Delayed Skin Testing for Systemic Medications: Helpful or Not?

Cutaneous adverse drug reactions collectively are delayed drug reactions such as morbilliform drug eruption and severe cutaneous adverse reactions (SCARs). Morbilliform drug eruption may wane over time, be the result of drug viral interactions, and be amenable to slow reintroduction or rechallenge, whereas SCARs are HLA class I restricted, T-cell-mediated reactions that demonstrate durable immunity and warrant lifelong avoidance. SCARs such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption often occur in the setting of multiple drugs dosed together. Collectively, they lead to significant morbidity, mortality, and drug safety concerns that could severely limit future treatment options. Currently, no single or combination of diagnostic tests for SCARs such as ex vivo or in vitro testing, in vivo (skin) testing, or other adjunctive tests such as HLA typing have 100% negative predictive value. In this "Controversies in Allergy Review" article, we review the current literature on delayed skin testing (patch and delayed prick/intradermal test) and critically assess the evidence base of its utility across different drugs and clinical phenotypes of delayed hypersensitivity reactions.

Dupilumab in Patients with Atopic Dermatitis: A Multicentric, Long-Term, Real-World Portuguese Study.

INTRODUCTION: Several clinical trials have established the efficacy and safety of dupilumab for treating atopic dermatitis (AD). However, literature remains scarce in reporting the long-term effectiveness, safety, and drug survival of dupilumab in real-world settings. This study aimed to describe the latter outcomes of dupilumab in patients with AD. METHODS: This Portuguese, multicentric, observational, retrospective study included consecutive adult patients with AD who initiated dupilumab between January 2019 and September 2023, with a follow-up period up to 30 months. Drug discontinuation and adverse effects data were used to estimate drug survival. Clinical assessments included the Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), and Dermatology Life Quality Index (DLQI). RESULTS: A total of 312 patients were included in the study, with 56.4% being male (median age of 30 years, range 18-83). The 30-month drug survival rate was 82.0%. During the study period, 12.5% of the sample (n = 39 patients) discontinued treatment: 7.3% due to treatment failure, 2.9% due to safety concerns, 1.3% due to complete disease control, 0.6% due to pregnancy, and 0.3% due to lack of compliance. Adverse events not leading to drug discontinuation were noted in 25.6% of the sample (n = 80). Conjunctivitis was the most frequently reported adverse event (17%), followed by facial erythema (9%). At 30 months, the mean EASI decreased significantly from 27.30 ± 11.89 at baseline to 2.92 ± 3.96 (p < 0.001), reflecting an overall improvement of 89.3%. Similarly, pruritus NRS decreased from 7.36 ± 1.90 at baseline to 1.74 ± 2.16 at month 30 (p < 0.001), improving by 76.4%, and mean DLQI changed from 18.0 ± 7.09 at baseline to 2.67 ± 3.95 at month 30 (p < 0.001), decreasing by 85.2%. CONCLUSIONS: This study increases our current understanding of dupilumab in real-world settings, demonstrating its long-term effectiveness and safety in treating AD.

Current frequency of contact allergy to isothiazolinones (methyl-, benz- and octylisothiazolinone) across Europe.

BACKGROUND: The use of methylisothiazolinone (MI) as a preservative in cosmetic products caused an alarming increase in MI contact allergy across Europe in the 2010s. This was followed by regulations of use with a total ban on leave-on (implemented in 2017) and reduced use concentrations in rinse-off cosmetics (2018). OBJECTIVE: To follow-up on the prevalence of contact allergy to MI and the related benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in consecutively patch-tested patients in Europe. METHODS: A cross-sectional audit following the design of two previous audits on MI contact allergy from 1 May 2022 to 31 October 2022 included all patients patch tested with the European baseline series, including or supplemented with MI, BIT and OIT across 10 departments in eight European countries. RESULTS: A total of 2554 patients were consecutively patch tested with the three isothiazolinones during the study period. The prevalence of MI and BIT contact allergy was 2.9% (95% confidence interval [CI]: 2.3%-3.7%; range 1.1%-5.8%) and 3.1% (95% CI: 2.4%-3.9%; range 0.0%-6.6%), respectively; that of OIT was 0.7% (95% CI: 0.4%-1.1%; range 0%-3.2%). Rinse-off cosmetic (73.3%) and leave-on cosmetic products (13.3%) were still associated with eliciting allergic contact dermatitis to MI. CONCLUSION: We confirmed a positive impact of regulatory measures on the prevalence of MI contact allergy in Europe, which halved compared to 2015. However, our data suggest that consumers may still be exposed to older cosmetic products containing MI. BIT has superseded MI in causing contact allergy, despite not being allowed for use in cosmetic products.

Differential diagnosis of contact dermatitis: A practical-approach review by the EADV Task Force on contact dermatitis.

The diagnosis of eczema ('dermatitis') is mostly clinical and depends on the clinical history and exploratory objective findings (primary lesions, patterns). Contact dermatitis remains as an important condition in the group of eczematous disorders, with important socioeconomic and occupational relevance. Although irritant and allergic contact dermatitis have a different pathogenesis, both are characterized by a rather typical morphology, are triggered by external factors and tend to occur primarily in the area of contact with the exogenous agent. In addition, allergic and irritant dermatitis may also co-exist. The importance of diagnosing contact dermatitis, especially when allergic in nature, is both due to the possibility of avoiding the trigger, and due to its role in aggravating other skin conditions. Nevertheless, the heterogeneity of clinical presentations in daily practice may pose an important challenge for the suspicion and correct diagnosis of contact dermatitis. Furthermore, other conditions, with different pathogenesis and treatment, may clinically simulate contact dermatitis. The Task Force aims to conduct a review of the unifying clinical features of contact dermatitis and characterize its main clinical phenotypes, and its simulators, in order to contribute to an early suspicion or recognition of contact dermatitis and enable a correct differential diagnosis.

Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus.

BACKGROUND: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. OBJECTIVE: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). METHODS: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). RESULTS: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. CONCLUSION: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Comparison of Perceptions of Skin Condition, Product Use and Allergen Reactivity Between People with Psoriasis and Controls in the European Dermato-Epidemiology Network (EDEN) Fragrance Study.

Psoriasis, a chronic inflammatory skin disease, goes beyond visible symptoms and affects the general well-being of patients. The aim of this study is to understand how patients with psoriasis perceive their skin characteristics and reactivity to allergens. The study population includes 11,283 participants within the European Dermato-Epidemiology Network (EDEN) Fragrance study, covering several European regions. The study compared perceptions of skin dryness, sensitivity, product avoidance and reactivity to allergens between patients with psoriasis and controls, evaluating the potential influence of psoriasis severity. The results showed that subjects with psoriasis reported dry skin (71.1%) and sensitive skin (49.4%) more often than did controls (51.6% and 38.5%, respectively). Psoriasis patients were more likely to avoid specific products. Interestingly, there were no significant differences in patch-test results between the 2 groups and the severity of psoriasis did not have a consistent impact on these perceptions. In conclusion, people with psoriasis tend to perceive their skin as drier and more sensitive. Notably, the severity of psoriasis did not consistently influence these perceptions and objective reactivity to allergens did not align with subjective perception. Understanding these aspects is crucial for tailoring treatments to improve the well-being of patients with psoriasis, which warrants further research to explore subjective perceptions of skin well-being in patients with psoriasis.

Results of patch testing with five fragrance materials hitherto not tested: A dose-finding study in the clinical population.

BACKGROUND: Quantitative risk assessment (QRA) for skin sensitization is used to derive safe use levels of sensitising fragrance ingredients in products. Post-marketing surveillance of the prevalence of contact allergy to these ingredients provides relevant data to help evaluate the performance of these measures. OBJECTIVES: To determine a suitable patch test concentration for five fragrance materials that had hitherto not been tested on a regular basis. These concentrations are then to be used in a surveillance study with patch testing consecutive patients over an extended monitoring period. MATERIALS AND METHODS: Furaneol, CAS.3658-77-3; trans-2-hexenal, CAS.6728-26-3; 4,8-dimethyl-4,9-decadienal, CAS.71077-31-1; longifolene, CAS.475-20-7; benzaldehyde, CAS.10052-7, were patch tested with other fragrance allergens in four clinics. Patch testing was conducted in three rounds, starting with the lowest concentrations of the five ingredients. The doses were increased in the subsequent rounds if no late-appearing positive reactions and virtually no irritant reactions were reported. RESULTS: Overall, 373 patients were tested. No positive allergic reaction was reported to the five ingredients. Patch test results of other fragrance allergens are reported. CONCLUSIONS: The highest test concentrations are each considered safe for patch testing consecutive patients. Further surveillance based on these preparations will evaluate the hypothesis that QRA-driven consumer product levels of these fragrances can prevent sensitization.

CRUSE® -An innovative mobile application for patient monitoring and management in chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is unpredictable and can severely impair patients' quality of life. Patients with CSU need a convenient, user-friendly platform to complete patient-reported outcome measures (PROMs) on their mobile devices. CRUSE® , the Chronic Urticaria Self Evaluation app, aims to address this unmet need. METHODS: CRUSE® was developed by an international steering committee of urticaria specialists. Priorities for the app based on recent findings in CSU were defined to allow patients to track and record their symptoms and medication use over time and send photographs. The CRUSE® app collects patient data such as age, sex, disease onset, triggers, medication, and CSU characteristics that can be sent securely to physicians, providing real-time insights. Additionally, CRUSE® contains PROMs to assess disease activity and control, which are individualised to patient profiles and clinical manifestations. RESULTS: CRUSE® was launched in Germany in March 2022 and is now available for free in 17 countries. It is adapted to the local language and displays a country-specific list of available urticaria medications. English and Ukrainian versions are available worldwide. From July 2022 to June 2023, 25,710 observations were documented by 2540 users; 72.7% were females, with a mean age of 39.6 years. At baseline, 93.7% and 51.3% of users had wheals and angioedema, respectively. Second-generation antihistamines were used in 74.0% of days. CONCLUSIONS: The initial data from CRUSE® show the wide use and utility of effectively tracking patients' disease activity and control, paving the way for personalised CSU management.

Differential diagnosis between urticarial vasculitis and chronic spontaneous urticaria: An international Delphi survey.

BACKGROUND: Urticarial vasculitis (UV) should be differentiated from chronic spontaneous urticaria (CSU) in patients initially presenting with recurrent wheals, although criteria for differential diagnosis remain ill-defined. OBJECTIVES: To set the goals, define criteria and unmet needs in UV diagnosis and differential diagnosis with CSU, and explore the possibility of coexistence of both diseases. METHODS: Thirteen experts experienced in UV research participated in a Delphi survey of European Academy of Allergy and Clinical Immunology taskforce. This Delphi survey involved three rounds of anonymous responses to n = 32 questions with the aim to aggregate the experts' opinions and to achieve consensus. Urticaria specialists (n = 130, most from Urticaria Centers of Reference and Excellence) evaluated the consensus statements and recommendations in the fourth and final round. RESULTS: The panel agreed that essential criteria to guide a skin biopsy in patients with recurrent wheals should include at least one of the following features: wheal duration >24 h, bruising/postinflammatory hyperpigmentation, and systemic symptoms. Leukocytoclasia and fibrin deposits were identified as a minimum set of UV histological criteria. As agreed by the panel members, CSU and normocomplementemic UV (NUV) may coexist in some patients. CONCLUSIONS: The use of established criteria for the diagnosis and differential diagnosis of UV in patients with recurrent wheals can help guide the diagnostic approach and prompt earlier treatment. Further studies should investigate whether CSU and NUV are different entities or part of a disease spectrum.

Urticarial Vasculitis Differs From Chronic Spontaneous Urticaria in Time to Diagnosis, Clinical Presentation, and Need for Anti-Inflammatory Treatment: An International Prospective UCARE Study.

BACKGROUND: Chronic spontaneous urticaria (CSU) and urticarial vasculitis (UV) share several clinical features including the occurrence of wheals. As of yet, the criteria for differentiating the 2 disorders are not clearly defined. OBJECTIVE: Here, we aimed to identify differences, similarities, and the likelihood for specific clinical features in patients with UV versus those with CSU. METHODS: Across 10 Urticaria Centers of Reference and Excellence, 106 patients with skin biopsy-confirmed UV and 126 patients with CSU were prospectively recruited to complete a questionnaire on the clinical features, course, and response to treatment of their disease. RESULTS: As compared with CSU, patients with UV more often experienced postinflammatory skin hyperpigmentation, wheals of ≥24-hour duration, eye inflammation, and fever (6.9, 4.0, 3.6, and 2.4 times, respectively). Clinical features that increased the risk for UV diagnosis when present at the onset of disease included wheals of ≥24-hour duration (7.3-fold), pain of the skin (7.0-fold), postinflammatory hyperpigmentation (4.1-fold), and fatigue (3.1-fold). The diagnostic delay was markedly longer for normocomplementemic UV as compared with hypocomplementemic UV and CSU (21 vs 5 vs 6 months, respectively). Oral corticosteroids and omalizumab were the most effective treatments in patients with UV and CSU, respectively. Patients with UV showed a higher need for immunosuppressive and anti-inflammatory therapies than patients with CSU. CONCLUSIONS: Long wheal duration, skin pain and hyperpigmentation, and systemic symptoms point to UV rather than CSU as the underlying disease and should prompt further diagnostic workup including a skin biopsy.

Analysis of Hexavalent Chromium in Cement Samples From Countries Within and Outside the EU: A Study From the International Contact Dermatitis Research Group.

Background: Allergic contact dermatitis (ACD) caused by hexavalent chromium (Cr(VI)) is often severe and difficult to treat. The content of Cr(VI) in cement can be reduced by, for example, addition of iron(II) sulfate. Since 2005 the content of Cr(VI) in cement is regulated in the EU Directive 2003/53/EC and must not exceed 2 ppm. Since this regulation came into force, ACD caused by cement has markedly been reduced. Objective: To investigate Cr(VI) and total chromium content in samples of cement from countries within and outside the EU. Methods: The members of the International Contact Dermatitis Research Group (ICDRG) were invited to participate in the study with the aim to collect cement samples from geographically different areas. The content of Cr(VI) in the samples was estimated by the diphenyl carbazide spot test, atomic absorption spectroscopy was used to assess the total chromium content. Results: Forty-five cement samples were analyzed, containing amounts of Cr(VI) from <0.1 to >70 ppm. Twenty-one samples contained >2 ppm Cr(VI), 24 contained less. Four of 17 samples from within the EU contained >2 ppm Cr(VI), that is, higher amounts than stipulated in the EU directive, as compared with 17 samples from countries outside the EU. Conclusion: In countries outside the EU, significantly more cement samples contained >2 ppm Cr(VI).

Shedding a light on the importance of photopatch testing: A 12-year experience in a dermatology unit.

BACKGROUND: Photopatch testing has been standardized for diagnosing photoallergic contact dermatitis but is still infrequently used. OBJECTIVES: To characterize photopatch test (PPT) results and their clinical relevance. METHODS: We collected retrospective data from patients photopatch tested in our Dermatology Unit (2010-2021), using the European PPT 'baseline' series, other allergens, and patient's own products, when appropriate. RESULTS: Out of 223 patients, 75 patients (33.6%) were reactive with 124 positive PPT reactions, considered relevant in 56/223 patients (25.1%) and in 72/124 reactions (58.1%). Most reactions were caused by topical drugs (n = 33; 45.8%), such as ketoprofen or promethazine, and 7 (9.8%) by systemic drugs, such as hydrochlorothiazide and fenofibrate. 'Classical' ultraviolet filters were responsible for six positive PPT reactions whereas there was only three relevant PPT to the 'newer' UV filters. Patients' sunscreens/cosmetics or plant extracts caused 10 positive PPT each. Additional patch test reactions were observed, mostly to Tinosorb® M. CONCLUSION: Contrary to the trend in ACD, most positive PPT reactions were caused by topical drugs, outweighing ultraviolet filters and cosmetics. We stress the low reactivity to the 'newer' UV filters included in the PPT series. PPT was occasionally positive in systemic drug photosensitivity, but overall PPT reactivity was low.

The European baseline series and recommended additions: 2023.

The European baseline series was last updated in 2019. This article discusses the reasoning behind a further iteration of the series for 2023.