Treatment patterns and outcomes in patients with chronic urticaria during pregnancy: Results of PREG-CU, a UCARE study.

BACKGROUND: Although chronic urticaria (CU) is a common and primarily affects females, there is little data on how pregnancy interacts with the disease. OBJECTIVE: To analyse the treatment use by CU patients before, during and after pregnancy as well as outcomes of pregnancy. METHODS: PREG-CU is an international, multicentre study of the Urticaria Centers of Reference and Excellence network. Data were collected via a 47-item-questionnaire completed by CU patients who became pregnant during their disease course. RESULTS: Questionnaires from 288 CU patients from 13 countries were analysed. During pregnancy, most patients (60%) used urticaria medication including standard-dose second generation H1-antihistamines (35.1%), first generation H1-antihistamines (7.6%), high-dose second-generation H1-antihistamines (5.6%) and omalizumab (5.6%). The preterm birth rate was 10.2%; rates were similar between patients who did and did not receive treatment during pregnancy (11.6% vs. 8.7%, respectively). Emergency referrals for CU and twin birth were risk factors for preterm birth. The caesarean delivery rate was 51.3%. More than 90% of new-borns were healthy at birth. There was no link between any patient or disease characteristics or treatments and medical problems at birth. CONCLUSION: Most CU patients used treatment during pregnancy especially second-generation antihistamines which seem to be safe during pregnancy regardless of the trimester. The rates of preterm births and medical problems of new-borns in CU patients were similar to population norms and not linked to treatment used during pregnancy. Emergency referrals for CU increased the risk of preterm birth and emphasize the importance of sufficient treatment to keep urticaria under control during pregnancy.

Effects of pregnancy on chronic urticaria: Results of the PREG-CU UCARE study.

BACKGROUND: Chronic urticaria (CU) predominantly affects women, and sex hormones can modulate disease activity in female CU patients. As of now, the impact of pregnancy on CU is largely unknown. AIM: To analyze the course and features of CU during and after pregnancy. PATIENTS AND METHODS: PREG-CU is an international, multicenter study of the Urticaria Centers of Reference and Excellence (UCARE) network. Data were collected via a 47-item questionnaire completed by CU patients, who became pregnant within the last 3 years. RESULTS: A total of 288 pregnancies of 288 CU patients from 13 countries were analyzed (mean age at pregnancy: 32.1 ± 6.1 years, duration of CU: 84.9 ± 74.5 months; CSU 66.9%, CSU + CIndU 20.3%, CIndU 12.8%).During pregnancy, 51.1% of patients rated their CU as improved, 28.9% as worse, and 20.0% as unchanged.CU exacerbations most commonly occurred exclusively during the third trimester (in 34 of 124 patients; 27.6%) or the first (28 of 124; 22.8%). The risk factors for worsening of CU during pregnancy were having mild disease and no angioedema before pregnancy, not taking treatment before pregnancy, CIndU, CU worsening during a previous pregnancy, treatment during pregnancy, and stress as a driver of exacerbations. After giving birth, urticaria disease activity remained unchanged in 43.8% of CU patients, whereas 37.4% and 18.1% experienced worsening and improvement, respectively. CONCLUSIONS: These results demonstrate the complex impact of pregnancy on the course of CU and help to better counsel patients who want to become pregnant and to manage CU during pregnancy.

Clinical Remission of Chronic Spontaneous Urticaria (CSU): A Targeted Literature Review.

INTRODUCTION: Chronic spontaneous (previously known as idiopathic) urticaria (CSU) is a chronic skin disease with the potential for natural remission. The objectives of this targeted literature review were to identify evidence on the clinical course of CSU, including remission rates, and to estimate cumulative remission rates for different time points. METHODS: Electronic databases (MEDLINE, MEDLINE-In Process, Embase, Web of Science, BIOSIS Previews and the Cochrane Library) and relevant conference proceedings were searched to identify studies involving patients with CSU aged ≥ 12 years that provide data on remission rates and disease duration. Observational studies with patient follow-ups of ≥ 1 year or review articles were included. Data extracted from five selected studies were used to run Kaplan-Meier (KM) analyses and best-fit distributions to calculate remission rates per 4-week period and weighted averages. RESULTS: Ten publications were included in this review. The proportion of patients achieving remission within year 1 ranged from 21 to 47%, while reported remission rate estimates at year 5 were 34% and 45%. Based on calculated 4-weekly remission rates, cumulative remission estimates ranged from 9 to 38% at year 1, from 29 to 71% at year 5 and from 52 to 93% at year 20. Cumulative weighted average estimates for the proportion of patients remitting at years 1, 5 and 20 were 17%, 45% and 73%, respectively. CONCLUSIONS: Published evidence suggests that CSU is a self-limiting condition with variable disease severity and duration, apparently dependent on multiple factors. However, data sources differed in terms of definitions of disease severity and remission, as well as in conclusions on influencing factors. Further studies and uniform definitions are required.

Predicting Clinical Remission of Chronic Urticaria Using Random Survival Forests: Machine Learning Applied to Real-World Data.

INTRODUCTION: The time required to reach clinical remission varies in patients with chronic urticaria (CU). The objective of this study is to develop a predictive model using a machine learning methodology to predict time to clinical remission for patients with CU. METHODS: Adults with ≥ 2 ICD-9/10 relevant CU diagnosis codes/CU-related treatment > 6 weeks apart were identified in the Optum deidentified electronic health record dataset (January 2007 to June 2019). Clinical remission was defined as ≥ 12 months without CU diagnosis/CU-related treatment. A random survival forest was used to predict time from diagnosis to clinical remission for each patient based on clinical and demographic features available at diagnosis. Model performance was assessed using concordance, which indicates the degree of agreement between observed and predicted time to remission. To characterize clinically relevant groups, features were summarized among cohorts that were defined based on quartiles of predicted time to remission. RESULTS: Among 112,443 patients, 73.5% reached clinical remission, with a median of 336 days from diagnosis. From 1876 initial features, 176 were retained in the final model, which predicted a median of 318 days to remission. The model showed good performance with a concordance of 0.62. Patients with predicted longer time to remission tended to be older with delayed CU diagnosis, and have more comorbidities, more laboratory tests, higher body mass index, and polypharmacy during the 12-month period before the first CU diagnosis. CONCLUSIONS: Applying machine learning to real-world data enabled accurate prediction of time to clinical remission and identified multiple relevant demographic and clinical variables with predictive value. Ongoing work aims to further validate and integrate these findings into clinical applications for CU management.

How to Measure Disease Activity, Impact, and Control in Patients with Recurrent Wheals, Angioedema, or Both.

Chronic spontaneous urticaria and chronic inducible urticaria are characterized by wheals, angioedema, or both, whereas other conditions such as hereditary angioedema present only with angioedema. The unpredictability of outbreaks, disfigurement, pruritus, and associated sleep and work disturbance can cause a significant impact on quality of life (QoL). Significant breakthroughs in the understanding of these conditions in recent years have led to the development of novel therapies. Assessment of patients with these conditions not only focuses on the clinical activity of the condition, but also on the impact on QoL and disease control with treatment. Patient-reported outcome measures, especially if sufficiently validated, give due prominence to the patient's perspective regarding disease impact and treatment outcomes. This article will review the tools readily available to assess activity, impact, and control in patients with recurrent wheals, angioedema, or both.

Seborrhoeic dermatitis and sebopsoriasis developing in patients on dupilumab: Two case reports.

Cutaneous adverse events to dupilumab can be varied; this necessitates keeping a broad differential diagnosis to identify seemingly paradoxical reactions. It may be possible to treat the adverse event concurrently without stopping dupilumab.

Treatment of chronic spontaneous urticaria with an inadequate response to H1-antihistamines: an expert opinion.

Chronic spontaneous urticaria (CSU) is characterized by the sudden, continuous or intermittent appearance of pruritic wheals (hives), angioedema, or both for six weeks or more, with no known specific trigger. The international EAACI/GA2LEN/EDF/WAO urticaria guideline advises standard-dose, second-generation H1-antihistamines as first-line therapy. However, H1-antihistamine treatment leads to absence of symptoms in fewer than 50% of patients. Updosing of second-generation H1-antihistamines (up to fourfold) as recommended by the EAACI/GA2LEN/EDF/WAO urticaria guideline as second-line therapy, can improve response, but many patients remain symptomatic. Definitions of response are often subjective and a consensus is needed regarding appropriate treatment targets. There is also an unmet need for biomarkers to assess CSU severity and activity and to predict treatment response. The EAACI/GA2LEN/EDF/WAO urticaria guideline recommends add-on omalizumab, ciclosporin A (CsA), or montelukast third-line treatment in patients with an inadequate response to high-dose H1-antihistamines. Omalizumab is currently the only licensed systemic biologic for use in CSU. Both omalizumab and CsA are effective third-line CSU treatments; montelukast appears to have lower efficacy in this setting. Omalizumab carries a label warning for anaphylaxis, although no cases of anaphylaxis were reported in the phase III trials of omalizumab in CSU and it is generally well tolerated in patients with CSU. Omalizumab arguably has a better safety profile than CsA.

Retrospective case note review of chronic spontaneous urticaria outcomes and adverse effects in patients treated with omalizumab or ciclosporin in UK secondary care.

BACKGROUND: Omalizumab is approved in the UK as add-on treatment for chronic spontaneous urticaria (CSU) in patients with inadequate response to H1-antihistamines. Ciclosporin is an established but unlicensed 3rd line option for CSU. Two parallel retrospective observational studies were conducted to describe outcomes of treatment and adverse events with omalizumab or ciclosporin for CSU treatment. METHODS: Data from UK specialist centres prescribing omalizumab (five centres) or ciclosporin (three centres) in CSU patients were collected from hospital records by clinical staff and pooled for analysis. RESULTS: Forty-six patients prescribed omalizumab and 72 patients prescribed ciclosporin were included. Twenty-two (48%) omalizumab-treated patients had paired Urticaria Activity Scores (UAS7), showing a 25.4 point improvement during treatment (P < 0.0001). Paired Dermatology Life Quality Index (DLQI) was available in 28 (61%) omalizumab-treated and 17 (24%) ciclosporin-treated patients. At least a 75% improvement in DLQI score was observed in 79% of omalizumab-treated and 41% of ciclosporin-treated patients, and 65% of omalizumab-treated patients had complete resolution of their quality-of-life impairment (DLQI 0-1) versus 21% of ciclosporin-treated patients. Clinician comments reported symptom clearance in 15/36 (42%) omalizumab-treated and 10/60 (17%) ciclosporin-treated patients. Proportions of patients with adverse events were similar but those for omalizumab resembled CSU symptoms, making causality assignment difficult, whereas those for ciclosporin were consistent with its known adverse effect profile. CONCLUSIONS: Validated patient-reported measures of disease severity and quality of life should be used routinely in CSU management. Based on clinician comments and DLQI scores, symptoms and quality of life showed a greater improvement in the omalizumab-treated cohort than in the ciclosporin-treated cohort.

Therapeutic potential of macrolide immunosuppressants in dermatology.

Dermatologists are frequently presented with inflammatory dermatoses that are responsive to treatment with immunomodulating drugs. Corticosteroids, particularly when applied topically, have been the mainstay of treatment in the past. Their undoubted efficacy, however, has been undermined by problems with repeated use including tachyphylaxis and side effects such as skin atrophy and hypertension. Macrolide immunosuppressive drugs, originally used for prophylaxis of organ transplant rejection, have been shown to be effective in the treatment of inflammatory dermatoses. The original drugs used in dermatology in this class have their own limitations including poor absorption when used topically and their distinct side-effect profiles. A search for other immunosuppressive macrolide antibiotics has led to the development of new agents, which have enhanced profiles for the treatment of skin disease. This review discusses the main dermatoses that may be targeted by this class of drugs and summarises the topical and systemic macrolides either currently in use, in clinical trials or preclinical development.

The macrolide immunosuppressants in dermatology: mechanisms of action.

Macrolides are xenobiotics, produced by soil fungi, which have immunosuppressant properties. They will probably revolutionise the treatment of inflammatory dermatoses. This article outlines the context and putative mechanisms of action of this novel class of drugs. Cyclosporin, and the structurally distinct macrolides tacrolimus and pimecrolimus (an ascomycin derivative), modulate immune-cell function by inhibiting calcineurin-dependent dephosphorylation-activation of specific nuclear factors, thus preventing transcription of pro-inflammatory cytokines. The macrolide rapamycin (sirolimus) acts by abrogating Target of Rapamycin, a key signalling protein that controls activation of a number of proteins which direct progression of the cell cycle in response to pro-inflammatory cytokines. Tacrolimus and pimecrolimus are small enough molecules to penetrate skin and are available in topical formulations. "Skin-specific" pimecrolimus seems not to cause systemic immunosuppression when given orally. Neither topical tacrolimus nor pimecrolimus are capable of producing skin atrophy. Sirolimus has anti-angiogenic properties that may be beneficial to the treatment of psoriasis and perhaps skin cancer.

Facial fat necrosis following autologous fat transfer and its management.

Autologous fat transfer (AFT) is an increasingly popular cosmetic procedure practiced by dermatologic surgeons worldwide. As this is an office based procedure performed under local or tumescent anaesthesia with fat transferred within the same individual and limited associated down time its is considered relatively safe and risk free in the cosmetic surgery arena. We describe a case of AFT related fat necrosis causing significant facial dysmorphia and psychosocial distress. We also discuss the benefits and risks of AFT highlighting common causes of fat graft failure.

Autoimmunity and complement in the pathogenesis of chronic urticaria.

Chronic urticaria is a debilitating skin disease that is believed to have an underlying autoimmune etiology in 35% to 50% of cases. Patients with autoimmune urticaria have functional antibodies in their sera that release histamine from basophils and mast cells. The C5a component of complement is required for mast cell degranulation in this process and at least augments basophil histamine release. In this article, the evidence that is key to our understanding of autoimmunity and complement in the pathogenesis of a subset of patients with chronic urticaria is outlined. Some of the issues in testing for and treating autoimmune urticaria are discussed.