Quality of life and healthcare costs of patients with allergic respiratory diseases: a cross-sectional study.

BACKGROUND: Allergic rhinitis (AR) and allergic asthma (AA) are chronic respiratory diseases that represent a global health problem. One aim of this study was to analyze the Health-related Quality of Life (HRQoL) of the patients in order to identify statistically significant influencing factors that determine HRQoL. Another aim was to assess and analyze data on cost-of-illness from a statutory health insurance perspective. METHODS:  The EQ-5D-5L was used to evaluate the patients' HRQoL. To identify the factors influencing the HRQoL, a multinomial logistic regression analysis was conducted using groups based on the EQ-5D-5L index value as dependent variable. Routine data were analyzed to determine total healthcare costs. RESULTS:  The average EQ-5D-5L index was 0.85 (SD 0.20). A high age, the amount of disease costs, low internal health-related control beliefs and high ozone exposure in the residential area were found to be statistically significant influencing factors for a low HRQoL, whereas low age, male sex and a good possibility to avoid the allergens were found to be statistically significant factors influencing a high HRQoL. On average, the study participants incurred annual costs of €3072 (SD: 3485), of which €699 (SD: 743) could be assigned to allergic respiratory diseases. CONCLUSIONS:  Overall, the patients in the VerSITA study showed a high level of HRQoL. The identified influencing factors can be used as starting points for improving the HRQoL of patients with allergic respiratory diseases. From the perspective of a statutory health insurance, per person expenditures for allergic respiratory diseases are rather low.

Assessment of the Immune Response to Tumor Cell Apoptosis and Efferocytosis.

Apoptotic cells are cleared from the body principally through recognition and engulfment by neighboring phagocytes, a process known as efferocytosis. During efferocytosis, phagocytes are recruited to the site/activated by "find me" signals released from apoptotic cells, precisely identify apoptotic cells by the recognition of "eat me" signals on the apoptotic cell surface, and engulf the apoptotic cells to prevent secondary necrosis and inflammation. Thus, efferocytosis is critical for tissue homeostasis in normal physiology. However, efferocytosis of apoptotic tumor cells-performed by tumor-associated macrophages-suppresses immunity within the tumor microenvironment and limits the antitumor response. This phenomenon is further exacerbated in tumor residual disease because of the high apoptotic cell burden generated by cytotoxic therapies. Blocking efferocytosis could be a powerful approach to boost tumor immunogenicity, particularly as a combination approach with cytotoxic therapies that produce many apoptotic cells, but little is currently known about the immune response to efferocytosis. Moreover, there is a dearth of in vivo models available to study the immunologic and therapeutic consequences of blocking efferocytosis in tumor residual disease.Here, we describe a model that enables in vivo studies of tumor immunology in the aftermath of cytotoxic therapy with an emphasis on the impact of efferocytosis. Orthotopic HER2+ mammary tumors are established in immune-competent mice, followed by a single administration of lapatinib, a receptor tyrosine kinase inhibitor of HER2, to the mice that induces widespread, transient apoptosis in the tumor microenvironment. In the days following lapatinib treatment, agents that block efferocytosis such as BMS-777607 are administered. Tissue is collected from cohorts of mice at day 2 (after lapatinib treatment only) to assess apoptosis, day 8 (after lapatinib treatment followed by blockade of efferocytosis) to assess the immune response to apoptosis and efferocytosis, and day 28 (after 4 consecutive weeks of treatment) to assess therapeutic efficacy. This model enables mechanistic studies of tumor immunology in residual disease as well as therapeutic efficacy studies of targeted agents that disrupt efferocytosis.

Assessment of the effects of a work-related allergy to seafood on the reduction of earning capacity in the context of BK No. 5101.

Fish, crustaceans, and mollusks are among the most potent allergenic foods of animal origin and are thus important triggers of work-related immediate-food allergies. In Germany, work-related seafood allergies are of great importance in the fishing and processing industries as well as in the areas of food preparation, food control, and food sales. There is no causal therapy of seafood allergy, only the strict and lifelong avoidance of allergens remains. The following recommendations serve to assess the impact of a seafood allergy with regard to the work opportunities ended by it for the assessment of the reduction of earning capacity (MdE (German for Minderung der Erwerbsfähigkeit)) in the context of the occupational disease number 5101 of the Annex to the German regulation for occupational diseases. As a special feature of work-related seafood allergy with regard to insurance law aspects, it must be taken into account that there is a potential risk of systemic reaction with subsequent multi-organ involvement. For the estimation of MdE in the general labor market, the impact of a seafood allergy can therefore be assessed, depending on its clinical severity, as generally "mild" to "severe" in justified individual cases.

Efficacy and safety of dupilumab for moderate-to-severe atopic dermatitis: A systematic review for the EAACI biologicals guidelines.

This systematic review evaluates the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled moderate-to-severe atopic dermatitis (AD). Pubmed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important AD-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Seven RCTs including 1845 subjects >12 years treated with dupilumab 16 to 52 weeks were evaluated. For adults, there is high certainty that dupilumab decreases SCORAD (MD -30,72; 95% CI -34,65% to -26,79%) and EASI-75 (RR 3.09; 95% CI 2.45 to 3.89), pruritus (RR 2.96; 95% CI 2.37 to 3.70), rescue medication (RR 3.46; 95% CI 2.79 to 4.30), sleep disturbance (MD -7.29; 95% CI -8.23 to -6.35) and anxiety/depression (MD -3.08; 95% CI -4.41 to -1.75) and improves quality of life (MD -4.80; 95% CI -5.55 to -4.06). The efficacy for adolescents is similar. Dupilumab-related adverse events (AEs) slightly increase (low certainty). The evidence for dupilumab-related serious AE is uncertain. The incremental cost-effectiveness ratio ranged from 28 500 £ (low certainty) to 124 541 US$ (moderate certainty). More data on long-term safety are needed both for children and for adults, together with more efficacy data in the paediatric population. Registration: PROSPERO (CRD42020153645).

Online survey to identify current challenges in atopic dermatitis management and guideline implementation in German-speaking countries.

BACKGROUND: Atopic dermatitis (AD) is a relapsing chronic inflammatory skin disease with a significant public health burden. OBJECTIVES: To conduct a survey in order to gain information on current problems on the care and treatment of AD patients from a wide range of care providers, as well as information on ways of improving AD guidelines. MATERIALS & METHODS: An online survey was conducted via professional associations, focussing on AD health care professionals with regards to current gaps in knowledge of AD management and experience based on the German guidelines (GL). RESULTS: In total, 542 respondents treated a median of 200 AD patients yearly. The most frequent problems in the management of AD concerned emollients (50%), largely due to patient costs and the inability to prescribe emollients/moisturizers. Barriers to prescribing biologics included cost. Respondents stated that the GL lacks information regarding patient education (27%) and use of basic emollients (27%). Consideration should be given to feasibility issues (32%) and the addition of care pathways (41%) to improve the GL. CONCLUSION: In this survey, we identified inadequate basic AD care mainly due to patient costs and lack of time for counselling as real-life challenges. These issues remain to be addressed in future guidelines.

Impact of increasing treatment rates on cost-effectiveness of subcutaneous immunotherapy (SCIT) in respiratory allergy: a decision analytic modelling approach.

BACKGROUND: Specific immunotherapy is the only causal treatment in respiratory allergy. Due to high treatment cost and possible severe side effects subcutaneous immunotherapy (SCIT) is not indicated in all patients. Nevertheless, reported treatment rates seem to be low. This study aims to analyze the effects of increasing treatment rates of SCIT in respiratory allergy in terms of costs and quality-adjusted life years (QALYs). METHODS: A state-transition Markov model simulates the course of disease of patients with allergic rhinitis, allergic asthma and both diseases over 10 years including a symptom-free state and death. Treatment comprises symptomatic pharmacotherapy alone or combined with SCIT. The model compares two strategies of increased and status quo treatment rates. Transition probabilities are based on routine data. Costs are calculated from the societal perspective applying German unit costs to literature-derived resource consumption. QALYs are determined by translating the mean change in non-preference-based quality of life scores to a change in utility. Key parameters are subjected to deterministic sensitivity analyses. RESULTS: Increasing treatment rates is a cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of 3484€/QALY compared to the status quo. The most influential parameters are SCIT discontinuation rates, treatment effects on the transition probabilities and cost of SCIT. Across all parameter variations, the best case leads to dominance of increased treatment rates while the worst case ICER is 34,315€/QALY. Excluding indirect cost leads to a twofold increase in the ICER. CONCLUSIONS: Measures to increase SCIT initiation rates should be implemented and also address improving adherence.

Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes.

The cytokine thymic stromal lymphopoietin (TSLP) is involved in the development and the progression of allergic diseases. It is mainly released by epithelial cells at barriers such as skin and gut in response to danger signals. Overexpression of TSLP in keratinocytes (KC) can provoke the development of a type 2 inflammatory response. Additionally, TSLP directly acts on sensory neurons and thereby triggers itch. Since histamine is also increased in lesions of inflammatory skin diseases, the aim of this study was to investigate possible effects of histamine as well as different histamine receptor subtype agonists and antagonists on TSLP production in KC. We therefore stimulated human KC with histamine in the presence or absence of the known TSLP-inductor poly I:C and measured TSLP production at protein as well as mRNA level. Histamine alone did not induce TSLP production in human KC, but pre-incubation with histamine prior to challenge with poly I:C resulted in a significant increase of TSLP production compared to stimulation with poly I:C alone. Experiments with different histamine receptor agonists (H1R: 2-pyridylethylamine; H2R: amthamine; H2R/H4R: 4-methylhistamine (4MH)) revealed a dominant role for the H4R receptor, as 4-MH in combination with poly I:C displayed a significant increase of TSLP secretion, while the other agonists did not show any effect. The increase in TSLP production by 4MH was blocked with the H4R antagonist JNJ7777120. This effect was reproducible also in the murine KC cell line MSC. Taken together, our study indicates a new role for the H4 receptor in the regulation of TSLP in keratinocytes. Therefore, blocking of the H4R receptor in allergic diseases might be promising to alleviate inflammation and pruritus via TSLP.

International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics.

This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal. The conclusions below focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein.

Psoriasis predisposition and occupational triggering factors in the appraisal of occupational medical expertises.

BACKGROUND: Psoriasis is an immune-mediated disease with a genetic background. Local psoriatic changes can be triggered by exogenous mechanical or irritant factors. Causative occupational factors have to be distinguished from the spontaneous course of psoriasis in occupational medical evaluations. The objective of this work is to demonstrate the medico-legal grounds for a homogenous assessment. PATIENTS AND METHODS: The presented recommendations were developed in a working group for Occupational and Environmental Dermatology (ABD) and the German contact dermatitis group (DKG) of the German Dermatologic Society (DDG) based on the German medico-legal framework. RESULTS: Causality between the insured activity and the appearance of psoriasis is a prerequisite for the recognition of the occupational nature of the disease. This is the case if the occupational activity is the exclusive or a legally essential contributing factor either for first manifestation or aggravation of the disease. A connection must be denied if everyday events are sufficient to trigger the psoriasis. From 1995 to 2010, 130 cases of psoriasis have been recognized as occupationally related by the German statutory accident insurance. CONCLUSIONS: The appraisal of psoriatic disease in the occupational medical evaluation is subject to the case assessment of the expert witness. In this position paper we present recommendations for a homologous basis for diagnosis, causality assessment, estimation of reduction in earning capacity and rehabilitation of occupational psoriasis.

Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor.

BACKGROUND: Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood. OBJECTIVE: Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes. METHODS: The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin. RESULTS: We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan. CONCLUSION: H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.

Therapy of moderate and severe psoriasis.

OBJECTIVE AND METHODS: This health technology assessment (HTA) report synthesises systematically randomized controlled studies (RCT) on the therapy of moderate and severe psoriasis vulgaris which were published between 1999 and 2004; it includes some important clinical studies which have been published after 2004 and thus updates the English HTA report by Griffiths et al. [1]. The major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany. RESULTS: The major conclusions from the results of medical RCT on moderate and severe psoriasis vulgaris are: Oral fumarates are effective in the treatment of moderate to severe psoriasis vulgaris. However, fumarates quiet frequently cause moderate side effects. Cyclosporine and methotrexate are both effective in the treatment of severe psoriasis vulgaris. Both substances have a different spectrum of side effects which may limit the individual applicability. Acetritin is only moderately effective in the treatment of severe psoriasis of the plaque type. Calcipotriol or UV-radiation used at the same time can increase the clinical effectiveness of acetritin. Systemic PUVA, balneo-PUVA and UVB therapy are all effective for the treatment of severe psoriasis. The combination of UV therapy with vitamin D3 analogues or with topical steroids is more effective than the treatment with UV radiation alone. Saltwater baths increase the effectiveness of UVB therapy. No RCT on the therapeutical effects of topical tar or of dithranol in combination with UV therapy have been published so far. A continuous therapy with PUVA should not be applied due to its proven photocarcinogenicity. Three substances from the group of biologicals (Efalizumab, Etanercept, and Infliximab) are now available in Europe and a further substance (Alefacept) is available in the USA for the treatment of moderate to severe psoriasis. All biologicals have been effective in placebo controlled studies. The substances differ in the times until a clinical effect is observable, in the spectrum of side effects and in their efficiency on psoriasis arthritis. From health-economic studies considering both costs and clinical efficiency oral fumarates appear to be superior to acitretin or cyclosporine (although cyclosporine appears to be more effective in severe psoriasis). From the health economic view methotrexate is equivalent with UVB or PUVA and superior to cyclosporine. The therapy options UVB, UVB plus calcipotriol and PUVA are equivalent and superior to balneo-phototherapy. Biologicals are cost intensive and should be used when other approaches are not sufficient or are not applicable due to their side effects. The HTA report summarizes some health-economic studies on dithranol, on calcipotriol and on the combination with tar and UV light. No RCT have been published for the treatment of severe psoriasis with these agents alone but it appears to be certain that these substances are effective in severe psoriasis as well. DISCUSSION: The spectrum of therapeutical options has fortunately increased during the last years. It must be emphasized that a number of therapeutical procedures exist which are not discussed in detail in this HTA. This is due to the search strategy of literature: Only RCT performed with patients with moderate and/or severe psoriasis vulgaris were included into this evaluation. This led to the exclusion of a number of substances which are traditionally used alone or in combination for the treatment of moderate or severe psoriasis vulgaris (e.g. dithranol, salicyc acid, tar, corticosteroids and topical retinoids). Moreover, other approaches which include neither drugs nor UV light are not discussed in this HTA although the authors believe in the importance of psychotherapeutical interventions, educational approaches and combined medical and non-medical approaches in rehabilitational medicine in the management of psoriasis vulgaris. The transferability of the health economic evaluations is strongly limited by the fact that all included health economic evaluations except one were not aligned to a German setting. A future research question will be the evaluation of the duration of remission and relapse ratios in the context of different therapy options of moderate and severe psoriasis. Moreover, the consideration of combined outcomes such as the improvement of psoriatic symptoms and the decrease of symptoms in accompanying psoriasis arthritis represents a future requirement of health assessment. CONCLUSIONS: From the clinical point of view it is positive that the spectrum of therapeutic procedures for a chronic severe skin disease has increased continuously during the last years. In cases of individual contraindications or individual inefficacies it is now possible to try alternative approaches. Moreover the risk of long-term side effects can be reduced by changing the therapeutical procedure after some time (so-called rotation therapy). The therapeutical algorithm for severe psoriasis vulgaris now includes photo(chemo-)therapy in combination with topical substances, oral fumaric acid esters, retinoids (in combination with phototherapy or topical substances), methotrexate, cylosporine and the new biologics. Future studies should address therapeutical approaches which can not easily be studied by RCT, e.g. physical, balneological, climate approaches, educational programs and complex rehabilitation therapy which all may have positive effects on individuals with severe psoriasis. As in medical therapy management of moderate and severe psoriasis the economic evaluation also points out the way of a strategic therapy concept which corresponds to a large extent to the algorithm in medical practice.

Therapy of atopic eczema.

OBJECTIVES: Major objective is the evaluation of the medical effectiveness of different therapeutical approaches and the cost effectiveness with relevance for Germany. METHODS: This health technology assessment (HTA) evaluates systemically randomized controlled studies (RCT) on the therapy of atopic dermatitis which were published between 1999 and 2004. Further it includes some important clinical studies which have been published after 2004 and other updates the English HTA report by Hoare et al. [1]. RESULTS: Topical corticosteroids and topical calcineurin-inhibitors are the principal substances which are currently used for anti-inflammatory therapy in atopic dermatitis. These substances have shown a significant therapeutic efficacy in controlled studies. In newer controlled studies no difference was observable when corticosteroids were applied once or more than once daily onto the skin. Moreover, there is now one controlled study available which points to the fact that an interval therapy with a stronger topical corticosteroid over a limited time (some weeks) may lower the risk of recurrent flares of atopic dermatitis. Both topical calcineurin-inhibitors pimecrolimus and tacrolimus have shown a significant therapeutical efficacy in a number of placebo-controlled prospective studies. The wealth of data is high for these substances. Both substances have been shown to be efficient in infants, children and adult patients with atopic dermatitis. The importance of a so-called basic therapy with emollients which have to be adapted to the current status of skin is generally accepted in clinical practice. Controlled studies show the efficacy of "basic therapy" - although the level of evidence is quite low for this approach. The skin of patients with atopic dermatitis is colonized in the majority with Staphylococcus aureus, a gram-positive bacterium. Therefore, a therapeutical approach for the treatment of atopic dermatitis is the anti-bacterial or anti-septic treatment of the skin. Due to the lack of randomized controlled studies there is still not certain proof that antimicrobial or anti-septic treatment of non-infected eczematous skin is efficient for the treatment of atopic dermatitis. A reduction of Staphylococcus aureus is observable during an anti-inflammatory treatment of the skin with topical corticosteroids and/or the topical calcineurin-inhibitor tacrolimus. Antihistaminic drugs which are orally applied in atopic dermatitis may support the therapy of the itching skin disease. One controlled study showed a rapid reduction of itch during the use of a non-sedating antihistaminic drug. There are, however, no controlled studies which show the efficacy of antihistaminic drugs on the skin condition in atopic dermatitis. Dietetic restrictions should be applied only after a specific allergological diagnostic clarification. The "gold standard" is still a (blinded) oral provocation test which has to show an influence of a given food on the skin condition. There is sufficient evidence that there is no general dietetic approach which shows efficacy in atopic dermatitis. The treatment of patients with lactobacillae is still controversially discussed. Available studies which showed an efficacy show methodological weaknesses so that this approach can not be generally recommended for clinical practice at the time now. Approaches reducing house dust mite in the surroundings of patients with atopic dermatitis can have an effect on the skin condition so that at least in mite sensitized patients this approach appears to be reasonable. The specific immunotherapy with house dust mite showed clinical efficacy in a controlled study and in some open studies. The education of patients with atopic dermatitis or their parents is a further efficient approach in the management of this chronic skin disease. Interdisciplinary approaches in patients' education containing also psychological elements appear to be an attractive new approach for the treatment of atopic dermatitis. Phototherapy is a further possibility of intervention in atopic dermatitis in adolescent or adult patients. The available evidence points to the fact that UVB radiation (both small and broad spectrum), UVA-1 radiation and balneo-phototherapy are efficient therapeutical options for atopic dermatitis. The systemic treatment with the immunosuppressive substance cyclosporine A is efficient in the treatment of severe atopic dermatitis. Cyclosoprine A is approved for the treatment of adult patients with this skin disease. The immunosuppressive substance azathioprine showed a high clinical efficacy in two controlled studies for severe atopic dermatitis in adults. There are still controversial results for the application of antagonists to leucotriens in the treatment of atopic dermatitis: in some open studies a therapeutical efficacy was described which was, however, not reproducible in a newer controlled study. The phosphodiesterase-4-inhibitor cipamphyllin was efficient in the treatment of atopic dermatitis in a controlled study but weaker than a topical class II (i. e. moderate strength) corticosteroide. The HTA assessment further describes so-called complementary therapeutical approaches which have either not properly been studied in controlled clinical trials or which have been shown to be of no value for the treatment of atopic dermatitis. Altogether six full health-economic evaluations were found which did not cover the whole therapy spectrum of atopic dermatitis. The choice of the most cost effective treatment option of topic corticosteroids depends less on application frequency, but rather on the drug price and more used or unused quantity of the standard packages, so even smallest improvements justify a more frequent application. The results from health economic evaluations of calcineurin-inhibitors are not reliable. The therapy of severe atopic dermatitis in adults with ciclosporin shows comparable cost effectiveness in comparison to UVA/UVB therapy. DISCUSSION: The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. CONCLUSIONS: The spectrum of therapeutical procedures has increased for atopic dermatitis but is still not sufficient. The spectrum of established substances is much smaller compared to psoriasis, another chronic and common inflammatory skin disease. There is need for the development new substances which can be applied topically and which are aimed to treat atopic dermatitis in early childhood. Another need for new developments can be found for the treatment of severe atopic dermatitis in adults. Due to lack of health economic evaluations therapy decisions in the treatment of atopic dermatitis must take place on the basis of clinical decision criteria. The prescription of topic corticosteroids should prefer low priced drugs. Reliable statements about the cost effectiveness of the new calcineurin-inhibitors tacrolimus and pimecrolimus.