Efficacy of Omalizumab for the treatment of Bullous Pemphigoid. Spanish multicenter real-world experience.

BACKGROUND: Bullous Pemphigoid (BP) is the most common autoimmune blistering disease. Most patients are elderly and associate multiple comorbidities. Topical and systemic corticosteroids are considered as the first-line treatment for BP and immunosuppressors are used as steroid-sparing treatments but both have side effects and contraindications which are even more common in this elderly population. New treatments targeting interleukins and receptors related to BP pathogenesis have been proposed to decrease this side effects while achieving equal or better effectiveness response rates.Omalizumab is a monoclonal antibody that targets IgE that has been proposed for the treatment of BP due to the evidence that IgE autoantibodies play an essential role in BP pathogenesis. OBJECTIVES AND METHODOLOGY: To assess the efficacy and security of Omalizumab for the treatment of BP, we carried out a multicenter, retrospective, observational study including patients diagnosed of BP who received omalizumab for at least 3 months from 15 tertiary hospitals in Spain. IgE levels prior to treatment was measured and we evaluate the possible correlation with clinical response. We excluded patients treated with Omalizumab for less than 3 months as we consider this duration is insufficient for a comprehensive assessment of its efficacy. To evaluate the effectiveness of the treatment we used the percentage of BSA improvement. RESULTS: We included 36 patients. The vast majority associate multiple comorbidities and all patients had used other systemic therapies apart from corticoids before Omalizumab.83% experienced some kind of treatment response and 42% of all patient treated achieved complete response.We did not find any correlation between higher levels and a better response (p=0,1791).All patients tolerated Omalizumab without reported side-effects. CONCLUSIONS: Omalizumab is a good therapeutic alternative for BP as it obtained clinical response in most patients and nearly half of the cases achieving complete response. It showed no side effects which is crucial in elderly patients suffering from BP.

Assessment of potential predictive factors of dupilumab response in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Dupilumab has shown to be an effective and safe treatment for patients with moderate-to-severe atopic dermatitis (AD). OBJECTIVE: To evaluate the predictive factors of response (PRF) in patients with moderate-to-severe AD treated with dupilumab. METHODS: Observational, retrospective and multicentre study conducted on adult patients diagnosed with moderate-to-severe AD treated with dupilumab, with a post-treatment follow-up of at least 16 weeks. The primary endpoints were EASI-75 and the IGA scale at week 52. RESULTS: A total of 198 patients were included in the analysis. Mean age was 38 ± 15.1 years and 116 (58.6%) were men. The most prevalent AD-predominant phenotypes were flexural eczema (45.3%), head-and-neck eczema (18.2%) and erythroderma (17.7%). At week 52, 140 (86.4%) patients achieved EASI-75 and 119 (93.0%) achieved an improvement in ≥2 points from baseline in IGA score. Women were 3.6 times more likely to achieve EASI-75 response than men (Odds ratio: 3.58; p = 0.020). While increased body mass index significantly reduced the probability of obtaining an improvement of ≥2 points in the IGA scale at week 52 (odds ratio: 0.88; p = 0.049). CONCLUSIONS: Dupilumab was an effective treatment in patients with moderate-to-severe AD. Additionally, sex and body mass index were significantly associated with achieving EASI-75 and an improvement of ≥2 points in the IGA scale, respectively, at week 52.

Clinical Features of Chronic Spontaneous Urticaria that Predict Disease Prognosis and Refractoriness to Standard Treatment.

Chronic spontaneous urticaria (CSU) is characterized by heterogeneous activity, evolution, associated comorbidities and response to treatment. The aim of this study was to identify prognostic factors in patients with CSU that predict disease course and response to standard treatments. An observational retrospective study was conducted in a cohort of 549 patients with CSU, comparing patients with isolated CSU and those with CSU with concomitant inducible urticaria (CSU-CIndU). The factors associated with a worse prognosis in terms of duration and/or CSU activity and its episodes were: multiple episodes of CSU (19.2% had more than one lifetime episode of CSU), late-onset (63.6% of patients developed first onset of CSU after the age of 45 years), concomitant CIndU (20.2%) and functional serum autoreactivity. Patients with CSU-CIndU required more frequent therapy after 5 years and higher doses of 2nd-generation H1-antihistamines. Of patients with a baseline Urticaria Activity Score 7 (UAS7) between 16 and 42, 84.6% required cyclosporine or omalizumab to achieve symptom control, compared with 15.4% of patients with a baseline UAS7 between 0 and 15 (p?=?0.0013). Baseline CSU activity is the only factor found to be predictive for refractoriness to treatment with H1-antihistamines.

Basophil FcεRI Expression in Chronic Spontaneous Urticaria: A Potential Immunological Predictor of Response to Omalizumab Therapy.

Although the efficacy of omalizumab has been clearly demonstrated in the treatment of chronic spontaneous urticaria (CSU), its mechanism of action, which results in improvement in CSU symptoms, is not entirely understood. This study investigated the effect of omalizumab on expression of the high-affinity IgE receptor (FcεRI) on blood basophils from patients with active CSU, and its association with the clinical response. Patients exhibiting significant clinical improvement showed a sharp reduction in the levels of basophil FcεRI after 4 weeks, which was maintained throughout the total duration of the treatment. Such evolution was not observed in non-responder patients. Furthermore, non-responders showed significantly lower baseline levels of FcεRI than responders. Baseline basophil FcεRI expression was found to be a potential immunological predictor of response to omalizumab (100% sensitivity and 73.2% specificity). The results of this study contribute to our knowledge of the therapeutic benefit and mechanism of action of anti-IgE therapy in CSU.

Acquired cold urticaria: Clinical features, particular phenotypes, and disease course in a tertiary care center cohort.

BACKGROUND: Data about special phenotypes, natural course, and prognostic variables of patients with acquired cold urticaria (ACU) are scarce. OBJECTIVES: We sought to describe the clinical features and disease course of patients with ACU, with special attention paid to particular phenotypes, and to examine possible parameters that could predict the evolution of the disease. METHODS: This study was a retrospective chart review of 74 patients with ACU who visited a tertiary referral center of urticaria between 2005 and 2015. RESULTS: Fourteen patients (18.9%) presented with life-threatening reactions after cold exposure, and 21 (28.4%) showed negative results after cold stimulation tests (classified as atypical ACU). Nineteen patients (25.7%) achieved complete symptoms resolution at the end of the surveillance period and had no subsequent recurrences. Higher rates of atypical ACU along with a lower likelihood of achieving complete symptom resolution was observed in patients who had an onset of symptoms during childhood (P < .05). In patients with atypical ACU, shorter disease duration and lower doses of antihistamines required for achieving disease control were detected (P < .05). Age at disease onset, symptom severity, and cold urticaria threshold values were found to be related to disease evolution (P < .05). LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: The knowledge of the clinical predictors of the disease evolution along with the clinical features of ACU phenotypes would allow for the establishment of an early and proper therapeutic strategy.

Rupatadine 20 mg and 40 mg are Effective in Reducing the Symptoms of Chronic Cold Urticaria.

Chronic cold urticaria (ColdU) is a rare disease characterized by mast cell-mediated wheals and angioedema following cold exposure. Second-generation H1-antihistamines, such as rupatadine, are the recommended first-line therapy. As of yet, the effects of rupatadine up-dosing on development of ColdU symptom have only been partially characterized. Two-centre, randomized, double-blind, 3-way crossover, placebo-controlled study in patients with a confirmed ColdU was designed to assess the effects of up-dosing of rupatadine. A total of 23 patients were randomized to receive placebo, rupatadine 20 mg/day, and rupatadine 40 mg/day for 1 week. The primary outcome was change in critical temperature thresholds and critical stimulation time thresholds after treatment. Secondary endpoints included assessment of safety and tolerability of rupatadine. Both 20 and 40 mg rupatadine were highly effective in reducing critical temperature thresholds (p < 0.001) and critical stimulation time thresholds (p < 0.001). In conclusion, rupatadine 20 and 40 mg significantly reduced the development of chronic cold urticaria symptom without an increase in adverse effects.

Temperature thresholds in assessment of the clinical course of acquired cold contact urticaria: a prospective observational one-year study.

Cold contact urticaria is the second most common subtype of physical urticaria. Cold stimulation standardized tests are mandatory to confirm the diagnosis. The aim of this study is to define the utility of determining thresholds (critical time and temperature) in assessment of the clinical course of typical acquired cold contact urticaria. Nineteen adult patients (10 women and 9 men; mean age 45 years) were included in the study and the diagnosis was confirmed with the ice-cube test and TempTest 3.0. Patients were treated continuously for 1 year with 20 mg/day rupatadine (anti-H1). Thresholds measurements were made before and after treatment. Improvements in temperature and critical time thresholds were found in the study sample, demonstrating the efficacy of continuous treatment with rupatadine. In most cases association with a clinical improvement was found. We propose an algorithm for the management of acquired cold contact urticaria based on these results.

Epidermal Choristoma of the Tongue Mimicking a Congenital Melanotic Macule.

We report the fifth case of epidermal choristoma of the oral cavity in a Caucasian newborn with a congenital melanotic macule on the dorsum of the tongue. Epidermal choristoma is an exceedingly rare and benign condition probably caused by a developmental abnormality. It is identified according to the presence of normal skin in an abnormal location. Histologically it is identified according to areas of stratified epithelium and hyperpigmentation of the basal layer along with cutaneous adnexal structures (hair follicles, sebaceous or sweat glands). The clinical presentation is variable, but most of the cases described presented with a congenital lingual pigmented macule. These lesions should be included within the differential diagnosis of congenital lingual macules and distinguished from other entities such as congenital lingual melanotic macules and melanocytic lesions. Surgical excision is the treatment of choice. Epidermal choristoma is a benign condition that probably is underdiagnosed because it is a new and rare entity, and dermatologists should be aware of it.

Verruciform xanthoma developing in recessive dystrophic epidermolysis bullosa: A sheep in wolf's clothing.

A 23-year-old male affected of recessive dystrophic epidermolysis bullosa presented with a 2-month history of a growing verrucous plaque on the right flank. The clinical features and evolution suggested the diagnosis of cutaneous squamous cell carcinoma. Histopathological examination showed hyperkeratosis, parakeratossis, and verrucous acanthosis and numerous large xanthoma cells in the papillary dermis. Reflectance confocal microscopy disclosed the absence of epidermal atypia and the presence of aggregates of reflecting cells at dermal-epidermal junction and upper dermis. These cells were ultrastructurally characterized and corresponded to foamy histiocytes. Verruciform xanthoma is a benign reactive lesion that has occasionally been reported to develop in chronically eroded areas in patients with recessive dystrophic epidermolysis bullosa. In this group of patients, verruciform xanthoma may clinically mimic cutaneous squamous cell carcinoma and a correct diagnosis is crucial to avoid inappropriate aggressive therapeutic approaches. In vivo noninvasive image technologies such as reflectance confocal microscopy may be helpful diagnostic tools in this clinical setting.

Autoimmune Diseases and Low Baseline IgE in Chronic Spontaneous Urticaria: A Clinical and Therapeutic Prospective Analysis in Real-Life Clinical Practice.

BACKGROUND: Autoimmunity contributes to the pathogenesis of chronic spontaneous urticaria (CSU). The subtyping of CSU has revealed an autoimmune form of CSU. Despite autoimmune diseases having been associated with CSU, there are few prospective studies that have evaluated the characteristics and biomarkers of patients with CSU and autoimmune disease in a real-life practice setting. OBJECTIVE: To evaluate the presence of specific biomarkers for the presence of autoimmune disease in CSU and to analyze the clinical and therapeutic features of patients with CSU and autoimmune disease. METHODS: The clinical, laboratory, and therapeutic features of patients with CSU at a tertiary-level center were prospectively collected. Data obtained were compared in function of the presence/absence of autoimmune disease and typified according to IgE levels. RESULTS: Patients with CSU who had associated autoimmune disease corresponded to middle-aged women with a common pattern of blood test findings: both low baseline IgE and high-affinity receptor of IgE expression, basopenia, eosinopenia, higher baseline erythrocyte sedimentation rate and D-dimer, increased presence of antinuclear antibodies, IgG against thyroid peroxidase, and positive autologous serum skin test result. Total baseline IgE less than or equal to 43.8 IU/mL was both the optimal cutoff to predict autoimmune disease in the CSU cohort and a significant risk factor for the presence of autoimmune disease in the regression analysis. CONCLUSIONS: In real-life clinical practice, characteristics of patients with CSU and autoimmune disease share common features with type IIb autoimmune CSU. Total baseline IgE less than or equal to 43.8 IU/mL has been detected as a possible biomarker of autoimmune disease in patients with CSU.

Allergen sensitization stratifies IL-31 production by memory T cells in atopic dermatitis patients.

Background: The role of allergen sensitization in IL-31 production by T cells and specifically in the clinical context of atopic dermatitis (AD) has not been characterized. Methods: The response to house dust mite (HDM) in purified memory T cells cocultured with epidermal cells from AD patients (n=58) and control subjects (n=11) was evaluated. AD-associated cytokines from culture supernatants, plasma proteins and mRNA expression from cutaneous lesions were assessed and related with the clinical features of the patients. Results: HDM-induced IL-31 production by memory T cells defined two subsets of AD patients according to the presence or absence of IL-31 response. Patients in the IL-31 producing group showed a more inflammatory profile, and increased HDM-specific (sp) and total IgE levels compared to the IL-31 non-producing group. A correlation between IL-31 production and patient's pruritus intensity, plasma CCL27 and periostin was detected. When the same patients were analyzed based on sp IgE and total IgE levels, an increased IL-31 in vitro response, as well as type 2 markers in plasma and cutaneous lesions, was found in patients with sp IgE levels > 100 kUA/L and total IgE levels > 1000 kU/L. The IL-31 response by memory T cells was restricted to the cutaneous lymphocyte-associated antigen (CLA)+ T-cell subset. Conclusion: IgE sensitization to HDM allows stratifying IL-31 production by memory T cells in AD patients and relating it to particular clinical phenotypes of the disease.

New transcriptome and clinical findings of platelet-activating factor in chronic spontaneous urticaria: Pathogenic and treatment relevance.

The objective of the study was to assess the pathogenic and treatment relevance of Platelet Activating factor (PAF) in chronic spontaneous urticaria (CSU). The expression and cellular location of PAF receptor (PAFR) and serum levels of PAF and PAF acetylhydrolase (PAF-AH) in patients with moderate/severe CSU (n = 45) and healthy controls (HCs, n = 17) were studied. Skin samples from the active wheal (LS-CSU, 13 samples for qPCR and 33 for immunohistochemistry) and non-lesional skin (NLS-CSU, 13 samples) of CSU patients and HCs (13 samples and 5 for immunohistochemistry) were analyzed. Serum PAF and PAF-AH levels were measured by ELISA and compared between HC (10 samples) and CSU patients (25 samples) and, among them, between those refractory and non-refractory to second-generation H1 -antihistamines (sgAH). PAFR mRNA expression was significantly higher in LS-CSU versus HCs (p = 0.014). PAFR positive staining in immunohistochemistry was mainly found in the epidermal basal layer in HCs, whereas it was broadly present along the epidermis in LS-CSU samples. Endothelial cells showed PAFR expression exclusively in LS-CSU and NLS-CSU samples. PAFR expression was observed in the nerves of HC, LS-CSU, and NLS-CSU samples. Double PAFR/CD43 expression showed that T-lymphocytes were the main cell type from the wheal inflammatory infiltrate expressing PAFR. A significantly lower PAF-AH/PAF ratio was observed in sgAH non-responders versus responders (6.1 vs. 12.6; p = 0.049). Our study confirms that PAF is a mediator of wheal pathogenesis in CSU. The significantly lower PAF-AH/PAF ratio in sgAH non-responders vs responders suggests that PAF could be a potential biomarker of sgAH refractoriness.

Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamine.

The second-generation H1-antihistamines (sgAH) are the first-line symptomatic treatment of patients with chronic spontaneous urticaria (CSU). Up to 50% of the patients will not respond to licensed doses of sgAH. According to the guidelines, the dose of sgAH may be increased up to 4 times the conventional dose. However, even at higher doses, there is a subgroup of patients refractory to the antihistamine treatment. The purpose of this article was to review the different treatment options of antihistamine-refractory CSU patients. This revision examines the available literature for therapies used in chronic urticaria, including omalizumab, ciclosporin A, oral glucocorticoids, leukotriene receptor antagonists, H2 antihistamines, doxepin, dapsone, hydroxychloroquine, phototherapy, methotrexate, mycophenolate mofetil, azathioprine, autohemotherapy, intravenous immunoglobulins and rituximab, between others. After the exhaustive review of the medical literature only few high-quality studies have been identified, mostly for omalizumab. Omalizumab is an anti-immunoglobulin E monoclonal antibody, approved for the treatment of CSU, that has radically changed the management of the patients without good response to sgAH, allowing to reach complete responses in a high percentage of patients. Although actually the therapeutic management of CSU is more effective and safer than before 2014, there is place even for new and more effective treatments. A good number of partial responders and slow responders to omalizumab and a little percentage still of non-responders to available therapies stimulate the development of new drugs that will also be discussed.