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BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.
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Antialérgicos , Anticorpos Monoclonais Humanizados , Urticária Crônica , Urticária , Adolescente , Adulto , Feminino , Humanos , Masculino , Antialérgicos/efeitos adversos , Doença Crônica , Urticária Crônica/tratamento farmacológico , Método Duplo-Cego , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Omalizumab/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Urticária/tratamento farmacológicoRESUMO
BACKGROUND: Evidence on safety and effectiveness of omalizumab for treatment of chronic urticaria in pediatric patients is scarce and limited to case reports. In particular, drug survival of omalizumab has not yet been investigated, which is a key element in the evaluation of its clinical performance. The aim of this study was to investigate safety, effectiveness, and drug survival rates of omalizumab in a daily practice cohort of pediatric patients with chronic urticaria (CU). METHODS: This is a multicenter study including all pediatric patients from an academic center (Wilhelmina Children's Hospital) and a general center (Diakonessenhuis Hospital) in the Netherlands, who started omalizumab treatment before the age of 18 years. Data on safety, effectiveness, time to discontinuation, and reasons for discontinuation of treatment were assessed. Drug survival of omalizumab was estimated using the Kaplan-Meier survival analysis. RESULTS: A total of 38 patients, who started treatment between January 2014 and January 2020, were included. Most patients (68.4%) used omalizumab without reporting any side effects and a complete or good response to treatment was achieved in 76.3% of patients. The 1- and 2-year drug survival rates were 62% and 50%, respectively, with well-controlled disease activity as the most frequent reason for discontinuation in 69.2% of patients, followed by ineffectiveness in 23.1% and side effects in 7.7% of patients. CONCLUSIONS: This study demonstrates high safety and effectiveness of omalizumab treatment in pediatric patients with CU, which will aid clinical decision making and management of expectations when choosing omalizumab treatment for pediatric patients with CU.
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Antialérgicos , Urticária Crônica , Urticária , Adolescente , Antialérgicos/efeitos adversos , Criança , Doença Crônica , Humanos , Omalizumab/efeitos adversos , Resultado do Tratamento , Urticária/tratamento farmacológicoRESUMO
BACKGROUND: Chronic spontaneous urticaria (CSU) is characterized by recurrent itchy weals and/or angioedema and is believed to be driven by mast cell activation. It was shown that excessive mast cell activation during anaphylaxis initiates contact activation, resulting in bradykinin release. Evidence for bradykinin release was never demonstrated in CSU. OBJECTIVE: To study biomarkers of bradykinin release in CSU. METHODS: Plasma samples of CSU patients were collected during routine visits at the outpatient clinic. Cleaved high molecular weight kininogen (cHK) was used as a biomarker for bradykinin release. cHK, factor XIIa-C1-inhibitor (FXIIa-C1-INH), kallikrein-C1-INH, plasmin-antiplasmin (PAP) complexes and soluble urokinase-type plasminogen activator receptor (suPAR) levels were determined by ELISA. Clinical data and data on tryptase levels were collected from medical records. cHK levels were compared to previously determined levels in hereditary angioedema (HAE). RESULTS: One hundred seventeen samples from 88 CSU patients and 28 samples from healthy controls were analysed. Median cHK level in CSU was 9.1% (range: 1.4%-21.5%), significantly increased compared to healthy controls (median 6.0% range: 0%-19.9%; P = .0005) and comparable to HAE (n = 46, median 10.3%, range 0%-44.3%, P > .9999). cHK levels normalized in patients during disease remission (median 6.5% range 1.5%-20.8%) but were not dependent on the presence of angioedema, acute angioedema attacks or response to antihistamines. Surprisingly, cHK levels were inversely correlated to serum tryptase (r = -0.65 P = .0137). C1-INH complexes and suPAR levels were not elevated in patients compared to healthy controls. PAP-complex levels in patients were elevated compared to healthy controls but there was no correlation between PAP-complex and cHK levels. CONCLUSIONS: cHK levels are elevated in symptomatic CSU patients compared to healthy controls, indicating increased bradykinin production. Increased cHK levels are not limited to patients with angioedema. CLINICAL RELEVANCE: If elevated bradykinin generation has clinical implications in the pathology of CSU is open to debate.
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Bradicinina , Urticária Crônica , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Bradicinina/sangue , Bradicinina/imunologia , Urticária Crônica/sangue , Urticária Crônica/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The pathogenesis of chronic spontaneous urticaria (CSU) and the mechanism of action of omalizumab in CSU remain unclear. OBJECTIVE: In this study, we assessed the responsiveness and FcεRI expression of various subsets of leucocytes in patients with CSU treated with omalizumab. METHODS: In this prospective cohort study, 30 patients were treated with 6 administrations of 300 mg omalizumab every 4 weeks, followed by a follow-up period of 12 weeks. FcεRI expression and the percentage of basophils, monocytes, and dendritic cell subsets were analysed before and during treatment, and after follow-up. In addition, anti-IgE- and C5a-induced basophil degranulation was measured. The results were correlated with disease activity and response to omalizumab. RESULTS: In addition to a rapid and significant reduction in FcεRI on basophils, we demonstrated a reduction in FcεRI on plasmacytoid dendritic cells during omalizumab treatment, which persisted until 3 months after discontinuation. FcεRI expression on basophils and its reduction did not correlate with the treatment response. Omalizumab led to an increased percentage of basophils in blood but not of the other FcεRI-bearing leucocytes. Basophil responsiveness was differentially affected; anti-IgE-, but not C5a-induced basophil degranulation increased during the treatment. Apart from clinical non-responders showing a stronger increase in anti-IgE-induced basophil degranulation over a period time, no differences were found in omalizumab responders vs non-responders. CONCLUSIONS/CLINICAL RELEVANCE: FcεRI expression on basophils decreased rapidly, while anti-IgE-induced degranulation significantly increased due to omalizumab treatment in patients with CSU, persisting at least for 3 months after stopping the treatment. None of the markers were able to predict the effectiveness of treatment. Whether basophils play a role in omalizumab responsiveness in CSU remains unclear.
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Urticária Crônica/tratamento farmacológico , Urticária Crônica/imunologia , Leucócitos/imunologia , Omalizumab/administração & dosagem , Receptores de IgE/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Secondary care studies showed that a recorded allergy to beta-lactams could not be confirmed by valid allergy testing in >85% of cases. In daily practice, recorded beta-lactam allergies probably cause prescription of secondary choice antibiotics. This overrating of beta-lactam allergy hampers appropriate use of narrow spectrum antibiotic and generates unnecessary cost and bacterial resistance. OBJECTIVE: To assess registration and over diagnosis of allergies against beta-lactams in Dutch primary care. METHODS: A retrospective cohort study in 8288 primary care subjects was performed. Patients with recorded allergy were identified through International Classification for Primary Care coding. Signs and symptoms of the recorded allergic reaction and patient's characteristics were extracted from patient's files and patients were sent a questionnaire. The probability of allergy was based on a composite reference standard that was scored by two authors independently. RESULTS: One hundred sixty-three subjects had a recorded allergy (2.0%). In 51.5% of cases, no characteristics of the recorded allergic reaction were reported in patients' medical files. Based on our composite reference standard, allergy was excluded in 19 subjects (11.7%). Risk factors for allergy registration were female gender, age <4 years, and the comorbidities-asthma, allergies and skin disorders. CONCLUSIONS: The prevalence of recorded allergy against beta-lactam antibiotics in a large Dutch primary care centre was 2%. Due to lack of registration of accompanying signs and symptoms of the recorded allergy, this diagnosis is uncertain in most patients. Better documentation and classification by a screening algorithm of future possible allergic reactions to beta-lactams are needed in primary care.
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Erros de Diagnóstico/estatística & dados numéricos , Hipersensibilidade a Drogas/diagnóstico , Atenção Primária à Saúde/estatística & dados numéricos , beta-Lactamas/imunologia , Adolescente , Adulto , Distribuição por Idade , Antibacterianos/efeitos adversos , Antibacterianos/imunologia , Asma/epidemiologia , Criança , Pré-Escolar , Comorbidade , Hipersensibilidade a Drogas/epidemiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Doenças do Sistema Imunitário/epidemiologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Atenção Primária à Saúde/métodos , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Distribuição por Sexo , Dermatopatias/epidemiologia , Adulto Jovem , beta-Lactamas/efeitos adversosRESUMO
BACKGROUND: Serum thymus and activation-regulated chemokine (sTARC) levels reflect disease severity of atopic dermatitis (AD) in small study populations. It remains unclear whether sTARC is a reliable outcome measurement for AD severity in heterogeneous AD populations in daily practice. OBJECTIVE: We sought to assess the utility of sTARC as a biomarker for monitoring AD severity in adults in daily practice. METHODS: sTARC, clinical skin score (Six Area, Six Sign AD [SASSAD]), and body surface area measurements were collected from all adult patients with AD visiting our clinic between March 2009 and March 2012, at first visit or exacerbation (baseline). In addition, data from short-term and long-term follow-up visits were collected. RESULTS: At baseline sTARC levels ranged widely (n = 320; minimum-maximum: 3-50,400 pg/mL) and sTARC and SASSAD or body surface area correlated moderately. In the majority of patients, sTARC and SASSAD or body surface area changed congruently during follow-up. LIMITATIONS: Data were collected retrospectively. CONCLUSION: sTARC may represent a suitable biomarker for monitoring of AD severity in daily practice.
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Quimiocina CCL17/sangue , Dermatite Atópica/sangue , Índice de Gravidade de Doença , Adulto , Biomarcadores/sangue , Superfície Corporal , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Importance: Treating patients with chronic urticaria using omalizumab has been shown to be safe and effective in randomized clinical trials. Multinational studies on long-term omalizumab performance in chronic urticaria in clinical practice settings are lacking, especially on drug survival. Drug survival, which refers to the length of time that patients are treated with a specific drug, is a comprehensive outcome covering effectiveness, safety, and patient and physician preferences. Furthermore, little is known about the reasons and potential predictors for omalizumab discontinuation. Objective: To investigate omalizumab drug survival as well as reasons and potential predictors for discontinuation in a large, diverse population. Design, Setting, and Participants: This international multicenter cohort study was conducted at 14 Urticaria Centers of Reference and Excellence in 10 countries, including all patients with chronic urticaria from these centers who were ever treated with omalizumab. Main Outcomes and Measures: Drug survival analysis was performed to assess time to discontinuation. Patient characteristics and treatment protocols were investigated by Cox regression analysis to identify potential predictors for omalizumab discontinuation. Results: In 2325 patients with chronic urticaria who started omalizumab between June 2009 and July 2022, the mean (SD) age of the cohort was 42 (6) years, and 1650 participants (71%) were female. Overall omalizumab survival rates decreased from 76% to 39% after 1 to 7 years, respectively (median survival time, 3.3 [95 % CI, 2.9-4.0] years), primarily due to discontinuation from well-controlled disease in 576 patients (65%). Ineffectiveness and adverse effects were reasons for discontinuation in a far smaller proportion of patients, totaling 164 patients (18%) and 31 patients (4%), respectively. Fast treatment response was associated with higher rates of omalizumab discontinuation due to well-controlled disease (hazard ratio, 1.45 [95% CI, 1.20-1.75]), and disease duration of more than 2 years was associated with lower rates of discontinuation due to well-controlled disease (HR, 0.81 [95% CI, 0.67-0.98]). Immunosuppressive cotreatment at the start of omalizumab and autoimmune disease was associated with a higher risk for discontinuation due to ineffectiveness (HR, 1.65 [95% CI, 1.12-2.42]). The presence of spontaneous wheals (HR, 0.62 [95% CI, 0.41-0.93]) and access to higher dosages (HR, 0.40 [95% CI, 0.27-0.58) were both associated with a lower risk for discontinuation of omalizumab due to ineffectiveness. Conclusion and Relevance: This multinational omalizumab drug survival cohort study demonstrated that treatment of chronic urticaria with omalizumab in a clinical setting is effective and safe, and well-controlled disease is the main reason for treatment discontinuation. These findings on omalizumab drug survival rates and reasons and potential predictors for discontinuation may guide patients and physicians in clinical decision-making and expectation management. These results may call for the identification of biomarkers for chronic urticaria remission in complete responders to omalizumab treatment.
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BACKGROUND: The pathogenesis of chronic spontaneous urticaria (CSU), including the mechanism of action of omalizumab, remain unclear. We hypothesized complement system involvement given the often fast clinical response induced by treatment, including omalizumab. Therefore, we assessed the role of various complement factors surrounding omalizumab treatment. METHODS: Thirty CSU patients (median age 42 [range 21-70]; 73 % female) with a median once daily Urticaria Activity Score over 7 days (UAS7) score at baseline of 31.5 points were enrolled. Treatment consisted of six administrations of 300 mg omalizumab every 4 weeks succeeded by a follow-up period of 12 weeks. Four punch skin biopsies were taken per patient; at baseline from lesional skin, at baseline from nonlesional skin, and after 1 and 7 days from formerly lesional skin. Complement activity, including C1q, C3, C3bc/C3, C4, C4bc/C4, C5a, and Membrane Attack Complex in peripheral blood were analyzed and complement activation in the skin was determined by the analysis of C4d deposition. Results were related to the clinical response to omalizumab. RESULTS: Fifteen patients showed a UAS7 score of 6 or lower (median 0) at Week 24, 15 patients did not (median 16). Lesional skin biopsies at baseline revealed complement deposition (C4d) in blood vessels in the papillary dermis of 53% (16/30) of the patients, which suggests involvement of immune complexes in the pathogenesis of urticaria. Moreover, indication of increased complement activation in CSU was substantiated by increased C5a levels in peripheral blood compared to healthy controls (p = 0.010). The clinical effect of omalizumab could not be linked to the variation of complement components. CONCLUSIONS: Both C4d deposition in lesional skin and elevated C5a levels in peripheral blood indicate the involvement of complement activation in the pathogenesis of CSU. No correlation was found between omalizumab and activation of complement indicative of independent processes in the immunopathogenesis of CSU.
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Glioblastoma multiforme is the most frequent primary brain tumor. The clinical course of glioblastoma is almost invariably fatal. Combined chemo-irradiation with temozolomide is currently the standard of care for newly diagnosed glioblastoma and concurrent Nivolumab, an anti-PD-1 monoclonal antibody is being studied for de novo glioblastoma. We present a 62-year old patient with glioblastoma, which was discovered during evaluation of sudden-onset moderate ataxia. Following craniotomy of the glial tumour he received chemo radiation. During this first-line treatment the patient participated in the CA209-548 phase III placebo controlled study investigating the addition of concurrent nivolumab. One month after the last administration of nivolumab after 60 weeks of study participation, magnetic resonance imaging scan showed progressive disease. Therefore stereotactic re-irradiation was given. Five days after completing radiation therapy and 50 days after his last nivolumab course he developed a mild diffuse generalized pruritic maculopapular exanthema. Skin biopsy was very indicative for a drug hypersensitivity reaction. The maculopapular rash and pruritus was successfully treated with moderate potency topical corticosteroids and prednisone. With the introduction of PD1/PD-L1 inhibitors and other immunotherapies tweaking the immune system to target cancer cells one can argue that once local radiation triggers a local immune mediated hypersensitivity reaction as seen in radiation recall dermatitis, the subsequent hypersensitivity reaction which would traditionally only be a local reaction is now possible to advance to more pronounced (systemic) reactions as seen in an abscopal effect. Therefore, we propose a combined name to coin this effect, the abscopal radiation recall phenomenon.
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Antihistamines are the most prescribed therapy in recurrent idiopathic angioedema, yet little is known about their efficacy. Herein, we report on clinical improvement with antihistamine therapy in 120 patients evaluating angioedema attack frequency. A high incidence (36%) of antihistamine refractory cases was observed. Forty percent of patients on antihistamine prophylaxis suffered from 1 or more angioedema attacks per month. Our findings stress the need for additional treatment options for recurrent idiopathic angioedema.
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Poluentes Ocupacionais do Ar/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatite Ocupacional/etiologia , Fabaceae/efeitos adversos , Adulto , Anti-Inflamatórios/uso terapêutico , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Ocupacional/tratamento farmacológico , Humanos , Masculino , Furoato de Mometasona , Testes do Emplastro , Pregnadienodiois/uso terapêutico , Madeira/efeitos adversosRESUMO
BACKGROUND: Suspected penicillin allergy (Pen-A) is often not verified by diagnostic testing. In third line penicillin allergy labels were associated with prescription of broad spectrum antibiotics, hospital stay duration and readmission. OBJECTIVE: Assess the impact of Pen-A labels on antibiotic and health care use in primary care. METHODS: A retrospective cohort study was conducted in primary care in the Utrecht area, the Netherlands. All patients registered with a penicillin allergy on 31 December 2013 were selected from the General Practitioner Network database. Each patient with a Pen-A label was matched for age, gender, follow-up period with three patients without Pen-A label. Risk (OR) of receiving a reserve and second choice antibiotic, number and type of antibiotics prescribed during follow-up and number of GP contacts were compared between the two cohorts. RESULTS: Of 196,440 patients, 1254 patients (0.6%) with a Pen-A label were identified and matched with 3756 patients without Pen-A label. Pen-A labels resulted in higher risk of receiving ≥1 antibiotic prescription per year (OR 2.56, 95% CI 2.05-3.20), ≥1 s choice antibiotic prescription per year (OR 2.21 95% CI 1.11-4.40), and ≥4 GP contacts per year (OR 1.71 95% CI 1.46-2.00). The chance of receiving tetracyclins (OR 2.24, 95% CI 1.29-3.89), macrolides/lincosamides/streptogamins (OR 8.69, 95% CI 4.26-17.73) and quinolones (OR 2.59, 95% CI 1.22-5.48) was higher in Pen-A patients. CONCLUSIONS: In primary health care Pen-A labels are associated with increased antibiotic use, including second choice antibiotics, and more health care use.
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BACKGROUND: The extent of co-sensitization within and between food protein families in an adult population is largely unknown. This study aimed to identify the most frequently recognized components in the PR-10 and storage protein family, as well as patterns in (co-)sensitization, in a birch-endemic area. METHODS: Results of ImmunoCAP ISAC, performed during routine care in Dutch adult outpatients suspected of food allergy, were collected. RESULTS: A total of 305 patients were selected, aged 16-79 years (median 32 years). Sensitization to one or more PR-10 proteins was most frequent (74% of all subjects), followed by 35% to storage protein and 15% to nsLTPs. Within the PR-10 family, subjects were most often sensitized to Bet v 1 (73% of 305), Cor a 1.04 (72%) and Mal d 1 (68%). Sensitization to PR-10s from soy, celery and kiwi occurred distinctively less often (< 55% of Bet v 1 sensitized subjects) compared to other food PR-10s (all > 70%). Subjects sensitized to these 'less common PR-10 proteins' were sensitized to more food and inhalant components on the ISAC, compared to subjects sensitized to 'common PR-10 proteins' (median 22 vs 13 out of 112, p < 0.0001). Seven subjects demonstrated sensitization to food PR-10 proteins, without concomitant sensitization to pollen PR-10s. Within the storage proteins, sensitization to multiple peanut allergens was most common (on average 3 out of 4). CONCLUSIONS: Sensitization to PR-10 food proteins could occur without concomitant sensitization to common PR-10 from pollen in a subset of subjects. Less commonly recognized PR-10 proteins appear to be an indication of polysensitization.
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BACKGROUND: Treatment with second-generation antihistamines is recommended in patients with chronic spontaneous urticaria (CSU). Some patients remain unresponsive even after up-dosing up to fourfold. Many third line treatment options have limited availability and/or give rise to significant side effects. We investigated effectiveness and safety of antihistamine treatment with dosages up to fourfold and higher. METHODS: This retrospective analysis of patients' records was performed in adult CSU patients suffering wheals and/or angioedema (AE). Demographic, clinical, and therapeutic data was extracted from their medical records. We recorded the type, maximum prescribed dosage, effectiveness, and reported side effects of antihistamine treatment. RESULTS: Of 200 screened patients, 178 were included. Treatment was commenced with a once daily dose of antihistamines. Persisting symptoms meant that up-dosing up to fourfold occurred in 138 (78%) of patients, yielding sufficient response in 41 (23%). Up-dosing antihistamines was necessary in 110 (80%) patient with weals alone or weals with angioedema and 28 (64%) with AE only (p = 0.039). Of the remaining 97 patients with insufficient response, 59 were treated with dosages higher than fourfold (median dosage 8, range 5-12). This was sufficient in 29 patients (49%). Side effects were reported in 36 patients (20%), whereof 30 (17%) experienced somnolence. Side effects after up-dosing higher than fourfold were reported in six out of 59 patients (10%). CONCLUSION: Up-dosing antihistamines higher than fourfold dosage seems a feasible therapeutic option with regards to effectiveness and safety. The need for third line therapies could be decreased by 49%, with a very limited increase of reported side effects.
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Apoptotic deficiency is one of the mechanisms leading to chemoresistance due to the potential of many chemotherapeutic drugs to induce apoptosis. We have examined drug-induced apoptosis in the chemosensitive human melanoma cell line MeWo, as well as in its resistant sublines, which were selected by continuous exposure to etoposide (MeWo(Eto1)) and cisplatin (MeWo(Cis1)). In former studies, activation of the mitochondrial pro-apoptotic pathway could not be demonstrated in etoposide-resistant cells after exposure to etoposide. A significant reduction of PARP [poly (ADP-ribose) polymerase] cleavage and caspase activation, but unimpaired DNA fragmentation, was seen in cisplatin-resistant cells after treatment with cisplatin. In the current study, we investigated effects of chemotherapeutic drugs different from the selecting agents cisplatin and etoposide on the observed modulations of the mitochondrial apoptotic pathway. We analysed dose-dependent release of cytochrome c, caspase-9 activation, cleavage of PARP and activation of effector caspases in etoposide and cisplatin-resistant cells after exposure to etoposide, teniposide, cisplatin or fotemustine. In analogy to etoposide exposure, we could not demonstrate any activation of the apoptotic pathway in etoposide-resistant cells after exposure to teniposide, another topoisomerase-II inhibitor. In contrast, exposure to cisplatin and fotemustine led to apoptotic cell death in these cells. This suggests that the deficiency of apoptosis in etoposide-resistant cells is dependent on the trigger by topoisomerase-II inhibitors. Analysis of cisplatin-resistant cells after etoposide and fotemustine exposure revealed an increased activity of the apoptotic pathway when compared with cisplatin exposure at corresponding survival rates in these cells. These results suggest that the observed modulations of the apoptotic pathway in resistant melanoma cell lines are specific for an anti-neoplastic drug and are not fixed at the molecular level, as different chemotherapeutic drugs are capable of overcoming these alterations.
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Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Melanoma/patologia , Transdução de Sinais , Western Blotting , Caspases/metabolismo , Citocromos c/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Células Tumorais CultivadasRESUMO
We describe a 42-year-old woman who had erythemateous plaques with sharply demarcated margins and fine scaling on her right trunk and leg. The lesions had a linear distribution following the lines of Blaschko. Histological findings supported the diagnosis of subacute cutaneous lupus erythematosus (SCLE) on the lines of Blaschko. Treatment with systemic corticosteroids and anti-malarial agents resulted in remission. Up to now, eighteen cases of linear lupus erythematosus have been described. Linear lupus erythematosus mostly affects children presenting with lesions on the scalp that were classified as discoid lupus erythematosus. To our knowledge, this is the first case of subacute cutaneous lupus erythematosus on the lines of Blaschko.