Cutaneous adverse events following COVID-19 vaccination: A case series of 30 Japanese patients and a review of 93 Japanese studies.

In Japan, cutaneous adverse events (AEs) following the coronavirus disease 2019 (COVID-19) vaccination have been frequently described; however, a larger case series and literature review are lacking. There is an urgent need for an extensive investigation of new cases and previous reports to provide a thorough body of information about post-COVID-19 immunization cutaneous AEs. We aimed to analyze patients with cutaneous AEs after COVID-19 vaccination in our hospital and review previous studies of cutaneous AEs. We analyzed post-COVID-19 vaccination cutaneous AEs in our department, the Japanese Registry, and previous literature. We enrolled 30 patients with cutaneous post-vaccination AEs in our department over 2 years (April 1, 2021, to March 31, 2023). We also confirmed cases registered in the Ministry of Health, Labor, and Welfare COVID-19 vaccine side effect reporting system (February 17, 2021-March 12, 2023). A total of 587 records were retrieved and 93 articles were included for data extraction. A total of 28 non-injection-site cutaneous AEs and two injection-site AEs were identified. Six (20.0%) patients developed new-onset erythematous eruptions, and five (16.7%) patients developed urticaria. Pruritic eruption, eczema, shingles, and sweating symptoms have also been reported. In previous studies on non-injection-site cutaneous AEs, individuals who received the BNT162b2 vaccine were older than those who received mRNA-1273 (P < 0.01). Cutaneous AEs were mostly nonsignificant and self-limiting reactions; however, rare, severe, or life-threatening AEs were also reported. Physicians should be aware of the various possible cutaneous AEs associated with the COVID-19 vaccination.

Ixekizumab-induced urticaria is associated with the short duration of remission in psoriasis by activation of mast cells.

BACKGROUND: Mast cell degranulation plays a pivotal role in urticaria and is also an early histologic characteristic of psoriasis. However, whether the activation of mast cells contributes to psoriasis recurrence after discontinuation of interleukin (IL)-17A blockers remains unclear. OBJECTIVE: To investigate the role of mast cells in ixekizumab treatment-associated urticaria (ITAUR) and assess the effect of urticaria eruption on psoriasis relapse. METHODS: A retrospective analysis was performed on biopsies of patients who experienced psoriasis relapse after discontinuation of ixekizumab. Transcriptomic and histopathologic features were assessed. Patterns were compared between patients with ITAUR and nonurticaria (NUR) as well as psoriasis-like mice with mast cell activation or inactivation. RESULTS: Patients with ITAUR experienced early relapse compared with NUR group after treatment withdrawal. Transcriptomic and histopathologic analyses revealed that patients with ITAUR had an elevated proportion of mast cells in resolved skin. Especially, the proportion of IL-17A+ mast cells was inversely correlated with the duration of remission. LIMITATIONS: The mechanism of mast cell activation in ITAUR has not been precisely elucidated. CONCLUSION: Ixekizumab treatment increases IL-17A+ mast cells in lesions of ITAUR, which is associated with early psoriasis relapse after ixekizumab withdrawal.

Remibrutinib demonstrates favorable safety profile and sustained efficacy in chronic spontaneous urticaria over 52 weeks.

BACKGROUND: Remibrutinib (LOU064), an oral, highly selective Bruton tyrosine kinase inhibitor, offers fast disease control in patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite treatment with second-generation H1 antihistamines. It is currently in phase 3 development for CSU. OBJECTIVE: We sought to evaluate long-term safety and efficacy of remibrutinib in patients with CSU inadequately controlled with H1 antihistamines. METHODS: In this phase 2b extension study, patients who completed the core study and had a weekly Urticaria Activity Score (UAS7) ≥16 at the beginning of the extension study received remibrutinib 100 mg twice daily for 52 weeks. The primary objective was to assess long-term safety and tolerability. Key efficacy end points included change from baseline in UAS7 and proportion of patients with complete response to treatment (UAS7 = 0) and well-controlled disease (UAS7 ≤6) at week 4 and over 52 weeks. RESULTS: Overall, 84.3% (194/230) of patients entered the treatment period and received ≥1 doses of remibrutinib. The overall safety profile of remibrutinib was comparable between the extension and core studies. Most treatment-emergent adverse events were mild to moderate and considered unrelated to remibrutinib by investigators. The 3 most common treatment-emergent adverse events by system organ class were infections (30.9%), skin and subcutaneous tissue (26.8%), and gastrointestinal disorders (16.5%). At week 4 and 52, mean ± SD change from baseline in UAS7 was -17.6 ± 13.40 and -21.8 ± 10.70; UAS7 = 0 (as observed) was achieved in 28.2% and 55.8% and UAS7 ≤6 (as observed) was achieved in 52.7% and 68.0% of patients, respectively. CONCLUSIONS: Remibrutinib demonstrated a consistent favorable safety profile with fast and sustained efficacy for up to 52 weeks in patients with CSU.

Occupational asthma, rhinitis and contact urticaria from greenhouse work.

BACKGROUND: The current knowledge about occupational allergic diseases among greenhouse workers is scant. AIMS: To describe greenhouse workers' occupational allergic diseases. METHODS: We identified 28 greenhouse workers with occupational allergic diseases in 2002-2020 by conducting a systematic search in the patient register of the Finnish Institute of Occupational Health. All the patients worked in tomato- or cucumber-growing greenhouses and showed immunoglobulin-E-mediated sensitization to occupational agents. Specific inhalation challenges or workplace peak expiratory flow monitoring confirmed occupational asthma (OA), nasal allergen challenges confirmed occupational rhinitis (OR) and open skin tests confirmed occupational contact urticaria (OCU). RESULTS: Most patients had more than one occupational disease and were sensitized to several workplace agents. Tomato plants were the most common cause of occupational diseases and induced 22 allergic diseases in 14 patients. Cucumber plants caused occupational diseases in 10 patients (3 OA, 7 OR and 6 OCU). The pest control mite Amblyseius swirskii and a mixture of parasitic wasps Encarsia formosa and Eretmocerus eremicus both induced two OA cases. Three patients had an occupational disease caused by storage mites and three others had a work-related systemic reaction to a bumblebee sting. CONCLUSIONS: The greenhouse workers typically suffered from several occupational allergic diseases and were sensitized to cultivated plants, various pest control organisms and storage mites. All these can cause OA and OR, but in this study, OCU was only induced by cultivation plants. Cucumber plant is a novel cause of OA and OR, and A. swirskii is a novel cause of OA.

Embryonic-stem-cell-derived mesenchymal stem cells relieve experimental contact urticaria by regulating the functions of mast cells and T cells.

Contact urticaria (CU) is an inflammatory skin disorder triggered by specific substances upon skin contact, leading to immediate acute or chronic manifestations characterized by swelling and redness. While mesenchymal stem cells (MSCs) are increasingly recognized for their therapeutic potential in immune diseases, research on the efficacy and mechanisms of stem cell therapy for urticaria remains scarce. This study investigates the regulatory role of embryonic-stem-cell-derived multipotent MSCs (M-MSCs) administered in a CU mouse model. Therapeutic effects of M-MSC administration were assessed in a Trimellitic anhydride-induced contact urticaria model, revealing significant inhibition of urticarial reactions, including ear swelling, itchiness, and skin lesion. Moreover, M-MSC administration exerted control over effector T cell activities in major lymphoid and peripheral tissues, while also suppressing mast cell degranulation in peripheral tissues. Notably, the inhibitory effects mediated by M-MSCs were found to be TGF-ß-dependent. Our study demonstrates the capacity of M-MSCs to regulate contact urticaria in a murine model, harmonizing the activation of inflammatory T cells and mast cells. Additionally, we suggest that TGF-ß derived from M-MSCs could play a pivotal role as an inhibitory mechanism in contact urticaria.

Case Report: Insulin hypersensitivity in youth with type 1 diabetes.

Objective: Immediate type I, type III, and delayed type IV hypersensitivity reactions to insulin are rare, but potentially serious complications of exogenous insulin administration required for the treatment of type 1 diabetes (T1D). Methods: We present four cases of insulin hypersensitivity reactions occurring in youth with T1D and a literature review of this topic. Results: Insulin hypersensitivity reactions included types I, III, and IV with presentations ranging from localized urticaria, erythematous nodules, and eczematous plaques to anaphylaxis with respiratory distress. Reactions occurred in youth with newly diagnosed T1D and in those with long-standing T1D who were using both injection and insulin pump therapy. Multidisciplinary care involving pediatric endocrinology and allergy/immunology utilizing trials of many adjunct therapies yielded minimal improvement. Despite the use of various treatments, including antihistamines, topical therapies, immunosuppressant medications, desensitization trials, and intravenous immune globulin, cutaneous reactions, elevated hemoglobin A1c levels, and negative effects on quality of life remain persistent challenges. One patient became one of the youngest pancreas transplant recipients in the world at age 12 years due to uncontrollable symptoms and intolerable adverse effects of attempted therapies. Conclusion: Although rare, insulin hypersensitivity reactions negatively affect glycemic control and quality of life. These cases demonstrate the varying severity and presentation of insulin hypersensitivity reactions along with the limited success of various treatment approaches. Given the life-sustaining nature of insulin therapy, further studies are needed to better understand the underlying pathophysiology of insulin hypersensitivity and to develop targeted treatment approaches.

Inhibition of KIT for chronic urticaria: a status update on drugs in early clinical development.

INTRODUCTION: Chronic urticaria (CU), including chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), is a prevalent, enduring, mast-cell driven condition that presents challenges in its management. There is a clear need for additional approved treatment options beyond H1 receptor antagonists and the anti-IgE monoclonal antibody (mAb), omalizumab. One of the latest therapeutic strategies targets KIT, which is considered the primary master regulator for mast cell-related disorders. AREAS COVERED: This review provides a status update on KIT inhibiting drugs in early clinical development for CU. EXPERT OPINION: Whereas multi-targeted tyrosine kinase KIT inhibitors carry the risk of off-target toxicities, initial data from anti-KIT mAbs indicate significant potential in CSU and CIndU. The prolonged depletion of mast cells over several weeks by barzolvolimab could effectively control urticarial symptoms. Regarding safety, based on theoretical considerations and the available preliminary results, it is already evident that there may be more side effects compared to omalizumab. However, long-term safety data beyond 12 weeks are still lacking. The outcome of ongoing or planned clinical trials with several anti-KIT mAbs will need to demonstrate benefits compared to anti-IgE in CU or whether one approach is better suited for specific urticaria endotypes.

Angioedema without urticaria after recent initiation of celecoxib.

Angioedema is potentially life-threating swelling of integument and mucosa that has multiple potential aetiologies with varying mechanisms. Drug-induced angioedema is often easily correlated with the offending agent and can be prevented with discontinuation of the medication. Many medications have now been implicated in drug-induced angioedema but the two most common are ACE inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs). This case highlights severe angioedema secondary to celecoxib and reviews varying aetiologies of angioedema and NSAID hypersensitivity reactions.

Omalizumab Drug Survival in Chronic Urticaria: A Retrospective Multicentric French Study.

BACKGROUND: Omalizumab (OMA) dramatically improves disease control and quality of life in patients with chronic urticaria (CU). OBJECTIVE: We aimed to evaluate the discontinuation patterns of OMA and their determinants in a cohort of French patients with CU. METHODS: We conducted a retrospective multicenter study in 9 French tertiary referral hospitals. All patients diagnosed with either spontaneous (CSU) and/or inducible (CIndU) CU who received at least 1 injection of OMA between 2009 and 2021 were included. We analyzed OMA drug survival and investigated possible determinants using Kaplan-Meier curves and log-rank tests. RESULTS: A total of 878 patients were included in this study; 48.8% had CSU, 10.1% CIndU, and 41.1% a combination of both. OMA was discontinued in 408 patients, but the drug was later reintroduced in 50% of them. The main reason for discontinuing treatment was the achievement of a well-controlled disease in 50% of patients. Half of the patients were still being treated with OMA 2.4 years after the initiation of treatment. Drug survival was shorter in patients with CIndU and in those with an autoimmune background. In atopic patients, OMA was discontinued earlier in patients achieving a well-controlled disease. A longer OMA drug survival was observed in patients with a longer disease duration at initiation. CONCLUSION: In French patients with CU, the drug survival of OMA appears to be longer than that observed in previous studies conducted elsewhere, highlighting discrepancies in prescription and reimbursement possibilities. Further studies are warranted to develop customized OMA treatment schemes based on individual patterns.

Evidence-based use of antihistamines for treatment of allergic conditions.

Available since the 1940s, H1 antihistamines are mainstay treatments for allergic conditions such as allergic rhinitis and urticaria. They function as inverse agonists that bind to the H1 receptor to inhibit histamine-induced inflammation. The older, first-generation drugs are no longer recommended for patient use because of their well-documented negative adverse effect profile. Evidence has been accumulating to support a newer generation of H1 antihistamines in oral and intranasal formulations, including in combination with intranasal corticosteroids. The literature is replete with large meta-analyses and systematic reviews establishing the safety and efficacy of second-generation H1 antihistamines in adult and pediatric allergic rhinitis populations, including combination nasal spray agents (eg, MP29-02 or MP-AzeFlu). Although intraclass differences do exist, patient preference, access, and costs should be the priority. Robust data on the regular, not as needed use of H1 antihistamines for urticaria have been published, including in the management of children and pregnant or lactating women. In addition, H1 antihistamines can be used in other related allergic conditions, such as the secondary symptoms of anaphylaxis, to provide patients with greater comfort, including in allergic asthma, depending on the individual.

Potential Therapeutic Approaches for Chronic Urticaria: Beyond H1-Antihistamines and Biologics.

Chronic urticaria is a disease that can significantly impact a patient's quality of life and ability to function. There are effective treatment options, such as nonsedating antihistamines or biologics, but some patients do not respond to these therapies, or the therapies are not available or affordable to all patients. This review aims to summarize potential treatment strategies for patients (1) who do not respond to antihistamines and (2) cannot readily access or do not respond to biologics. The review emphasizes the importance of sound clinical practice, including correct diagnosis of chronic urticaria phenotypes, treatment of associated comorbidities, and consideration of add-on pharmacological and nonpharmacological approaches. Although some treatments may lack high-quality evidence, they may still be justifiable in certain cases, provided that there is shared decision-making, regular reassessment, and early recognition of adverse events.

Association Between Serum Total IgE Levels and Clinical Response to Omalizumab for Chronic Spontaneous Urticaria: A Systematic Review and Meta-Analysis.

BACKGROUND: Omalizumab is the only biological agent approved for patients with chronic spontaneous urticaria (CSU), but no biomarker is well established for predicting clinical response to omalizumab. OBJECTIVE: We aimed to determine the association between baseline total serum IgE levels and the effects of omalizumab in patients with CSU. METHODS: PubMed, Web of Science, Scopus, and Cochrane Library were systematically searched for relevant studies from inception to August 23, 2022. The research protocol was registered on PROSPERO (CRD42022355592). No language restrictions were applied. A random-effects model was used for meta-analysis. RESULTS: Ten interventional studies, including 1 randomized controlled trial, were included in the final meta-analysis, and a total of 866 patients with CSU were included. A pooled analysis showed significantly higher serum total IgE levels in complete responders (CRs) than in nonresponders (NRs) (mean difference [MD]: 56.509 IU/mL; 95% confidence interval [CI]: 24.230-88.789) and in partial responders (PRs) than in NRs (MD: 62.688 IU/mL; 95% CI: 32.949-92.427), but no significant difference was detected between CRs and PRs. The mean total IgE levels for CRs, PRs, and NRs were 163.154, 179.926, and 51.535 IU/mL, respectively. Further, the serum total IgE levels in early CRs were significantly higher compared with late CRs (MD: 55.194 IU/mL; 95% CI: 13.402-96.986). The sensitivity analyses with the leave-one-out method validated the robustness of all findings. CONCLUSIONS: This systematic review and meta-analysis provide convincing evidence that pretreatment total serum IgE levels in patients with CSU are associated with clinical responses to omalizumab.

Normocomplementemic urticarial vasculitis in a patient with multiple sclerosis on glatiramer acetate.

Glatiramer acetate is one of the oldest and safest disease modifying therapies used to treat relapsing-remitting multiple sclerosis. Urticarial vasculitis is a rare complication of treatment with glatiramer acetate, having been reported by only two others previously. Here, we describe a case of normocomplementemic urticarial vasculitis diagnosed on skin punch biopsy in a patient with multiple sclerosis treated with glatiramer acetate for five years. Upon treatment with steroids and an antihistamine along with discontinuation of glatiramer acetate, the urticaria resolved.

Exacerbation of Chronic Spontaneous Urticaria Following Coronavirus Disease 2019 (COVID-19) Vaccination in Omalizumab-Treated Patients.

BACKGROUND: The rapid development and rollout of vaccines against coronavirus disease 2019 (COVID-19) has led to more than half of the world's population being vaccinated to date. Real-world data have reported various adverse cutaneous reactions, including delayed-onset urticaria, which was highly ranked as a common manifestation across studies. However, the impact of these novel mRNA or viral vector COVID-19 vaccines on preexisting chronic spontaneous urticaria (CSU) remains largely unknown. OBJECTIVE: To investigate the impact of COVID-19 vaccination on the clinical status of patients with relatively stable CSU who are undergoing omalizumab treatment and to identify risk factors for exacerbation. METHODS: We conducted a questionnaire-based cross-sectional study in a tertiary hospital. Adult patients with relatively stable CSU under regular omalizumab treatments who had received at least one COVID-19 vaccination were included. RESULTS: There were 105 study subjects who received 230 COVID-19 vaccinations between March and December 2021. Fifteen patients (14.3%) experienced aggravation of urticaria at least once after COVID-19 vaccination. The demographics and clinical characteristics of the patients were comparable regardless of the exacerbation of CSU. However, case-level analysis revealed that the presence of urticaria (vs none) before vaccination (odds ratio [OR] = 4.99; 95% CI, 1.57-15.82) and the development of systemic reactogenicity (OR = 4.57; 95% CI, 1.62-12.90) were associated with a higher risk for exacerbation. CONCLUSIONS: The novel COVID-19 vaccination induced exacerbation in more than one-tenth of patients with well-controlled CSU. The establishment of a proper management strategy during COVID-19 vaccination is necessary for patients with CSU.

Safety, pharmacokinetics, and pharmacodynamics of intravenous ferric carboxymaltose in children with iron deficiency anemia.

BACKGROUND: Iron deficiency is the primary cause of anemia in children. Intravenous (IV) iron formulations circumvent malabsorption and rapidly restore hemoglobin. METHODS: This Phase 2, non-randomized, multicenter study characterized the safety profile and determined appropriate dosing of ferric carboxymaltose (FCM) in children with iron deficiency anemia. Patients aged 1-17 years with hemoglobin <11 g/dL and transferrin saturation <20% received single IV doses of undiluted FCM 7.5 mg/kg (n = 16) or 15 mg/kg (n = 19). RESULTS: The most common drug-related treatment-emergent adverse event was urticaria (in three recipients of FCM 15 mg/kg). Systemic exposure to iron increased in a dose-proportional manner with approximate doubling of mean baseline-corrected maximum serum iron concentration (157 µg/mL with FCM 7.5 mg/kg; and 310 µg/mL with FCM 15 mg/kg) and area under the serum concentration-time curve (1901 and 4851 h·µg/mL, respectively). Baseline hemoglobin was 9.2 and 9.5 g/dL in the FCM 7.5 and 15 mg/kg groups, respectively, with mean maximum changes in hemoglobin of 2.2 and 3.0 g/dL, respectively. CONCLUSIONS: In conclusion, FCM was well tolerated by pediatric patients. Improvements in hemoglobin were greater with the higher dose, supporting use of the FCM 15 mg/kg dose in pediatric patients (Clinicaltrials.gov NCT02410213). IMPACT: This study provided information on the pharmacokinetics and safety of intravenous ferric carboxymaltose for treatment of iron deficiency anemia in children and adolescents. In children aged 1-17 years with iron deficiency anemia, single intravenous doses of ferric carboxymaltose 7.5 or 15 mg/kg increased systemic exposure to iron in a dose-proportional manner, with clinically meaningful increases in hemoglobin. The most common drug-related treatment-emergent adverse event was urticaria. The findings suggest that iron deficiency anemia in children can be corrected with a single intravenous dose of ferric carboxymaltose and support use of a 15 mg/kg dose.

Safety and outcomes of "at-home self-provocation tests" in patients with mild nonsteroidal anti-inflammatory drug-induced urticaria/angioedema.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity is common; however, many patients do not receive an accurate diagnosis and are using unnecessary alternative drugs or have medication restrictions. OBJECTIVE: To establish a protocol for provocation tests that can be performed safely and effectively at home to give patients an accurate diagnosis, whereas also delabeling NSAID hypersensitivity. METHODS: We retrospectively analyzed the medical records of 147 patients with NSAID hypersensitivity. All patients had NSAID-induced urticaria/angioedema with less than 10% body surface area skin involvement. One specialist developed the protocol through history taking and chart review. If NSAID hypersensitivity was confirmed, an oral provocation test was performed to confirm the safe alternative medications (group A). If it was undetermined, an oral provocation test was performed to confirm the diagnosis and alternative medications (group B). All oral provocation tests were performed by patients in their homes according to the protocol. RESULTS: Approximately 26% of group A patients had urticaria or angioedema symptoms with alternative drugs, whereas the remaining 74% was safe. In group B, 34% of the patients were diagnosed with having NSAID hypersensitivity. However, 61% did not respond to the culprit drug; therefore, NSAID hypersensitivity had been misdiagnosed. During this at-home self-provocation test, no severe hypersensitivity reactions occurred. CONCLUSION: Many patients originally suspected of having NSAID hypersensitivity were confirmed to have been misdiagnosed. We successfully conducted an effective and safe at-home self-provocation test.