical data are available pertaining to phototherapy in AD. Regulatory T cells may play a role in clearing AD. OBJECTIVES: We sought to compare the clinical and immunohistochemical effects of narrowband (NB) UVB and MD UVA1 treatment in patients with AD. METHODS: Thirteen adult patients with AD were included in this randomized investigator-blinded half-sided comparison study between NB UVB and MD UVA1. Disease activity was measured using the Leicester sign score. Skin biopsy specimens were taken before and after phototherapy. Regulatory T cells were stained with the forkhead box protein P3 (FoxP3). RESULTS: NB UVB and MD UVA1 both significantly decreased AD severity (P < .01) and the dermal cellular infiltrate. The percentage of FoxP3(+)CD3(+) T cells did not change after NB UVB or MD UVA1 treatment. LIMITATION: MD UVA1 therapy was given 3 times per week instead of the preferred regimen of 5 times per week. This was necessary to achieve good blinding of the study. CONCLUSIONS: NB UVB and MD UVA1 seem equally effective in the treatment of patients with moderate to severe AD. Neither MD UVA1 nor NB UVB had an effect on the percentage of FoxP3(+)CD3(+) T cells.