Defining trajectories of response in patients with psoriasis treated with biologic therapies.

BACKGROUND: The effectiveness and cost-effectiveness of biologic therapies for psoriasis are significantly compromised by variable treatment responses. Thus, more precise management of psoriasis is needed. OBJECTIVES: To identify subgroups of patients with psoriasis treated with biologic therapies, based on changes in their disease activity over time, that may better inform patient management. METHODS: We applied latent class mixed modelling to identify trajectory-based patient subgroups from longitudinal, routine clinical data on disease severity, as measured by the Psoriasis Area and Severity Index (PASI), from 3546 patients in the British Association of Dermatologists Biologics and Immunomodulators Register, as well as in an independent cohort of 2889 patients pooled across four clinical trials. RESULTS: We discovered four discrete classes of global response trajectories, each characterized in terms of time to response, size of effect and relapse. Each class was associated with differing clinical characteristics, e.g. body mass index, baseline PASI and prevalence of different manifestations. The results were verified in a second cohort of clinical trial participants, where similar trajectories following the initiation of biologic therapy were identified. Further, we found differential associations of the genetic marker HLA-C*06:02 between our registry-identified trajectories. CONCLUSIONS: These subgroups, defined by change in disease over time, may be indicative of distinct endotypes driven by different biological mechanisms and may help inform the management of patients with psoriasis. Future work will aim to further delineate these mechanisms by extensively characterizing the subgroups with additional molecular and pharmacological data.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Serum Vitamin D levels and Vitamin D supplementation do not correlate with the severity of chronic eczema in children.

BACKGROUND: Eczema is one of the most common chronic inflammatory skin diseases, affecting about 20% of children. The pathogenic mechanisms of eczema are still not fully understood, and current treatment of moderate-severe eczema is often difficult. Recently, it has been suggested that Vitamin D plays a key role in this disease, even if mechanisms are only partially known. OBJECTIVE: The purpose of our study was to assess the 25-Hydroxyvitamin D serum levels in a pediatric population suffering from chronic eczema (IgE-mediated and non-IgE-mediated), and to correlate these phenotypes with the SCORAD severity and selected clinical and biological parameters. Moreover, we aimed to evaluate whether a supplementation of Vitamin D3 could affect the same clinical and laboratory parameters. METHODS: 89 children with chronic eczema were enrolled in the study. Severity of eczema was assessed with the SCORAD index. Past and present history was taken, and patients were divided into two groups according to the state of sensitization. According to a randomization schedule, the enrolled children were assigned to the following groups: supplementation group, which received a daily oral Vitamin D3 supplementation (2000 IUs) for 3 months; control group which received no supplementation. RESULTS: Vitamin D concentrations in patients with moderate and severe eczema were not statistically different from Vitamin D concentration detected in the serum of patients with mild eczema. Furthermore, we did not find any correlation between Vitamin D levels, total IgEs and SCORAD index, both in the Sensitized and in the Not-Sensitized group. The Vitamin D3 supplementation did not influence the SCORAD severity or the total IgEs concentration. CONCLUSION: To our knowledge, our study is the first one that shows no correlation between serum levels of Vitamin D, eczema severity and IgE sensitization in a pediatric population suffering from chronic eczema.

The oral food desensitization in the Italian allergy centres.

BACKGROUND: Attempts aimed at inducing food tolerance through oral food desensitization (OFD) for the treatment of IgE-mediated food allergies are increasing. In Italy, a number of allergy centres offer this procedure. OBJECTIVE: To collect information on how these centres are organized, how patients are selected, the methods used to administer OFD and how adverse reactions are managed. METHODS: A questionnaire was e-mailed to all the Italian allergy centres offering OFD. RESULTS: The survey shows a high degree of variability between centres. A correct diagnosis of food allergy is crucial for selecting patients for OFD. In the Italian allergy centres, oral food challenges are mostly open label (84%), but in 16% of cases they are single-blind (8%) or double-blind (8%). A high proportion of allergy centres (83%) offer OFD to children presenting forms of anaphylaxis triggered by traces--or very low doses--of food allergen. The majority of allergy centres (76%) enroll patients over 3 years of age, with 44% enrolling patients above the age of 5. Not-controlled asthma, unreliability of parents in the management of OFD and/or risk of adverse events, are the main reasons for exclusion from the procedure. CONCLUSION: Although OFD may sometimes be successful and may be considered a valid alternative to an elimination diet, further randomized controlled trials are needed, in order to clarify some controversial points, such as the characteristics of the child undergoing OFD, and the methods of food preparation and administration. Moreover, further studies should further investigate OFD safety, efficacy and costs.

Skin prick test: the only predictive tool of anaphylaxis? A case report.

Currently, in the literature there is a lack of definite predictive values parameters to identify patients with the risk to develop anaphylaxis. The controlled oral food challenge remains the gold standard for food allergy diagnosis. We report a case of a girl allergic to cow's milk with low levels of specific IgE and large skin prick test wheal sizes for cow's milk. In some cases the high diameter of skin prick test wheal may be more reliable than specific IgE levels in predicting an anaphylactic reaction.

Cloricromene in endotoxemia: role of NF-kappaB.

In this study we investigated, for the first time in vivo, the effect of cloricromene, a cumarine derivative, on NF-kappaB activation in endotoxin-treated rats. Endotoxemia was induced in male rats by the intravenous injection of Salmonella typhosa lipopolysaccharide (LPS; 2 mg/kg/i.v.). In vivo treatment with cloricromene (2 mg/kg/i.v.) 30 min before lipopolysaccharide administration reversed the LPS-induced loss in tone of the aortic rings, improved their reactivity to phenylephrine, decreased both nitric oxide (NO) and TNF-alpha serum levels by inhibiting LPS-induced inducible NO synthase and TNF-alpha mRNA expression, and interestingly inhibited LPS-induced NF-kappaB activation. Our data suggest that cloricromene protects rats from LPS by blocking LPS-induced NF-kappaB activation, leading to inhibition of NO and TNF-alpha overproduction and thereby reversing the LPS-induced vascular hyporeactivity.

Patch test response to house dust mites is positive in children with atopic dermatitis and in their parents.

We studied the patch test response to Dermatophagoides pteronyssinus in 79 atopic children and in their parents. The atopic children were divided into 3 groups: 1) children with atopic dermatitis (group 1); 2) children who had suffered from atopic dermatitis but the disease was cured (group 2); and 3) atopic children with asthma and without atopic dermatitis (group 3). Our data show that a significantly higher proportion of children with atopic dermatitis (groups 1 and 2) have positive patch tests to Dermatophagoides pteronyssinus in comparison to atopic children without atopic dermatitis (group 3) and the controls (p < 0.001). In addition, we have shown that a positive patch test to Dermatophagoides pteronyssinus is significantly more common in parents of children with atopic dermatitis with respect to parents of children with asthma or parents of control children.

Effect of flunisolide on nasal eosinophils and IgE, and symptom score in children with allergic rhinitis.

We evaluated the effect of treatment with flunisolide nasal spray (100 micrograms/day for 3 months) in 24 children with allergic rhinitis on the following parameters: clinical symptoms, absolute number of peripheral and nasal eosinophils, and total IgE levels in nasal secretion. Therapy with flunisolide induced a significant reduction of clinical symptoms (p < 0.001), nasal eosinophils (p < 0.001) and nasal IgE concentration (p < 0.02), while it did not affect the number of peripheral eosinophils. These results indicate that flunisolide can reduce the allergic inflammation of the nasal mucosa.

Evaluation of the efficacy of oral cromolyn sodium or an oligoantigenic diet in children with atopic dermatitis: a multicenter study of 1085 patients.

One thousand eighty-five children with atopic dermatitis were enrolled in a multicenter study to evaluate the efficacy of 4 weeks of oral sodium cromoglycate or 4 weeks of a restricted diet. One thousand-eleven children (93%) concluded the study. At the end of the trial there was a significant improvement in skin lesions in the two groups: 61% of the patients in the sodium cromoglycate group and 69% in the restricted diet showed a significant improvement in atopic dermatitis. We concluded that, at least in our experimental design, both sodium cromoglycate and a restricted diet are equally effective in atopic dermatitis.

Immediate reactions following challenge-tests in children with atopic dermatitis.

It has been shown that atopic dermatitis improves in children when certain foods are eliminated from the diet. Because of the unreliability of the history and the low sensibility of the total and specific IgE and skin tests, at present the elimination-provocation test is the most definitive means to establish which are the offending food(s). Although many authors claim that reactions following the challenge test in atopic dermatitis are only of the delayed type, others assert that immediate reactions are frequent and can sometimes threaten life. The pathogenesis of such reactions is not yet completely understood. However, it has been suggested that a direct IgE-mediated mechanism, inducing a release of anaphylactic mediators, could play some role. The aim of our study is to investigate the incidence of immediate reactions which can follow the food challenge in children with atopic dermatitis who have never experienced such reactions and, in addition, to investigate the reliability of total and specific IgE and skin tests in predicting immediate reactions after the challenge test. Our preliminary data indicate that immediate reactions following food challenge are frequent. Moreover they can be severe and cannot be predicted by the history, by the total and specific IgE levels and by the skin tests' results.

[Trans-1-(4-phenylcyclohexyl)ethylamine derivatives with antidepressant activity. II]. / Derivati della trans-1-(4-fenilcicloesil)etilammina ad attivita' antidepressiva--Nota II.

Some derivatives of trans-1-(4-phenylcyclohexyl)ethylamine (A) with a substituent at position 4 of the phenyl group were prepared and tested for antireserpine activity on the CNS. All compounds showed reduced activity compared with that of (A) except the amino derivative (II) which proved more active but at the same time showed increased toxicity and other adverse effects on the CNS.

[From atopic dermatitis to asthma]. / Dalla dermatite atopica all'asma.

Atopic dermatitis (AD) is the most common chronic skin disorder in infancy and childhood and is the main hallmark of atopic constitution. The disease is multifactorial, and although genetic predisposition is certainly a prerequisite, a number of environmental factors modulate the phenotypic expression of AD. The majority of affected children shows IgE sensitisation towards a large variety of foods and aeroallergens. Since at least 1600, it has been recognized that patients with AD have a high predisposition to develop asthma. Recent epidemiological studies show that AD is commonly seen in individuals from families with a history of asthma. In addition, in population where asthma is uncommon, AD is also uncommon. The sex distribution of AD and asthma is the same, with boys affected significantly more often by these two atopic diseases and in similar proportions. The ETAC project (Early Treatment of the Atopic Child) is a large multicenter, multi-national, double blind, placebo controlled, randomised trial. The main objective of the study is to stop the progression from AD to asthma in young children with AD using early therapeutic intervention with Cetirizine and the second objective is to investigate the main risk factors for the onset of asthma. The results of this study indicate that exposure to potent allergens such as cat or mite significantly increased the risk of sensitisation to these allergens. Prolonged breast feeding was associated with a lowest sensitisation rate to cow milk proteins and to egg. Therefore environmental factors seem to play a crucial role in IgE sensitisation in children with AD.

[A new cyclohexylphenyl and cyclohexylphenylamine. Synthesis and pharmacological activity]. / Nuove fenilcicloesil e cicloesilfenilammine. Sintesi e attività farmacologica.

Derivatives of some primary amines and their N-benzyl derivatives containing a 4-cyclohexylphenyl or a 4-phenylcyclohexyl group were prepared. Pharmacological study showed clear analgesic activity in the phenylquinone test which was more accentuated for the 4-phenylcyclohexyl derivatives. All the compounds proved devoid of sympathomimetic activity on the cardiovascular system and without anorexic effect. Some of the compounds showed some antireserpine activity.

[New derivatives of clofibrate and probucol. Preliminary study of their hypolipemic activity]. / Nuovi derivati del clofibrato e del probucol. Studio preliminare dell'attività ipolipemizzante.

The preparation is reported of compounds with a free or esterified hydroxyisobutyric acid grouping characteristic of clofibrate, on various supporting molecules related to clofibrate itself or to probucol. Some compounds showed clear hypolipemic activity and for one compound (MG 6893) the effect was not accompanied by hepatomegalia.

A protocol for oral desensitization in children with IgE-mediated cow's milk allergy.

OBJECTIVES: To desensitize children with severe immunoglobulin (Ig)E-mediated cow's milk allergy in a period of 6 months by introducing increasing daily doses of cow's milk (CM) in order to enable the child to assume 200 ml of CM daily, or to induce tolerance of the highest possible CM dose. STUDY DESIGN: Twenty-one children at least 6 years old with severe IgE-mediated CM allergy were admitted to the study. A convincing history of IgE-mediated CM allergy or a positive double-blind placebo-controlled food challenge with CM confirmed the diagnosis. Oral desensitization was performed with increasing doses starting from 0.06 mg of CM proteins. RESULTS: Overall, 15 of 21 children (71.4%) achieved the daily intake of 200 ml during a 6-month period; three of 21 children (14.3%) tolerated 40-80 ml/day of undiluted CM; three of 21 children (14.3%) failed the desensitization because they presented allergic symptoms after ingesting minimal amounts of diluted CM. CONCLUSIONS: We successfully desensitized 15 of 21 children with severe IgE-mediated CM allergy in a period of 6 months. We stress the importance of the partial outcome in those three of 21 children who could not reach the maximum amount of 200 ml/day of whole CM, but were able to tolerate 40-80 ml/day of CM. In this way we dramatically reduced the risk of severe reactions after accidental or unnoticed introduction of low quantities of CM. We do not propose generalizing this method beyond trained staff.