The socio-economic burden of H1-antihistamine-refractory chronic spontaneous urticaria in Germany.

BACKGROUND AND STUDY AIM: Data from the AWARE study (A Worldwide Antihistamine-Refractory chronic urticaria patient Evaluation) illustrate a substantial disease burden in German patients with H1-antihistamine (-H1-AH)-refractory chronic spontaneous urticaria (CSU). Detrimental effects on patients' quality of life, poor disease control and impairment in the ability to work and perform other daily activities are reported. Based on these findings, this study aims to quantify the epidemiological and socio-economic burden of H1-AH-refractory CSU in Germany. METHODS: To determine the epidemiological burden of H1-AH-refractory CSU, the age- and gender-specific prevalence of CSU and the proportion of H1-AH-refractory patients in Germany anonymized data from the InGef research database have been used. In a second step, the socio-economic burden in terms of lost numbers of hours in paid and unpaid work was calculated by extrapolating the age- and gender-specific work productivity and activity impairment (WPAI) observed in AWARE to the H1-AH-refractory CSU population in Germany. Finally, productivity losses in paid and unpaid work were monetized using the human capital and the friction cost approach respectively. Moreover, socio-economic burden was calculated depending on symptom control of the patients (measured by urticaria control test [UCT]). RESULTS: In Germany, over 203,000 patients (20 years or older) had H1-AH-refractory CSU in 2018. The avoided lost paid and unpaid work hours attributable to H1-AH-refractory CSU summed up to over 100 million. Overall, the socio-economic burden of H1-AH-refractory CSU in monetary terms was evaluated at € 2.2 billion and the majority of this was due to unpaid work loss. Patients with poor disease control, as indicated by UCT score < 12, were more likely to suffer from high impairment than patients with controlled disease, resulting in a higher socio-economic burden. CONCLUSION: The results of our analyses picture the substantial socio-economic burden of H1-AH-refractory CSU and therefore the tremendous impact it has on daily lives of individuals and society overall.

Epidemiology, Management, and Treatment Access of Hereditary Angioedema in the Asia Pacific Region: Outcomes From an International Survey.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease with significant morbidity and mortality for which early diagnosis and effective therapy are critical. Many Asia Pacific (AP) countries still lack access to diagnostic tests and evidence-based therapies. Epidemiologic data from the AP is needed to formulate regional guidelines to improve standards of care for HAE. OBJECTIVE: To investigate the estimated minimal prevalence, needs, and potential interventions for the diagnosis and management of HAE in the AP. METHODS: A structured questionnaire was distributed to representative experts from member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology. Patient profiles and the presence of diagnostic facilities or tests, regional and national HAE guidelines, and patient support groups were reported and compared. RESULTS: Completed questionnaires were received from 14 representatives of 12 member countries and territories, representing 46% of the world population. Overall minimal prevalence of HAE in the AP region was 0.02/100,000 population, with significant heterogeneity across different centers. Only one-half and one-third had registered on-demand and prophylactic medications, respectively. Few had patient support groups (58%) or regional guidelines (33%), and their existence was associated with the availability of HAE-specific medications. Availability of C1-inhibitor level testing was associated with a lower age at HAE diagnosis (P = .017). CONCLUSIONS: Hereditary angioedema in the AP differs from that in Western countries. Hereditary angioedema-specific medications were registered in only a minority of countries and territories, but those with patient support groups or regional guidelines were more likely to have better access. Asia Pacific-specific consensus and guidelines are lacking and urgently needed.

Assessment of disease activity and quality of life in patients with recurrent bradykinin-mediated versus mast cell-mediated angioedema.

OBJECTIVE: Recurrent Angioedema (RAE) is characterized by sudden swelling of mucosal surfaces or deep dermis and is either mast cell-(MMAE) or bradykinin-mediated (BMAE). How patients with BMAE and MMAE differ in terms of disease activity and impact remains largely unknown. Here, we determined validity, reliability, and sensitivity to change of Turkish versions of angioedema activity score (AAS) and quality of life questionnaire (AE-QoL) and used both instruments to investigate and compare patients with BMAE and MMAE. METHODS: Turkish versions of AAS28 and AE-QoL were applied to 94 patients with RAE (18-72 years). Patients' global self-assessment of QoL (PGA-QoL), disease activity (PGA-DA-VRS, PatGA-DA-VAS), and 12-Item-Short Form Survey were used at week 4 (visit 2), and week 8 (visit 3). Demographic characteristics, clinical features, and AAS28 and AE-QoL values were compared between 31 patients with BMAE and 63 patients with MMAE. RESULTS: Turkish AAS28 and AE-QoL showed excellent internal consistency, high reproducibility and known-groups validity. Compared to patients with MMAE, BMAE patients were younger (34.6 ± 10.7 vs. 40.7 ± 13.3 years), had longer disease duration (236 ± 178 vs. 51 ± 78 months), high prevalence of family history (63% vs 14%), longer duration of attacks (65 ± 20 vs. 40 ± 25 h), and they were more commonly affected by upper airway angioedema (70% vs 23%). Disease activity (AAS28) was lower (29.3 ± 24.6 vs 55.2 ± 52.9), but AE-QoL was higher (44.2 ± 16.1 vs 34.5 ± 22.5) in BMAE patients as compared to MMAE patients. CONCLUSIONS: Patients with BMAE and MMAE have distinct disease characteristics. Recurrent bradykinin-mediated angioedema impacts quality of life more than mast cell-mediated angioedema. The discriminating characteristics of patients with BMAE and MMAE may help to improve the diagnosis and management of patients with RAE.

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).

The characteristics and impact of pruritus in adult dermatology patients: A prospective, cross-sectional study.

BACKGROUND: Pruritus often accompanies chronic skin diseases, exerting considerable burden on many areas of patient functioning; this burden and the features of pruritus remain insufficiently characterized. OBJECTIVE: To investigate characteristics, including localization patterns, and burden of pruritus in patients with chronic dermatoses. METHODS: We recruited 800 patients with active chronic skin diseases. We assessed pruritus intensity, localization, and further characteristics. We used validated questionnaires to assess quality of life, work productivity and activity impairment, anxiety, depression, and sleep quality. RESULTS: Nine out of every 10 patients had experienced pruritus throughout their disease and 73% in the last 7 days. Pruritus often affected the entire body and was not restricted to skin lesions. Patients with moderate to severe pruritus reported significantly more impairment to their sleep quality and work productivity, and they were more depressed and anxious than control individuals and patients with mild or no pruritus. Suicidal ideations were highly prevalent in patients with chronic pruritus (18.5%) and atopic dermatitis (11.8%). CONCLUSIONS: Pruritus prevalence and intensity are very high across all dermatoses studied; intensity is linked to impairment in many areas of daily functioning. Effective treatment strategies are urgently required to treat pruritus and the underlying skin disease.

Antihistamine-resistant chronic spontaneous urticaria remains undertreated: 2-year data from the AWARE study.

BACKGROUND: Real-world evidence describing the benefits of recommended therapies and their impact on the quality of life (QoL) of chronic urticaria (CU) patients is limited. OBJECTIVE: To investigate disease burden, current treatment schedule, and the use of clinical resources by patients with H1 -antihistamine-refractory CU in Europe. METHODS: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global, prospective, non-interventional study in the real-world setting, sponsored by the manufacturer of omalizumab. Disease characteristics, pharmacological treatments, and health-related QoL of patients (N = 2727) ≥18 years of age diagnosed with H1 -antihistamine-refractory chronic spontaneous urticaria (without inducible urticaria) for >2 months are reported here. RESULTS: Of the 2727 patients included, 1232 (45.2%) and 1278 (46.9%) were successfully followed up for any assessment and for the key outcome, the urticaria control test (UCT) score, respectively, and patients with complete remission (14.1%) were excluded from analyses.The proportion of patients with uncontrolled CSU (UCT score <12) dropped from 78% (n/N = 1641/2104) at baseline to 28.7% (n/N = 269/936) after two years of participation in the AWARE study. In addition, the proportion of patients with no impact of CSU on their QoL (assessed by the Dermatological Life Quality Index) increased to 57% (n/N = 664/1164) from 18.7% (n/N = 491/2621) at baseline. Emergency room visits (2.4% [n/N = 7/296] vs 33.5% [n/N = 779/2322]) and hospital stays (1.7% [n/N = 5/296] vs 24.2% [n/N = 561/2322]) reduced at Month 24 vs baseline. Overall, 23.2% (n/N = 26/112) patients on non-sedating H1 -antihistamines (nsAH) and 41.9% (n/N = 44/105) patients on up-dosed nsAH had uncontrolled CSU (UCT <12) at Month 24. In omalizumab-treated patients, 27.1% (n/N = 78/288) had uncontrolled CSU at Month 24. CONCLUSION: These data confirm improvements for most patients with CSU over a 2-year follow-up period. Further studies are needed to understand the differences between guideline recommendations and reported management.

Characteristics and determinants of patient burden and needs in the treatment of chronic spontaneous urticaria.

BACKGROUND: Treatment of chronic spontaneous urticaria (CSU) is founded on evidence-based guidelines. However, specific patient needs and benefits of therapy have not been outlined at the guideline level. OBJECTIVES: The aim of this study was to characterise the specific needs and treatment goals in chronic spontaneous urticaria from the patient's perspective. MATERIALS AND METHODS: This cross-sectional study was conducted in four German outpatient dermatology clinics. Patient needs and potential therapy goals were determined with the validated Patient Needs Questionnaire (PNQ) using a specific version for chronic urticaria. Further instruments to characterise the link between patient needs and disease burden were disease-specific (CU-Q2oL), skin-generic (DLQI) and health-generic (EQ VAS) scales. RESULTS: Data from 103 patients were analysed (age: 43.92 ± 14.96 years; 71.4% female). Among the most important therapeutic goals were the absence of visible skin lesions (92.3% important/very important), to be free of itching (91.5%) and the desire to be healed of all skin defects (89.5%). All 26 items were found to be quite important/very important by at least 30% of the respondents. Specific profiles of patient needs were found to be related to sex and disease duration. CONCLUSION: Innovative drugs and patient-centred individualised treatment may increase overall benefits. Regardless of the treatment chosen, shared decision making in the management of the disease should be a goal.

Development and content validity testing of a patient-reported outcomes questionnaire for the assessment of hereditary angioedema in observational studies.

BACKGROUND: Hereditary Angioedema (HAE), a rare genetic disease, manifests as intermittent, painful attacks of angioedema. Attacks vary in frequency and severity and include skin, abdominal and life-threatening laryngeal swellings. This study aimed to develop a patient reported outcome (PRO) tool for the assessment of HAE attacks, including their management and impact on patients' lives, for use in clinical studies, or by physicians in general practice. METHODS: The results of open-ended face to face concept elicitation interviews with HAE patients in Argentina (n = 10) and the US (n = 33) were used to develop the first draft questionnaire of the HAE patient reported outcomes questionnaire (HAE PRO). Subsequently, in-depth cognitive debriefing interviews were performed with HAE patients in the UK (n = 10), Brazil (n = 10), Germany (n = 11) and France (n = 12). Following input from eight multinational clinical experts further cognitive interviews were conducted in the US (n = 12) and Germany (n = 12). Patients who experienced abdominal, cutaneous or laryngeal attacks of varying severity levels were included in all rounds of interviews. Across the rounds of interviews patients discussed their HAE attack symptoms, impacts and treatments. Cognitive debriefing interviews explored patient understanding and relevance of questionnaire items. All interviews were conducted face to face following a pre-defined semi-structured interview guide in the patient's native language. RESULTS: Patients reported a variety of HAE symptoms, attack triggers, warning signs, attack impacts and treatment options which were used to develop the HAE PRO. The HAE PRO was revised and refined following input from patients and clinical experts. The final 18-item HAE PRO provides an assessment of the HAE attack experience including symptoms, impacts, treatment requirements, healthcare resource use and loss of productivity caused by HAE attacks. CONCLUSIONS: Patient and expert input has contributed to the development of a content valid questionnaire that assesses concepts important to HAE patients globally. HAE patients across cultures consider the HAE PRO a relevant and appropriate assessment of HAE attacks and treatment.

Cardioprotective C-kit⁺ bone marrow cells attenuate apoptosis after acute myocardial infarction in mice - in-vivo assessment with fluorescence molecular imaging.

Cardiomyocyte loss via apoptosis plays a crucial role in ventricular remodeling following myocardial infarction (MI). Cell-based therapy approaches using bone marrow derived c-kit⁺ pluripotent cells may attenuate apoptosis following ischemic injury. We therefore thought to examine the early course of apoptosis following myocardial infarction - in-vivo - and non-invasively determine the effect of c-kit⁺ bone marrow cells on post-MI remodeling. We studied apoptosis in wild-type Kit(+/+) , c-kit mutant Kit(W)/Kit(W-v) and Kit(W)/Kit(W-v) mice after cell therapy with bone-marrow derived c-kit⁺ cells after ischemia-reperfusion injury. Mice were followed by hybrid Fluorescence Molecular Tomography/X-ray Computed Tomography (FMT-XCT) at 6h, 24h and 7 days after ischemia-reperfusion injury using an Annexin V-based fluorescent nanosensor targeting phosphatidylserine. Kit(W)/Kit(W-v) mice showed increased and prolonged apoptosis compared to control Kit(+/+) mice while c-kit cell therapy was able to attenuate the altered apoptosis rates. Increased apoptosis was accompanied by severe decline in heart function, determined by cardiac Magnetic Resonance Imaging, and cell therapy was able to rescue the animals from deleterious heart failure. Post-mortem cryoslicing and immunohistochemistry localized the fluorescence signal of the Annexin V sensor within the infarcted myocardium. Flow cytometry of digested infarct specimens identified apoptotic cardiomyocytes as the major source for the in-vivo Annexin V signal. In-vivo molecular imaging using hybrid FMT-XCT reveals increased cardiomyocyte apoptosis in Kit(W)/Kit(W-v) mice and shows that c-kit⁺ cardioprotective cells are able to attenuate post-MI apoptosis and rescue mice from progressive heart failure.

German version of ItchyQoL: validation and initial clinical findings.

Pruritus is a major symptom of numerous skin and systemic diseases and causes a substantial burden on patients' quality of life (QoL). We report here the validation of the German version (GerItchyQoL) of the first pruritus-specific QoL instrument ItchyQoL. GerItchyQoL was created from the original version following standard protocols. It was completed by 308 patients with chronic pruritus of different origin and tested for validity, reliability and responsiveness. Factor analysis of Ger-ItchyQoL revealed the 4 domains symptoms, functioning, feelings, and self-perception. Reliability was demonstrated by good internal consistency of all domains. We confirmed convergent validity by comparing the instrument with itch severity, as measured with a visual analogue scale (VAS 0-10), and with the Short-Form-12 (SF-12), a widely used generic health-related QoL instrument. Concurrent validity was shown by the ability to discriminate between patient groups of different itch severity. Changes in GerItchyQoL scores correlated with changes in itch severity (VAS), suggesting responsiveness of the German tool. This study provides preliminary evidence of validity, reliability and responsiveness of GerItchyQoL and also shows a high impact of chronic pruritus on QoL. Further translations of ItchyQoL into additional languages will enable large-scale international, multilingual trials.

Turkish version of the chronic urticaria quality of life questionnaire: cultural adaptation, assessment of reliability and validity.

Chronic spontaneous urticaria has a substantial impact on patients' quality of life. The first disease-specific tool to assess quality of life impairment in this condition, the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), was developed recently. The aim of this study was to adapt the original Italian version to the Turkish language and to evaluate its reliability, validity, and sensitivity to change. The Turkish version was developed by performing forward- and back-translation. It was then applied to 140 consecutive patients with chronic spontaneous urticaria, along with the Dermatology Life Quality Index and the Skindex-29. Disease activity was assessed using the Urticaria Activity Score. Sensitivity to change was measured in 101 patients, who completed the instruments twice at intervals of 4 weeks. Confirmatory factor analysis demonstrated that the six-scale structure of the original Italian version ("pruritus", "swelling", "impact on life activities", "sleep problems", "limits", "looks") can be retained in the Turkish instrument. Analysis regarding convergent validity showed good correlations of the Turkish CU-Q2oL with the other instruments. In addition, it was found to discriminate well between patients with different levels of urticaria activity, and to be sensitive to change. In conclusion, the Turkish version of CU-Q2oL is a reliable, valid, and sensitive instrument, which will help to characterize better the clinical impact of chronic spontaneous urticaria and treatment outcomes in Turkish patients. Its identical scale structure to that of other CU-Q2oL instruments makes it ideal for cross-cultural comparisons and for its application in future national and multinational studies.

Cost-intensive, time-consuming, problematical? How physicians in private practice experience the care of urticaria patients.

BACKGROUND: Urticaria is a common and frequently debilitating disease. Nevertheless, there are only few studies examining the situation of urticaria patient care. PATIENTS AND METHODS: In this cross-sectional study, we surveyed dermatologists, pediatricians and general practitioners in the practice setting regarding the epidemiology, situation of care as well as the perception of their patients with chronic spontaneous urticaria. RESULTS: 776 data sets were available. The results show a high frequency of consultations due to chronic spontaneous urticaria. Most of the patients were reported to suffer moderately to severely and to have had history of disease of well over one year. The pediatricians indicated fewer diseases and shorter courses. The majority of participants stated that the time and cost spent on care, as well as the frequency of follow-up visits, are above average. In addition, chronic spontaneous urticaria patients were reported to be a group with a strong emotional burden and high expectations as well as a group that is difficult to satisfy and hard to guide. Only a small minority of physicians rated patient satisfaction with current treatment options and therapy success as high. CONCLUSIONS: Chronic spontaneous urticaria plays an important role in daily practice. Problems are reported on various areas of care. Resolving these problems presents a major challenge and is crucial for improving the quality of patient care.