Conjunctivitis in adult patients with moderate-to-severe atopic dermatitis: results from five tralokinumab clinical trials.

BACKGROUND: Tralokinumab, a fully human IgG4 monoclonal antibody that specifically binds with high affinity to interleukin-13, effectively reduces moderate-to-severe atopic dermatitis (AD) when given every 2 weeks. The incidence of conjunctivitis is elevated vs. placebo, but severity and aetiology have not been examined. OBJECTIVE: To analyse conjunctivitis data recorded in five randomized, placebo-controlled trials of tralokinumab in adult patients with moderate-to-severe AD. METHODS: Overall, 2285 adults with AD were studied up to 16 weeks. Cochran-Mantel-Haenszel weights were applied to calculate the adjusted incidence of adverse events. RESULTS: The incidence of conjunctivitis was higher (7·5%) with tralokinumab than with placebo (3·2%). Most events were mild or moderate in severity, and 78·6% and 73·9% of events resolved during the trial in the tralokinumab and placebo groups, respectively. Two (1·4%) events led to the permanent discontinuation of tralokinumab. An increased incidence of conjunctivitis, regardless of treatment group, was associated with more severe baseline AD, and history of allergic conjunctivitis/atopic keratoconjunctivitis, as well as the number of atopic comorbidities. LIMITATIONS: This analysis reports events up to week 16 only, with limited confirmation of conjunctivitis and its aetiology by an ophthalmologist, and insufficient reporting of ophthalmic treatments. CONCLUSIONS: Treatment with tralokinumab was associated with an increased incidence of conjunctivitis vs. placebo, but these cases were mostly mild and transient.

Validation of five patient-reported outcomes for atopic dermatitis severity in adults.

BACKGROUND: Structured patient-reported outcomes of atopic dermatitis (AD) severity are not standardized in clinical practice. OBJECTIVES: To determine the construct validity, internal consistency, cross-cultural validity and floor or ceiling effects of multiple AD severity assessments. METHODS: This is a cross-sectional, population-based study of 2893 adults, including 602 adults who met a modified set of U.K. diagnostic criteria for AD. AD severity was assessed using self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD) and its objective and subjective components, and numerical rating scale (NRS)-itch. Quality of life was assessed using Short-Form (SF)-12 mental and physical health scores, Short-Form Six Dimensions (SF-6D) health utility scores and Dermatology Life Quality Index (DLQI). Mental health was assessed with the Hospital Anxiety and Depression Scale (HADS). RESULTS: PO-SCORAD, PO-SCORAD objective and subjective subscores, NRS-itch and POEM all had moderate-to-strong correlations with each other and DLQI, fair-to-moderate correlations with HADS-anxiety and HADS-depression, and inverse correlations with SF-12 mental component score and SF-6D (Pearson correlations, P < 0·001). All scores showed good criterion validity as judged by anova and receiver operator characteristics. PO-SCORAD, PO-SCORAD objective subscore and POEM had similarly good internal consistency (Cronbach's alpha = 0·84, 0·82 and 0·86); the PO-SCORAD subjective subscore was less internally consistent (alpha = 0·57). All scores showed potentially poor cross-cultural validity as demonstrated by uniform and nonuniform differential item functioning by age, sex and/or race/ethnicity for multiple items. There were floor effects for POEM, but not for the other assessments. CONCLUSIONS: PO-SCORAD, PO-SCORAD objective and subjective subscores, NRS-itch and POEM appear to be valid for assessing AD severity in clinical practice. What's already known about this topic? Few studies have demonstrated the validity of the atopic dermatitis severity assessments Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD), PO-SCORAD subscores, numerical rating scale (NRS)-itch and Patient-Oriented Eczema Measure (POEM). What does this study add? This study demonstrates that PO-SCORAD, PO-SCORAD subscores, NRS-itch and POEM all had good construct validity in the assessment of atopic dermatitis severity in adults. Only POEM demonstrated floor effects. What are the clinical implications of this work? PO-SCORAD, PO-SCORAD subscores, NRS-itch and POEM all appear to have sufficient validity to be used as assessments of atopic dermatitis severity in clinical practice.

Symptoms and diagnosis of anxiety and depression in atopic dermatitis in U.S. adults.

BACKGROUND: The relationship between atopic dermatitis (AD), anxiety and depression in the U.S. adult population is not well established. OBJECTIVES: To determine the relationship of AD and its severity with symptoms and diagnosis of anxiety and depression in U.S. adults. METHODS: A cross-sectional, population-based study of 2893 adults was performed. AD was determined using modified U.K. Diagnostic Criteria. RESULTS: Adults with AD vs. those without AD had higher mean Hospital Anxiety and Depression Scale anxiety (HADS-A) (7·7 vs. 5·6) and depression (HADS-D) (6·0 vs. 4·3) scores and higher prevalences of abnormal (≥ 11) HADS-A (28·6% vs. 15·5%) and HADS-D (13·5% vs. 9·0%) scores. In multivariable linear and logistic regression models controlling for sociodemographics, AD was associated with significantly higher mean HADS-A and HADS-D scores (7·7 and 6·0) and higher odds of abnormal HADS-A [odds ratio (OR) 2·19, 95% confidence interval (CI) 1·65-2·91] and HADS-D scores (OR 1·50, 95% CI 1·04-2·17) (P ≤ 0·03 for all). Mean and abnormal HADS-A and HADS-D scores were increased in moderate and severe/very severe self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring AD (PO-SCORAD), PO-SCORAD itch and sleep (P < 0·0001 for all). All respondents with severe PO-SCORAD, POEM and PO-SCORAD itch had borderline or abnormal HADS-A and HADS-D scores. Adults with AD vs. those without AD had higher prevalence of self-reported healthcare-diagnosed anxiety or depression in the past year (40·0% vs. 17·5%). Many adults with AD who had borderline and/or abnormal HADS-A or HADS-D scores reported no diagnosis of anxiety or depression. CONCLUSIONS: AD is associated with significantly increased anxiety and depression, which may go undiagnosed. What's already known about this topic? Previous studies found higher rates of anxiety and depression in clinical cohorts of patients with atopic dermatitis. What does this study add? This study found dramatically higher rates of anxiety and depression among adults with atopic dermatitis in the U.S. population, which was primarily driven by atopic dermatitis severity. Anxiety and depression often go undiagnosed in adults with atopic dermatitis.

Distribution of atopic dermatitis lesions in United States adults.

BACKGROUND: The distribution of atopic dermatitis (AD) lesions and its impact on quality of life (QOL) is not well established in the US adult population. OBJECTIVE: To elucidate the distribution of AD lesions and its impact on QOL in US adults with AD. METHODS: A cross-sectional, population-based study of 602 adults was performed. AD was determined using modified UK Diagnostic Criteria, and its lesional distribution was assessed. QOL was assessed using Dermatology Life Quality Index (DLQI). Latent class analysis (LCA) was used to determine distinct phenotypes of AD lesional distribution. Multivariable logistic regression was used to determine the relationship between DLQI and distinct phenotypes. RESULTS: The most common sites of skin lesions were reported to be the popliteal fossae, lower legs, dorsal feet and antecubital fossae. Most persons reported partial (19.0%) or complete (63.0%) symmetry of lesions on the extremities. Lesions on the trunk were significantly more common in blacks and Hispanics. Age ≥ 60 years was associated with significantly lower proportions of active lesions on the face and scalp, and significantly higher proportion of lesions on the buttocks or genitals. LCA identified 5 classes of lesional distribution: 1. lower probabilities of lesions affecting any sites; 2. Higher probability of lesions involving the anterior and posterior neck and trunk; 3. lesions involving the antecubital fossae and upper extremities; 4. lesions involving the arms, posterior hands, genitals and buttocks, and to a lesser extent face, palms and legs; 5. lesions affecting all sites. Class-2 (multivariable logistic regression; adjusted odds ratio [95% confidence interval]: 7.19 [3.21-16.07], class-3 (7.11 [3.20-15.80]), class-4 (6.90 [3.07-15.50]) and class-5 (7.92 [3.54-17.71]) were all significantly associated with higher DLQI scores compared to class 1. CONCLUSION: AD is associated with heterogeneous distribution of AD lesions, and distinct phenotypes that are associated with QOL impact.

A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis.

BACKGROUND: Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production. OBJECTIVE: To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin. METHODS: This was a multi-centre, placebo-controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained. RESULTS: At baseline, 20% of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13 or EASI scores. CONCLUSIONS: This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted.

Atopic dermatitis complicated by eczema herpeticum is associated with HLA B7 and reduced interferon-γ-producing CD8+ T cells.

BACKGROUND: The increased susceptibility of patients with atopic dermatitis (AD) to disseminated viral skin infections such as eczema herpeticum (ADEH+) is poorly understood. OBJECTIVES: The primary goal of the current study was to determine whether ADEH+ subjects have identifiable defects in cell-mediated immunity that reduce their ability to control viral infections. MATERIALS AND METHODS: In this study, we evaluated cytokine expression by various subsets of peripheral blood mononuclear cells from ADEH+ (n = 24) compared with AD without a history of viral infections (ADEH-) (n = 20) before and after treatment with herpes simplex virus (HSV). RESULTS: We found that interferon (IFN)-γ expression after HSV treatment was lower in the CD8+ T cells and monocytes from patients with ADEH+ compared with patients who are ADEH- or nonatopic. Given the induction of CD8+ T cells as the result of antigen presentation by human leucocyte antigen (HLA) class I, consistent with the findings described above we also found that the HLA B7 allele was significantly associated with risk of the ADEH+ phenotype (odds ratio = 1·91, P = 0·02, 125 ADEH+ and 161 ADEH- subjects). CONCLUSIONS: These data suggest that defects in viral-induced IFN-γ from CD8+ T cells contribute to the ADEH+ phenotype.

Role of the thymus in natural tolerance to an autologous protein antigen.

C5-deficient mice grafted with thymus from C5-sufficient donors and immunized with C5 failed to make humoral antibody to C5, suggesting that the transfer of thymus had induced tolerance. Irradiated C5-deficient hosts repopulated with lymphoid cells from thymectomized C5-deficient mice grafted with C5-sufficient thymus also failed to respond to immunization with C5, thus showing that the state of tolerance can be adoptively transferred. These results demonstrate that natural tolerance to self-protein antigen is "learned" in the thymus.

Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis.

The mechanisms involved in the initiation and maintenance of skin inflammation in atopic dermatitis (AD) are poorly understood. Recent data suggest that the pattern of cytokines expressed locally plays a critical role in modulating the nature of tissue inflammation. In this study, we used in situ hybridization to investigate the expression of interleukin 4 (IL-4), IL-5, and interferon-gamma (IFN-gamma) messenger RNA (mRNA) in skin biopsies from acute and chronic skin lesions of patients with AD. As compared with normal control skin or uninvolved skin of patients with AD, acute and chronic skin lesions had significantly greater numbers of cells that were positive for mRNA, IL-4 (P < 0.01), and IL-5 (P < 0.01), but not for IFN-gamma mRNA expressing cells. However, as compared with acute AD skin lesions, chronic AD skin lesions had significantly fewer IL-4 mRNA-expressing cells (P < 0.01), but significantly greater IL-5 mRNA (P < 0.01). T cells constituted the majority of IL-5-expressing cells in acute and chronic AD lesions. Chronic lesions also expressed significantly greater numbers of activated EG2+ eosinophils than acute lesions (P < 0.01). These data indicate that although acute and chronic AD lesions are associated with increased activation of IL-4 and IL-5 genes, initiation of acute skin inflammation in AD is associated with a predominance of IL-4 expression whereas maintenance of chronic inflammation is predominantly associated with increased IL-5 expression and eosinophil infiltration.

Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis.

Evidence suggesting that prolonged effector cell survival may contribute to perpetuation of inflammation prompted us to ask whether monocyte macrophages, the predominate inflammatory cell in the lesion of chronic atopic dermatitis (AD), exhibit enhanced survival in AD. Cultures of peripheral blood monocytes from patients with chronic AD, psoriasis, and from normal (NL) donors were examined for morphologic features and DNA fragmentation characteristic of cells undergoing the process of apoptosis (programmed cell death). Cultures of AD monocytes exhibited a significantly lower incidence of apoptosis than did cultures of NL monocytes (45 vs 68%, P < 0.01), or psoriatic monocytes (45 vs 80%, P < 0.01). Furthermore, AD monocytes were unresponsive to both IL-1, an inhibitor of apoptosis, and IL-4, an enhancer of apoptosis, in comparison to cultured NL monocytes. Of note, GM-CSF in a concentration-dependent fashion, decreased the incidence of apoptosis in NL monocyte cultures and rendered them unresponsive to these cytokines. These findings suggested that GM-CSF may enhance monocyte survival in AD. In support of this hypothesis, AD monocyte cultures produced fivefold more GM-CSF than did cultures of NL monocytes or psoriatic monocytes (P < 0.05). Additionally, there was a significantly greater number of GM-CSF mRNA expressing cells detected by in situ hybridization in biopsies of lesions of chronic AD than in acute AD or NL skin (P < 0.05). Finally, NL monocytes incubated with supernatants obtained from monocytes of AD patients exhibited significant inhibition of apoptosis, an effect that could be ablated by a neutralizing antibody to GM-CSF. Taken together, these data strongly suggest that increased production of GM-CSF by cells from patients with AD inhibits monocyte apoptosis and may contribute to the chronicity of this inflammatory disease.

Recombinant gamma interferon in treatment of patients with atopic dermatitis and elevated IgE levels.

PURPOSE: Recombinant gamma interferon (rIFN-gamma) inhibits IgE synthesis in vitro by human peripheral blood mononuclear cells (PBMC). These data suggest a role for rIFN-gamma in the treatment of patients with severe atopic dermatitis (AD) and elevated IgE levels. The purpose of this study was to determine the effect of rIFN-gamma treatment on IgE production in patients with AD. PATIENTS AND METHODS: Twenty-two patients with chronic severe AD were treated with rIFN-gamma. In part I of the study, 14 patients were treated with daily subcutaneous injections at three successive dose levels (0.01 mg/m2, 0.05 mg/m2, and 0.1 mg/m2) for 5 days with 2 days off between each dose level. In part II, eight patients received rIFN-gamma at 0.05 mg/m2, daily for 6 weeks. One patient from part I and eight patients from part II of the study received three times per week maintenance thereby for up to 14 months. Prior to and at selected times during and after treatment, the clinical and immunologic status of the patients was assessed. RESULTS: In part I, spontaneous de novo IgE synthesis by PBMC was inhibited in 10 patients receiving rIFN-gamma at 0.01 mg/m2 (p = 0.038) and in nine at 0.1 mg/m2 (p = 0.066). There was no reduction of serum IgE levels at any of the three dose levels. Total clinical severity showed improvement at each dose level (p less than 0.04) with worsening 3 days after discontinuation of treatment. In part II, there was no significant inhibition of spontaneous IgE synthesis by PBMC nor was there any reduction of serum IgE. Nevertheless, there was a progressive and significant reduction (p less than 0.01) in total clinical severity over the 6 weeks of daily rIFN-gamma with a sustained improvement during maintenance therapy. CONCLUSION: The results of this pilot study suggest that rIFN-gamma may be efficacious in the treatment of AD and that further clinical trials are warranted.

Adverse reactions to antibiotics: is the patient really allergic?

Many patients who believe themselves allergic to an antibiotic could in fact be given the suspected drug or a related agent safely. A systematic approach incorporating knowledge of immunopathogenic mechanisms, availability and limitations of diagnostic tests and therapeutic options will lead to successful management of these challenging patients.

Legionella and Pneumocystis pneumonias in asthmatic children on high doses of systemic steroids.

Asthma is increasingly treated as an inflammatory disease with inhaled and/or systemic corticosteroids. We report 3 cases of unusual pneumonias associated with high doses of oral steroids. Two patients contracted Legionella pneumonia and one patient contracted Pneumocystis carinii pneumonia. With increasing usage, it is important for physicians to be aware of the possible infectious complications of high dose steroids. This report highlights the risk of corticosteroid treatment in asthma in predisposing to opportunistic infections that have not heretofore been readily associated with asthma.

Pathophysiologic mechanisms in atopic dermatitis.

Atopic dermatitis is a common, chronic inflammatory skin disease that frequently predates the development of asthma and/or allergic rhinoconjunctivitis. Recent studies have provided new insights into how the complex interrelationship of genetic, environmental, and immunologic factors may contribute to the development of atopic dermatitis. This article examines some of the factors involved in chronic cutaneous inflammation in this disease. Greater understanding of the mechanisms that underlie the pathophysiology of atopic dermatitis may lead to improved treatment strategies for this increasingly common skin disease.

Addition of topical pimecrolimus to once-daily mid-potent steroid confers no short-term therapeutic benefit in the treatment of severe atopic dermatitis; a randomized controlled trial.

BACKGROUND: Combination therapy with pimecrolimus cream 1%, a topical calcineurin inhibitor (TCI), and fluticasone propionate cream 0.05% (FP), a mid-potency topical corticosteroid, may have a synergistic effect for treatment of atopic dermatitis (AD) because their mechanism of action differs. OBJECTIVES: To assess the efficacy of concomitant pimecrolimus twice daily/FP once daily vs. vehicle twice daily/FP once daily in patients with severe AD. METHODS: An exploratory, 2-week, double-blind, randomized, within-patient study was conducted (n = 45). Two target areas of similar severity, size and location were assessed. Assessments included the modified Eczema Area and Severity Index (0-12 scale) (primary variable), localized investigator global assessment (0-4 scale) and Patients' Self-Assessment of Disease Severity (0-4 scale). RESULTS: Data for all variables were similar for the TCI/FP and vehicle/FP treatments. CONCLUSIONS: The efficacy observed for treatment of severe AD flares with this TCI/FP combination regimen was equivalent to that of vehicle/FP.