Erythroderma is defined as the scaling erythematous dermatitis involving 90% or more of the cutaneous surface.
Also known as exfoliative dermatitis
Idiopathic exfoliative dermatitis – also known as the “red man syndrome”, is characterized by marked palmoplantar keratoderma, dermatopathic lymphadenopathy,increased IgE.
Increased skin perfusion leads to
Temperature dysregulation >
Resulting in skin loss and hypothermia >
High output state >
Cardiac failure
BMR raises to compensate for heat loss
Increased dehydration due to transpiration (similar to burns)
All lead to negative nitrogen balance and characterized by edema, hypoalbuminemia, loss of muscle mass.
Cutaneous involvement is very common in the different types of vasculitis. Skin lesions may be the only manifestation or may occur in the context of systemic disease
Summary of updated information about the disease of Atopic dermatitis, aetiology, immunopathogenesis, main clinical features and dianostic criteria, concepts of managemnt of Atopic dermatitis including newest treatment trends.
Urticaria is a skin problem triggered by reaction to food, medicine or allergic to any other thing. Urticaria leads to red, itchy, and swollen skin. This disease is also known as Hives. Hives formed due to allergy, changes size rapidly and often move around, in different parts of the body.
Erythroderma is defined as the scaling erythematous dermatitis involving 90% or more of the cutaneous surface.
Also known as exfoliative dermatitis
Idiopathic exfoliative dermatitis – also known as the “red man syndrome”, is characterized by marked palmoplantar keratoderma, dermatopathic lymphadenopathy,increased IgE.
Increased skin perfusion leads to
Temperature dysregulation >
Resulting in skin loss and hypothermia >
High output state >
Cardiac failure
BMR raises to compensate for heat loss
Increased dehydration due to transpiration (similar to burns)
All lead to negative nitrogen balance and characterized by edema, hypoalbuminemia, loss of muscle mass.
Cutaneous involvement is very common in the different types of vasculitis. Skin lesions may be the only manifestation or may occur in the context of systemic disease
Summary of updated information about the disease of Atopic dermatitis, aetiology, immunopathogenesis, main clinical features and dianostic criteria, concepts of managemnt of Atopic dermatitis including newest treatment trends.
Urticaria is a skin problem triggered by reaction to food, medicine or allergic to any other thing. Urticaria leads to red, itchy, and swollen skin. This disease is also known as Hives. Hives formed due to allergy, changes size rapidly and often move around, in different parts of the body.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
Contact us if you are interested:
Email / Skype : kefaya1771@gmail.com
Threema: PXHY5PDH
New BATCH Ku !!! MUCH IN DEMAND FAST SALE EVERY BATCH HAPPY GOOD EFFECT BIG BATCH !
Contact me on Threema or skype to start big business!!
Hot-sale products:
NEW HOT EUTYLONE WHITE CRYSTAL!!
5cl-adba precursor (semi finished )
5cl-adba raw materials
ADBB precursor (semi finished )
ADBB raw materials
APVP powder
5fadb/4f-adb
Jwh018 / Jwh210
Eutylone crystal
Protonitazene (hydrochloride) CAS: 119276-01-6
Flubrotizolam CAS: 57801-95-3
Metonitazene CAS: 14680-51-4
Payment terms: Western Union,MoneyGram,Bitcoin or USDT.
Deliver Time: Usually 7-15days
Shipping method: FedEx, TNT, DHL,UPS etc.Our deliveries are 100% safe, fast, reliable and discreet.
Samples will be sent for your evaluation!If you are interested in, please contact me, let's talk details.
We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
1. Updates in Chronic Urticaria Management
BY
PROF. ASHRAF OKBA
HEAD OF THE DEPARTMENT OF
IMMUNOLOGY AND ALLERGY
AIN SHAMS UNIVERSITY
2. Agenda
2
Introduction and definitions
Prevalence
Mast cell and urticaria pathogenesis
Diagnosis
Urticaria burden
Assessment of disease severity and patient quality of life
Guidelines updates in urticaria treatment
3. Urticaria is a disease characterized by the
development of wheals (hives), angioedema, or both.
Urticaria Definition:
Acute urticaria is defined as the occurrence of spontaneous
wheals, angioedema, or both for <6 weeks, while in chronic
urticaria symptoms last for more than 6 weeks.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
4. Clinical Appearance
Wheals have three typical features:
• Central swelling of variable size, almost invariably
surrounded by a reflex erythema
• Associated with itching or sometimes a burning
sensation
• Fleeting nature, with the skin returning to its
normal appearance, usually within 1–24 hours.
• Sometimes wheals resolve even more quickly
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
5. Angioedema Definition
• /an·gio·ede·ma/ a vascular reaction involving the deep dermis or subcut
aneous or submucosal tissues,representing localized edema caused by
dilatation and increased permeability of the capillaries,
• Sometimes pain rather than itching.
• Frequent involvement below mucous membranes
• Its resolution is slower than that for wheals and can take up to 72
hours 1
• Angioedema most often involves the
eyelids , lips, tongue, genitalia,
hands and feet with the larynx ,
gastrointestinal and urinary bladder
being less commonly affected.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
Angio-oedema of the lip (a) during and (b) 3
days after an attack. (Courtesy of St John’s
Institute of Dermatology, London, UK.)
6. 7
Acute Urticaria: ˂ 6 Weeks
Chronic Urticaria: ≥ 6 Weeks
Classification of Urticarias
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
7. Classification of Urticarias1
1. Adapted from: Zuberbier T, et al. Allergy 2014;69 (7):868–87.
Chronic spontaneous
urticaria
Chronic
Acute
Spontaneous
Inducible
Urticaria
Known causes
(including autoimmunity,
infection, food
components, etc)
Unknown causes
Chronic spontaneous urticaria (CSU) can be defined as the spontaneous daily, or almost daily, occurrence of itchy
hives, angioedema or both, due to known or unknown causes, and lasting for 6 weeks or more
Symptoms daily or
almost daily for ≥6
weeks
No obvious external
specific trigger
Symptoms for
<6 weeks
Symptoms induced
by a specific trigger,
e.g. temperature,
pressure, cholinergic
10
New
2013
8. Chronic Urticaria: What is in Name?
Is it chronic urticaria, chronic idiopathic urticaria, or
chronic spontaneous urticaria?
The term chronic indicates that urticaria is present for
more than 6 weeks.
The cause of chronic urticaria is known in approximately
25% of patients (refers primarily to those with physically
inducible urticarias)
Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma Immunol.2014 (Article in press)
9. For CSU, the cause of the spontaneous urticarias
approaches zero because the etiology is not known even
though there is an association with autoimmunity in
approximately 45% of patients and,
The term spontaneous rather than idiopathic emphasizes
that it is endogenous rather than exogenous and non
inducible rather than inducible.
Chronic Urticaria: What is in Name?
Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma
Immunol.2014 (Article in press)
10. Chronic urticaria
Now classified into spontaneous and inducible forms
2013 guidelines* classify chronic urticaria into “spontaneous” and “inducible”2
Chronic Urticaria Subtypes
Chronic spontaneous urticaria Inducible urticaria
Spontaneous appearance of wheals,
angioedema or both ≥6 weeks due to known1
or unknown causes
The term “ Chronic Idiopathic Urticaria”
should be avoided
Physical urticarias
• Symptomatic dermographism2
• Cold urticaria3
• Delayed pressure urticaria4
• Solar urticaria
• Heat urticaria5
• Vibratory angioedema
Cholinergic urticaria
Contact urticaria
Aquagenic urticaria
1. For example, autoreactivity, i.e. the presence of mast cell-activating autoantibodies; 2. also called
urticaria factitia, dermographic urticaria; 3. also called cold contact urticaria; 4. also called pressure
urticaria; 5. also called heat contact urticaria
*Guidelines:
EAACI, European Academy of Allergology and Clinical Immunology
GA2LEN, Global Allergy and Asthma European Network
EDF, European Dermatology Forum
WAO, World Allergy Organization
1. Zuberbier T, et al. Allergy 2009;64:1417–26;
2. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification,
diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
11. Prevalence of Urticaria
Estimated to occur in 15-23% of the population
Up to 40% of patients who have chronic urticaria longer
than six months will still have urticaria 10 years later
Approximately 40% of patients with chronic urticaria have
angioedema
All age groups can be affected, however the peak
incidence is seen between 20 and 40 years of age. i.e,
patients are primarily affected during important years
of their working age.
13. Urticaria
Acute urticaria refers to hives lasting less than six weeks;
in approximately 15-20% of cases an inciting cause can
be identified
Chronic urticaria refers to hives lasting longer than 6-8
weeks; identification of a cause is less than 5%
14. Chronic spontaneous Urticaria is by far the most common
subtype of all forms of non-acute Urticaria.1
The duration of CSU varies greatly from patient to patient,
with some individuals suffering irritating symptoms such
as pruritus far decades.2
2- A/fergol et lmmunopatho/2001; 29(4): 129-132
1- Allergy 2011; 66: 317–330.
Prevalence and Burden
15. 1616
Frequency of angioedema in selected patients with
chronic spontaneous urticaria
n, number of patients/subjects; NR, not reported.
*Authors examined patients with all types of urticaria.
†Authors do not distinguish between chronic spontaneous urticaria and other
forms of nonacute urticaria.
‡Authors examined the total population.
Maurer M, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy.
2011 Mar;66(3):317-30
16. In most cases, the duration of CSU is estimated to be 1–5 years1
However, for some patients the disease can last longer, sometimes more than 25 years1
Year 25
Years since diagnosis
Another 20% will resolve
(with or without treatment)
within 5 years of onset2
50% will resolve (with or
without treatment) within
6 months of onset2
Another 20% will resolve
(with or without treatment)
within 3 years of onset2
Another <2% will resolve
(with or without treatment)
within 25 years2
Duration of Chronic Urticaria
Year 1 Year 2 Year 3 Year 4 Year 5
1. Maurer M, et al. Allergy 2011;66:317–30;
2. Beltrani VS. Clin Rev Allergy Immunol 2002;23:147–69
17. 18
CINDU: Chronic inducible Urticaria
Maurer M1, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical
needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011 Mar;66(3):317-30
19. 1. Altrichter S, et al. PLoS One 2011;6:e14794;
2. Hide M, et al. N Engl J Med 1993;328:1599−604
Mast cells in some patients are activated by autoallergic or
autoimmune mechanisms1
• histamine-releasing immunoglobulin G (IgG) autoantibodies against the
high-affinity immunoglogulin E (IgE) receptor (FcεRI) or IgE itself are present
in the circulation,2 and IgE autoantibodies may also be present1
Auto-allergy
allergen
1.Autoantigen/autoallergen
3. endogenous anti-IgE
antibody
Auto-immunity
2. anti-FcεRI
1.IgE against self
Allergy
MC
IgE
FcεRI
Pathophysiology of urticaria
Mast cell stimulation
20. Several mechanisms of mast cell activation in CU have
been identified:
• For example, IgG autoantibodies directed against IgE can cause cross-
linking of mast cell– bound IgE and subsequent mast cell degranulation.
• Another subgroup of patients with CU exhibits IgG autoantibodies directed
against the a-subunit of the high-affinity IgE receptor FceRI on mast cells.
• Recently identified, a subgroup of patients with CU who exhibit IgE
autoantibodies against thyroperoxidase (TPO), and IgE antibodies against
TPO (IgE– anti-TPO)–positive patients with CU exhibit significantly higher
IgG–anti-TPO levels and lymphocyte counts, as well as decreased C4
complement levels
CU: Chronic urticaria
(J Allergy Clin Immunol 2011;128:202-9.)
Pathophysiology of urticaria (Cont.)
Mast cell stimulation
22. 23
Complement Ca5
Thrombin
FcἐRI
Free IgE
IgG autoantibodies
Auto-antigen:TPO
IgE autoantibodies
mRNA
Pathophysiology of urticaria (Cont.)
Mast cell stimulation (Immune-mediated urticaria )
The slide is for illustrative purpose
23. Maurer M1, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report.
Allergy. 2011 Mar;66(3):317-30 24
24. Diagnosis of urticaria
• It is important to remember that not all possible causative
factors need to be investigated in all patients and the
first step in diagnosis is a thorough history:
25Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
25. 2626
1. Time of onset of disease
2. Frequency and duration of wheals
3. Diurnal variation
4. Occurrence in relation to weekends,
holidays, and foreign travel
5. Shape, size, and distribution of
wheals
6. Associated angioedema
7. Associated subjective symptoms of
lesion, e.g. itch, pain
8. Family and personal history
regarding urticaria, atopy
9. Previous or current allergies,
infections, internal diseases, or other
possible causes
10. Psychosomatic and psychiatric
diseases
11. Surgical implantations and events during
surgery.
12. Gastric/intestinal problems (stool, flatulence).
13. Induction by physical agents or exercise.
14. Use of drugs (NSAIDs, injections,
immunizations, hormones, laxatives,
suppositories, ear and eye drops, and alternative
remedies).
15. Observed correlation to food.
16. Relationship to the menstrual cycle.
17. Smoking habits.
18. Type of work.
19. Hobbies.
20. Stress (eustress and distress).
21. Quality of life related to urticaria and emotional
Impact.
22. Previous therapy and response to therapy.
The first step in diagnosis is a thorough history
Questions should be asked regarding the following items:
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
26. 1. Zuberbier T, et al. Allergy 2009;64:1417‒26
Timing, frequency, duration of attacks Shape, size, distribution and associated
symptoms of lesions
Family and medical history, including
allergies
Correlation to any triggers, e.g. foods,
exercise, drug use
Work, hobbies, smoking habits and
stress
Previous therapy and response to
treatment
The first step in diagnosis is a thorough history
Questions should be asked regarding the following items:
27. 2828
The second step of the diagnosis is the physical
examination of the patient.
This should include:
A diagnostic provocation test including drug,
food, and physical tests where it is indicated by
history.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
28. Physical examination
1. Zuberbier T, et al. Allergy 2009;64:1417‒26
Tests to identify triggers: these should be performed where indicated by history to
diagnose inducible urticaria subtypes1
29. 3030
Routine diagnostic tests
(recommended)
Extended diagnostic program* (suggested based
on history only)
Cold urticaria Cold provocation and threshold test
(ice cube, cold water, cold wind)
Differential blood count and ESR or CRP cryoproteins
rule out other diseases, especially infections
Delayed
pressure
urticaria
Pressure test and threshold test None
Heat urticaria Heat provocation and threshold test None
Solar urticaria UV and visible light of different
wavelengths
and threshold test
Rule out other light-induced dermatoses
Symptomatic
dermographism
Elicit dermographism and threshold
test (dermographometer)
Differential blood count, ESR or CRP
Vibratory
Angioedema
Test with, for example, vortex None
Aquagenic
urticaria
Wet cloths at body temperature
applied for 20 min
None
Cholinergic
urticaria
Exercise and hot bath provocation None
Contact
urticaria
Cutaneous provocation test. Skin
tests with immediate readings, for
example prick test
None
*Depending on suspected cause.
Zuberbier T, Aberer W, Asero R, et al. Allergy 2014;69:868–87
Recommended diagnostic tests for frequent urticaria subtypes
For Chronic inducible urticaria
30. 3131
Recommended diagnostic tests for frequent urticaria subtypes
For CSU
Routine diagnostic tests (recommended)
Spontaneous
urticaria
Acute spontaneous urticaria • None
Chronic spontaneous urticaria • Differential blood count and ESR or CRP
• Omission of suspected drugs (e.g. NSAIDs)
Extended diagnostic programme* (suggested based on history only) for identification of
underlying causes or eliciting factors and for ruling out possible differential diagnoses if indicated
Spontaneous
urticaria
Acute spontaneous urticaria • None‡
Chronic spontaneous urticaria • Infectious diseases (e.g. helicobacter Pylori)
• Type I allergy
• Functional autoantibodies
• Thyroid hormones and autoantibodies
• Skin tests including physical tests
• Pseudoallergen-free diet for 3 weeks
• Tryptase†
• Autologous serum skin test (ASST)
• Lesional skin biopsy
*Depending on suspected cause; ‡Unless strongly suggested by patient history, e.g. Allergy; †As indication of
severe systemic disease.
CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; NSAIDs = nonsteroidal anti-inflammatory drugs.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of
urticaria. The 2013 revision and update. Allergy 2014;69:868–87
Please refer to the slide notes for further information.
31. 3232
Autologous Serum Skin Test (Auto-reactivity)
A positive autologous serum skin test.
.
Sabroe RA, Greaves MW. Chronic idiopathic urticaria with functional autoantibodies: 12 years on. Br J Dermatol. 2006;154(5):813-9
32. ASST positivity and disease activity/severity
Approximately one third of CSU patients show a positive
response against their own serum in the autologous serum skin
test (ASST)1
• autoantibodies against the high-affinity IgE receptor or against IgE
itself can be detected in some of these patients1
• patients with autoimmune CSU appear to have more severe disease2
- more severe clinical features have been reported, including more wheals,
larger wheal size, higher itch scores3– 5
- longer duration of disease5–7
- higher requirement for antihistamine medication7
1. Maurer, M et al. Allergy 2011;66:317–30; 2. Kozel MMA, Sabroe RA. Drugs 2004;64:2515–36; 3. Sabroe RA, et al.
J Am Acad Dermatol 1999;40:443–50; 4. Caproni M, et al. Acta Derm Venereol 2004;84:288–90;
5. Alyasin S, et al. South Med J 2011;104:111–5; 6. Konstantinou GN, et al. Allergy 2009;64:1256–68;
7. Staubach P, et al. Dermatology 2006;212:150–9
33. • Should routine diagnostic measures be
performed in acute urticaria?
• We recommend against any routine diagnostic
measures in acute urticaria (strong
recommendation/clinical consensus).
34Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
34. • Should routine diagnostic measures be
performed in chronic spontaneous urticaria?
• We recommend for only very limited routine diagnostic
measures in chronic spontaneous urticaria (strong
recommendation/ clinical consensus).
35Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
38. ACAAI/AAAAI Practice Parameter 2013
• Limited non-specific laboratory evaluation
– CBC with diff
– ESR
– TSH
– BUN/Cr
– LFTs
• A thorough history and meticulous physical exam is essential for determining whether additional
tests are appropriate:
– Skin biopsy
– Physical challenge tests
– C3, C4, and CH50
– Functional autoantibody assay (for autoantibodies to FcεRI) and/or ASST
– Stool O&P
– UA
– Hepatitis B and C serologies
– CXR and/or other imaging studies
– ANA
– RF, Anti-CCP
– Cryoglobulin levels
– Serologic and/or skin testing for immediate hypersensitivity
39. WAO Guideline 2012
• History/physical examTime of onset
– Frequency and duration of wheals
– Presence of diurnal variation
– Shape, size, and distribution of wheals
– Associated angioedema
– Family and personal history of urticaria
– Atopy
– Medications (NSAIDs, hormones, laxatives, immunizations)
– Observed correlation with food and stress
• Diagnostic studiesCBC/diff
– LFTs
– ESR, CRP
– Screening for thyroid autoimmunity "may be considered" (Anti-Tg, Anti-TPO)
– Physical urticaria testing
– Role of H. pylori is controversial, and the evidence is weak
– Skin biopsy may be needed to confirm urticarial vasculitis or Schnitzler syndrome
40. Kaplan
• CBC/diff - high eosinophil counts might trigger a stool examination for ova and
parasites
• CRP or ESR
• TSH/FT4, anti-TPO, anti-TG antibodies - may be useful because so many CU
patients are found to be hypothyroid and are then treated with a thyroid hormone
• Other tests
– Routine food allergy skin testing - not recommended
– ANA - not recommended in the absence of symptoms (other than urticaria) that might suggest
the presence of SLE
– Anti-IgE/anti-IgE receptor antibodies - of theoretical interest, but none of the treatment
modalities distinguish patients with the antibodies from those without them
– Skin biopsy - when the diagnosis is not clear or when a vasculitis is suspected or at least needs
to be ruled out
• Examples of circumstances where a skin biopsy should be performed would be the presence of fever,
concomitant petechiae or palpable purpura, lesions that fade with bruising, individual lesions lasting
>24 h (and certainly >36 h), or prominent arthralgia
• ANA, C3, C4, and C1q binding assay for circulating immune complexes and cryoglobulin determination
would be included
•
41. Saini
• History/physical exam
– Duration of episodes and lesions appearance (photos)
– Medication/food history
– Identify physical triggers (significant in 20%)
– Consider infections
• Possible Lab Studies
– Basic series: CBC/diff, BMP, LFTs, UA
– Other testing guided by physical exam or history
– Extended: ESR, Anti-Tg, Anti-TPO, TSH, C3, C4
– Consider "autoimmune" tests: basophil CD203c level or CU index
– Skin biopsy to exclude urticarial vasculitis or define cellular picture in atypical cases (elevated
CRP or ESR, unresponsive to antihistamines, lesion duration >24h, painful rather than pruritic,
petechial or purpuric changes, leave residual pigment changes).
• Peroni: Up to 40-60% of patients with UV may present only with wheals, therefore, a skin biopsy
should be considered in all cases of otherwise clinically typical chronic urticaria, especially if the
urticaria is resistant to antihistamines
• Procedure
– 3 mm punch biopsy from a fresh lesion. Patients receiving steroids may need to discontinue these medications to
allow new lesions to form.
– Biopsy specimens should be submitted in formalin for routine H&E staining and in those patients in whom
urticarial vasculitis is a strong consideration, in Michel’s media or freshly snap frozen for DIF microscopy.
42. Bernstein
• History/physical exam
• Evaluate for evidence of physical urticarias, dermatographism
• Initial testing
– CBC/diff
– ESR
– TSH
– LFTs
– UA
– Allergy skin testing is not indicated in the initial evaluation of urticaria
• Testing for refractory cases
– C4
– Anti-Tg, Anti-TPO
– H. pylori antibodies
– Hepatitis panel
– Consider autologous serum skin test
– Consider skin biopsy if urticaria are atypical, not evanescent
43. Dreyfus
• Initial testing
– TSH, Anti-Tg
– CBC/diff
– SPEP
– LFTs
– Hepatitis titers
– H. pylori IgG, IgM and titers for other infectious illness - if suggested by history
– ANA and anti-DNA anti-bodies - if history or exam suggestive of vasculitis
– C1INH level and function, C2, C4 - if angioedema present
– Chromagranin A or urine catecholamines - if significant flushing, carcinoid features
– Tryptase - if significant component of anaphylaxis with urticaria, angioedema
– CXR and PFT - if associated respiratory symptoms such as cough, wheezing
– Total immunoglobulin levels, B/T cell subsets - if history suggestive of parasitic infection,
chronic infection
– Pregnancy testing - if relevant age and sex
– Serum basophil activation or histamine release in vitro and/or autologous skin testing - not
required but may be useful to confirm diagnosis
44. EAACI/WAO Guideline (2013)
• Routine diagnostic tests:
– CBC/diff
– ESR or CRP
– Omission of suspected drugs (e.g. NSAID)
• Extended diagnostic program for identification of eliciting factors and for ruling out
possible differential diagnoses if indicated:
– Infectious diseases (e.g. Helicobacter pylori)
– Test for type I allergy - rare cause of chronic urticaria in patients with daily or almost daily
symptoms, but must be considered in patients with intermittent symptoms
– Functional autoantibodies
– Thyroid hormones and autoantibodies
– Skin tests including physical tests
– Pseudoallergen-free diet for 3 weeks
– Tryptase level
– Autologous serum skin test
– Lesional skin biopsy
45. Diagnostic Approach for Children
(Boguniewicz)
• Routine testing
– Allergy testing
– CBC/diff
– ESR
– LFTs
– TSH, FT4, anti-Tg, anti-TPO
• Extended testing for selected patients
– Hepatitis serology
– Complement levels
– ANA and specific autoimmune testing
– EBV testing
– Stool ova and parasites
– Skin biopsy if vasculitis or mastocytosis are suspected
• Children whose CU persists should have yearly re-evaluation to rule-out late onset autoimmune
disease
•
46. Specialized Lab Testing for Urticaria
• CU Index - patient's serum is added to healthy donor basophils and quantity of histamine release is
measured. The reference range for a healthy non-CU population is <10. Values ≥10 indicate that
basophils were stimulated by patient serum to release histamine (the larger the value the more
histamine released).
– In one study, 23% of healthy controls vs. 57% of CU patients had a positive CU index
– Positive CU Index associated with more severe CIU
• Anti-FcεR1 (high affinity IgE receptor) IgG antibody- by Western blot, direct measurement of IgE
receptor autoantibodies
– These antibodies may not correlate with disease activity and have been identified in other autoimmune
diseases (even in the absence of urticaria), including pemphigus vulgaris, SLE, dermatomyositis, and
pemphigoid, suggesting that these antibodies may represent an epiphenomenon.
• Anti-IgE IgG antibody
• Basophil CD203c levels - by flow cytometry, indirect measure of autoantibodies to IgE receptor
which result in basophil activation.
• Anti-C1q antibody - Patients with hypocoplementemic urticarial vasculitis syndrome (HUVS) usually
have autoantibodies reactive with the collagen-like region of the C1q molecule, and can develop
angioedema.
•
47. Additional Testing Notes
• D-dimer - elevated D-dimer may be a biomarker of antihistamine-resistant chronic
urticaria (Asero)
– This subtype may respond to anticoagulation with tranexamic acid and low molecular weight
heparin
• Wedi - careful search for at least infections with H. pylori, strep, and perhaps also
staph and yersinia should be included in the work-up of severely affected patients;
our routine work-up includes:
– Helicobacter pylori monoclonal stool antigen test
– Serology for strep (ASO, anti-DNase B), staph (antistaphylolysin), yersinia (IgA, IgG,
immunoblot). If an infection is identified, it should be appropriately treated and it should be
checked whether eradication has been achieved.
• Initial evaluation for autoinflammatory syndromes (e.g. CAPS) should include:
– CBC/diff - to screen for neutrophilia
– CRP, ESR
– ANA - help rule out autoimmune disease
– UA - screen for proteinuria which suggests renal amyloidosis
– Serum amyloid A level - inflammation marker and screening parameter for amyloidosis
– Gene mutation analysis if specific diagnosis suspected (e.g. CAPS)
49. Impact of chronic spontaneous urticaria on the
patients
In addition to the classical clinical symptoms like pruritus,
whealing and the occurrence of angioedema, many other
factors are of major importance for patients with chronic
spontaneous urticaria these include:
1. The unpredictability of the attacks.
2. Lack of quality sleep (due to pruritus).
3. Fatigue caused by treatment.
4. Side-effects.
5. Cosmetic disfigurement.
Quality of life
Allergy 2011; 66: 317–330.
50
50. CSU adversely affects quality of life
Many aspects of QoL are found to be reduced in patients with CSU,1 with the
presence of angioedema further impairing QoL scores2
Mental status
Tired
Stressed
Overwhelmed
Anxious
Daily living
Physical activity
Eating
Concentrating
Sleeping
Leisure
Restricted choice of
clothing
Limiting hobbies
Avoiding sun
exposure
Self-perception
Loneliness
Conspicuousness
Anxiety over the future
Feeling unhygienic
Treatment-induced
restrictions
Effect on every day
activities
Financial burden
Discomfort
Social functions
Impact on
relationships
Impact on sexuality
Chronic
urticaria
impacts
1. Kang MJ, et al. Ann Dermatol 2009;21:226–9;
2. Silvares MRC, et al. Rev Assoc Med Bras 2011;57:577−82
51. Maurer M1, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical needs in chronic spontaneous
urticaria. A GA²LEN task force report. Allergy. 2011 Mar;66(3):317-30 53
52. 5454
Patients with CU feel similarly lacking in energy, socially
isolated, and emotionally upset as the patients with heart
disease
Comparison of the NHP (part I) scores in patients with chronic urticaria (CU, n 5 134)
and in patients with ischemic heart disease (IHD, n 5 98) awaiting coronary artery bypass
grafting. (From O’Donnell BF, Lawlor F, Simpson J, et al. The impact of chronic urticaria on
the quality of life. Br J Dermatol 1997;136(2):200;
O’Donnell BF. Urticaria: Impact on Quality of Life and Economic Cost. Immunol Allergy Clin N Am 2014; 34: 89–104
53. Socioeconomic burden
The socioeconomic cost of Chronic urticaria is high in terms of direct medical costs and
indirect costs, such as lost wages because of absences from work
0
50
100
150
200
250
300
Direct costs/patient/year ($US)
Laboratory
Outpatient visits
ED/hospital visits
Medication
Direct costs include laboratory costs, outpatient visits,
emergency department (ED)/hospital visits, and
medication
Indirect costs include income lost because of travel to
outpatient visits and work absenteeism
0
50
100
150
200
250
300
Indirect costs/patient/year in lost wages ($US)
Travel to
outpatient visit
Absence from
work
Based on a CSU prevalence of 0.04% among the US population, estimated mean total
indirect and direct costs would be $244 million per year
DeLong LK, et al. Arch Dermatol 2008;144:35−9
$US
$US
54. How to assess disease activity and quality of life?
56
Disease activity
Quality of life
UAS AAS
CU-Q2ol AE-Qol
Wheal Angioedema
55. 5757
Disease activity in spontaneous urticaria should
be assessed using the UAS7
The UAS7 is a validated method for assessing disease activity
A modification to the UAS7, in which signs and symptoms are
assessed two times per day, has also been validated
Score Wheals Pruritus
0 None None
1 Mild (<20 wheals/24 hours) Mild (present, but not annoying or troublesome)
2 Moderate (20–50 wheals/24 hours) Moderate (troublesome, but does not interfere with
normal daily activity or sleep)
3 Intense (>50 wheals/24 hours or
large confluent areas of wheals)
Intense (severe pruritus, which is sufficiently
troublesome to interfere with normal daily activity or
sleep)
Sum of score: 0–6 for each day is summarized over one week (maximum 42)
Urticaria activity score
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of
urticaria. The 2013 revision and update. Allergy 2014;69:868–87
57. 63
Goal of treatment
Should treatment aim at complete symptom
control in urticaria?
We recommend aiming for complete symptom control in
urticaria as safely as possible (strong recommendation/clinical
consensus following the WHO constitution in conformity with
the Charter of the United Nations).
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management
of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
58. 6464
Chronic urticaria is a mast cell-dependent disease
and should be managed accordingly
In CU, partly unknown stimuli cause mast cells to release
their mediators leading to small (wheals) or larger and
deeper (angioedema) edema of the skin
The therapeutic approach is universal and based on the
same principles as in other mast-cell dependent diseases:1,2
1. Elimination/avoidance of the cause or trigger/stimulus
2. Symptomatic pharmacological treatment by reducing mast cell mediator release
and/or the effect of these mediators at the target organ
3. Inducing tolerance
Management algorithms for CU should take account of:2
• Variation in symptoms from one patient to another
• Need to step up or step down treatment
• Differences between easy-to-treat and refractory patients
CU = chronic urticaria.
1. Zuberbier T, et al. EAACI/GA2LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64:1427–1443
2. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
59. 6565
Identification and elimination of the underlying cause
and/or trigger
Identification and subsequent elimination of the cause interrupts the pathogenic
process and should lead to resolution of symptoms
Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M, editors. Berlin: Springer-Verlag, 2010
Trigger
Cause
Mast cell-
activating
signal
Mast cell
activation
Mast cell
mediators
Urticaria
reaction
causal symptomatic
60. Elimination or avoidance of the cause or
trigger/stimulus requires an exact diagnosis
Drugs
When such agents are suspected in the course of diagnosis, they should be omitted entirely or
substituted by another class of agents if indispensable
Drugs causing non-allergic hypersensitivity reactions (e.g. NSAIDs) cannot only elicit, but can also
aggravate pre-existing CSU, so that elimination in the latter case will only improve symptoms in some
patients
Physical stimuli
Avoidance is desirable but not always simple
Eradication of infections and treatment of inflammatory processes
CSU is often associated with inflammatory or infectious diseases
Infections should be treated appropriately, but it is unclear whether they have significant causative role
Reduction of functional autoantibodies
There is little experience in the reduction of functional autoantibodies with plasmaphoresis in CSU
Such treatment should be reserved for patients unresponsive to all other forms of treatment
Dietary management
IgE-mediated food allergy is rarely the underlying cause of CSU
Pseudoallergic reactions to foods have been seen in some patients with CSU
In such cases, diet low in pseudoallergens should be implemented for ≥3–6 months
CU = chronic urticaria; CSU = chronic spontaneous urticaria; NSAID = non-steroidal anti-inflammatory drug.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
61. Induction of tolerance may be useful in some
urticaria subtypes
Inducing tolerance may be effective in cold, cholinergic and
solar urticaria
Tolerance only lasts for a few days, so consistent daily
exposure is required
• This may not be tolerated by patients (e.g. in the case of cold baths
for cold urticaria)
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of
urticaria. The 2013 revision and update. Allergy 2014;69:868–87
62. 6868
Trigger
Cause
Mast cell-
activating
signal
Mast cell
activation
Mast cell
mediators
Urticaria
reaction
symptomatic
Therapeutic strategies targeting mast cell mediators
When the cause of urticaria cannot be identified or eliminated,
treatment is targeted at mast cell mediators
Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M, editors. Berlin: Springer-Verlag, 2010
causal
63. Guidelines Recommendations Toward Urticaria
Management
*The order of third-line treatments does not reflect preference.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification,
diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
First line:
Modern second-generation antihistamines
Second line:
Increase dosage up to fourfold of modern second-generation antihistamines
Third line:
Add on to second-line*: omalizumab or ciclosporin A or montelukast
Short course (maximum 10 days) of corticosteroids may also be used at all times if
exacerbations demand this
If symptoms persist after 2 weeks
If symptoms persist after 1–4 further weeks
69
64. Continuous treatment with H1-antihistamines is
central to the management of CU
Many symptoms of urticaria are mediated primarily by histamine
• Histamine H1 receptors are located on endothelial cells and sensory nerves
• H1-antihistamines stabilize these receptors in an inactive state
In some cases, other mast cell mediators (PAF, leukotrienes, cytokines)
are also involved and a pronounced cellular infiltrate including
basophils, lymphocytes and eosinophils may be observed
• Such cases may respond to a brief course of corticosteroids and may be
relatively refractory to H1-antihistamines
Use of first-generation (sedating) antihistamines is not recommended for
routine management of urticaria
Modern second-generation H1-antihistamines should be considered as
the first-line treatment for urticaria
• Up-dosing (up to 4× licensed dose) is the second-line option
PAF = platelet activating factor.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
65. 71
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
66. 72
Up to 50% of CSU patients have an inadequate
response to H1-antihistamines at licensed doses.1,2
1. Maurer M, et al. Allergy 2011;66:317–30.
2. Weller K, et al. J Eur Acad Dermatol venereol 2013;27:43-50
How do you help your H1-antihistamines
refractory patients?
67. Ciclosporin A has a moderate, direct effect on mast cell
mediator release
• Shown to be effective in double-blind placebo-controlled studies
• Efficacy in combination with modern second generation H1-
antihistamines has been shown in placebo-controlled trials and open
controlled trials
• Not recommended as standard treatment due to high incidence of
adverse effects
• Recommended only use in severe disease refractory to any dose of
antihistamine
Information on ciclosporin A and corticosteroids is similar to that in the 2009 guidelines;
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
Treatment of antihistamine-refractory patients:
Ciclosporin A
68. LTRAs are associated with a low level of evidence for efficacy in
urticaria
• The best evidence is for montelukast
In urticaria, topical corticosteroids are not helpful (with the possible
exception of pressure urticaria on the soles of the feet [low evidence])
• If systemic corticosteroids are used, doses between 20–50 mg/day are
required
• Adverse effects occur during on long-term use
• There is a strong recommendation against long-term use of
corticosteroids outside specialist clinics
• In many countries, corticosteroids are not licenced for use in urticaria
Description of LTRAs has been changed since 2009 and now notes that the best evidence is for montelukast.
LTRA = leukotriene receptor antagonist.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
Treatment of antihistamine-refractory patients:
LTRAs and corticosteroids
69. Omalizumab (anti-IgE) has now been shown to be very
effective in the treatment for CSU, both in case reports
and case series as well as in double-blind placebo-
controlled studies in antihistamine refractory selected
patients.
75
Treatment of antihistamine-refractory patients:
Omalizumab
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
70. Treatment of antihistamine-refractory patients:
Other treatment options
H₂-antagonists and dapsone are no longer included as recommended
treatment options
• The 2009 version of the guidelines included them as fourth-line options,
but the evidence is too low to maintain the recommendation
Sulfasalazine, methotrexate, interferon, plasmaphoresis, phototherapy and
IVIGs are supported only by trials of low quality and case series
Antagonists of TNFα and IVIG have been used successfully in case reports
• These options are recommended only for used in specialized centres as a last resort
(i.e., anti-TNFα for delayed pressure urticaria and IVIG for CSU)
Phototherapy has been used successfully in mastocytosis and is helpful in
treatment-resistant patients with this condition
For the treatment of CSU and symptomatic dermographism, UV-A, PUVA and UV-B (nb-
UVB) treatment for 1–3 months can be added to antihistamine treatment
CSU = chronic spontaneous urticaria; IVIG = intravenous immunoglobulin; nb-UVB = narrowband ultraviolet B;
PUVA = psoralen and ultraviolet A; TNFα = tumour necrosis factor alpha; UV = ultraviolet.
Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and
management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87
71. Maurer.M, Magerl M, Metz M, Zuberbier.T, et al.Revisions to the international guidelines on the diagnosis and therapy of chronic urticaria. Journal of German Society of
Dermatology. 2013. DOI: 10.1111/ddg.12194
77. ACAAI/AAAAI Practice Parameter 2013
• Limited non-specific laboratory evaluation
– CBC with diff
– ESR
– TSH
– BUN/Cr
– LFTs
• A thorough history and meticulous physical exam is essential for determining whether additional
tests are appropriate:
– Skin biopsy
– Physical challenge tests
– C3, C4, and CH50
– Functional autoantibody assay (for autoantibodies to FcεRI) and/or ASST
– Stool O&P
– UA
– Hepatitis B and C serologies
– CXR and/or other imaging studies
– ANA
– RF, Anti-CCP
– Cryoglobulin levels
– Serologic and/or skin testing for immediate hypersensitivity
78. WAO Guideline 2012
• History/physical examTime of onset
– Frequency and duration of wheals
– Presence of diurnal variation
– Shape, size, and distribution of wheals
– Associated angioedema
– Family and personal history of urticaria
– Atopy
– Medications (NSAIDs, hormones, laxatives, immunizations)
– Observed correlation with food and stress
• Diagnostic studiesCBC/diff
– LFTs
– ESR, CRP
– Screening for thyroid autoimmunity "may be considered" (Anti-Tg, Anti-TPO)
– Physical urticaria testing
– Role of H. pylori is controversial, and the evidence is weak
– Skin biopsy may be needed to confirm urticarial vasculitis or Schnitzler syndrome
79. Kaplan
• CBC/diff - high eosinophil counts might trigger a stool examination for ova and
parasites
• CRP or ESR
• TSH/FT4, anti-TPO, anti-TG antibodies - may be useful because so many CU
patients are found to be hypothyroid and are then treated with a thyroid hormone
• Other tests
– Routine food allergy skin testing - not recommended
– ANA - not recommended in the absence of symptoms (other than urticaria) that might suggest
the presence of SLE
– Anti-IgE/anti-IgE receptor antibodies - of theoretical interest, but none of the treatment
modalities distinguish patients with the antibodies from those without them
– Skin biopsy - when the diagnosis is not clear or when a vasculitis is suspected or at least needs
to be ruled out
• Examples of circumstances where a skin biopsy should be performed would be the presence of fever,
concomitant petechiae or palpable purpura, lesions that fade with bruising, individual lesions lasting
>24 h (and certainly >36 h), or prominent arthralgia
• ANA, C3, C4, and C1q binding assay for circulating immune complexes and cryoglobulin determination
would be included
•
80. Saini
• History/physical exam
– Duration of episodes and lesions appearance (photos)
– Medication/food history
– Identify physical triggers (significant in 20%)
– Consider infections
• Possible Lab Studies
– Basic series: CBC/diff, BMP, LFTs, UA
– Other testing guided by physical exam or history
– Extended: ESR, Anti-Tg, Anti-TPO, TSH, C3, C4
– Consider "autoimmune" tests: basophil CD203c level or CU index
– Skin biopsy to exclude urticarial vasculitis or define cellular picture in atypical cases (elevated
CRP or ESR, unresponsive to antihistamines, lesion duration >24h, painful rather than pruritic,
petechial or purpuric changes, leave residual pigment changes).
• Peroni: Up to 40-60% of patients with UV may present only with wheals, therefore, a skin biopsy
should be considered in all cases of otherwise clinically typical chronic urticaria, especially if the
urticaria is resistant to antihistamines
• Procedure
– 3 mm punch biopsy from a fresh lesion. Patients receiving steroids may need to discontinue these medications to
allow new lesions to form.
– Biopsy specimens should be submitted in formalin for routine H&E staining and in those patients in whom
urticarial vasculitis is a strong consideration, in Michel’s media or freshly snap frozen for DIF microscopy.
81. Bernstein
• History/physical exam
• Evaluate for evidence of physical urticarias, dermatographism
• Initial testing
– CBC/diff
– ESR
– TSH
– LFTs
– UA
– Allergy skin testing is not indicated in the initial evaluation of urticaria
• Testing for refractory cases
– C4
– Anti-Tg, Anti-TPO
– H. pylori antibodies
– Hepatitis panel
– Consider autologous serum skin test
– Consider skin biopsy if urticaria are atypical, not evanescent
82. Dreyfus
• Initial testing
– TSH, Anti-Tg
– CBC/diff
– SPEP
– LFTs
– Hepatitis titers
– H. pylori IgG, IgM and titers for other infectious illness - if suggested by history
– ANA and anti-DNA anti-bodies - if history or exam suggestive of vasculitis
– C1INH level and function, C2, C4 - if angioedema present
– Chromagranin A or urine catecholamines - if significant flushing, carcinoid features
– Tryptase - if significant component of anaphylaxis with urticaria, angioedema
– CXR and PFT - if associated respiratory symptoms such as cough, wheezing
– Total immunoglobulin levels, B/T cell subsets - if history suggestive of parasitic infection,
chronic infection
– Pregnancy testing - if relevant age and sex
– Serum basophil activation or histamine release in vitro and/or autologous skin testing - not
required but may be useful to confirm diagnosis
83. EAACI/WAO Guideline (2013)
• Routine diagnostic tests:
– CBC/diff
– ESR or CRP
– Omission of suspected drugs (e.g. NSAID)
• Extended diagnostic program for identification of eliciting factors and for ruling out
possible differential diagnoses if indicated:
– Infectious diseases (e.g. Helicobacter pylori)
– Test for type I allergy - rare cause of chronic urticaria in patients with daily or almost daily
symptoms, but must be considered in patients with intermittent symptoms
– Functional autoantibodies
– Thyroid hormones and autoantibodies
– Skin tests including physical tests
– Pseudoallergen-free diet for 3 weeks
– Tryptase level
– Autologous serum skin test
– Lesional skin biopsy
84. Diagnostic Approach for Children
(Boguniewicz)
• Routine testing
– Allergy testing
– CBC/diff
– ESR
– LFTs
– TSH, FT4, anti-Tg, anti-TPO
• Extended testing for selected patients
– Hepatitis serology
– Complement levels
– ANA and specific autoimmune testing
– EBV testing
– Stool ova and parasites
– Skin biopsy if vasculitis or mastocytosis are suspected
• Children whose CU persists should have yearly re-evaluation to rule-out late onset autoimmune
disease
•
85. Specialized Lab Testing for Urticaria
• CU Index - patient's serum is added to healthy donor basophils and quantity of histamine release is
measured. The reference range for a healthy non-CU population is <10. Values ≥10 indicate that
basophils were stimulated by patient serum to release histamine (the larger the value the more
histamine released).
– In one study, 23% of healthy controls vs. 57% of CU patients had a positive CU index
– Positive CU Index associated with more severe CIU
• Anti-FcεR1 (high affinity IgE receptor) IgG antibody- by Western blot, direct measurement of IgE
receptor autoantibodies
– These antibodies may not correlate with disease activity and have been identified in other autoimmune
diseases (even in the absence of urticaria), including pemphigus vulgaris, SLE, dermatomyositis, and
pemphigoid, suggesting that these antibodies may represent an epiphenomenon.
• Anti-IgE IgG antibody
• Basophil CD203c levels - by flow cytometry, indirect measure of autoantibodies to IgE receptor
which result in basophil activation.
• Anti-C1q antibody - Patients with hypocoplementemic urticarial vasculitis syndrome (HUVS) usually
have autoantibodies reactive with the collagen-like region of the C1q molecule, and can develop
angioedema.
•
86. Additional Testing Notes
• D-dimer - elevated D-dimer may be a biomarker of antihistamine-resistant chronic
urticaria (Asero)
– This subtype may respond to anticoagulation with tranexamic acid and low molecular weight
heparin
• Wedi - careful search for at least infections with H. pylori, strep, and perhaps also
staph and yersinia should be included in the work-up of severely affected patients;
our routine work-up includes:
– Helicobacter pylori monoclonal stool antigen test
– Serology for strep (ASO, anti-DNase B), staph (antistaphylolysin), yersinia (IgA, IgG,
immunoblot). If an infection is identified, it should be appropriately treated and it should be
checked whether eradication has been achieved.
• Initial evaluation for autoinflammatory syndromes (e.g. CAPS) should include:
– CBC/diff - to screen for neutrophilia
– CRP, ESR
– ANA - help rule out autoimmune disease
– UA - screen for proteinuria which suggests renal amyloidosis
– Serum amyloid A level - inflammation marker and screening parameter for amyloidosis
– Gene mutation analysis if specific diagnosis suspected (e.g. CAPS)
89. Chronic infection and chronic urticaria
• Chronic infection — in most cases it is not clear whether the two
processes are related, occur simultaneously by chance, or are
influenced by medications
– The following infections reported to be associated with urticaria, with
improvement after infection resolved:
• Parasitic
– Ascaris, Ancylostoma, Strongyloides, Filaria, Giardia lamblia, Entamoeba spp, Blastocystis
spp, Echinococcus, Schistosoma, Trichinella,Toxocara, and Fasciola
– Anisakis simplex (a sea fish nematode) has been reported as possible cause of recurrent
acute urticaria in areas of the world where uncooked fish is eaten frequently
• Bacterial: H. pylori, Streptococcus spp, Staphylococcus spp, Yersinia
enterocolitica, Mycoplasma pneumonia
– In a meta-analysis, rate of CU remission when H. pylori was eradicated was 30.9% vs.
21.7% when not
• Viral: hepatitis C, CMV, EBV, norovirus, parvovirus B19
• Unspecified organisms: tonsillitis, sinusitis, dental infection, UTI
• Fungal: The existence of an ‘id’ reaction with urticaria secondary to a fungal
infection is no longer considered tenable (Kaplan)
90. Malignancy and chronic urticaria
• Lymphoproliferative disease/malignancy — rarely have
simple urticaria, typically have lesions consistent
with urticarial vasculitis, and present with other
systemic symptoms
– Schnitzler's syndrome - onset in 50's, monoclonal IgM or
IgG gammopathy with recurrent fever, weight loss, bone
pain, myalgias/arthralgias, lymphadenopathy, and non-
pruritc urticaria that may become pruritic. May be due to
circulating immune complexes and complement activation,
anakinra (IL-1R antagonist) effective.
– Also reported with B-cell lymphomas, Hodgkins, CML,
lung/colorectal/liver carcinomas
92. 98
Emerging a New Standard of Care for
Refractory CSU Patients
Xolair® (omalizumab)
Treatment of antihistamine-refractory patients (cont’d)
93. How do you help your
refractory CSU patients when…?
99
Up to 50% of CSU patients have an inadequate response
to H1-antihistamines at licensed doses.1,2
Beyond Omalizumab, there are no other licensed
treatment options.1
Until now, there has been no standard of care for these
refractory CSU patients.1
1. Maurer M, et al. Allergy 2011;66:317–30.
2. Weller K, et al. J Eur Acad Dermatol venereol 2013;27:43-50
94. Now you can change the lives of
refractory CSU patients with
Omalizumab
100
95. Introduction to Omalizumab
Xolair® (omalizumab) is a recombinant DNA-derived
humanized monoclonal antibody that selectively binds to
human immunoglobulin E (lgE).
Xolair® 300mg (2x150mg/4 weeks) injection is indicated
for adults and adolescents (12 years of age and above)
with chronic spontaneous urticaria refractory to standard
of care.
Xolair BPI, 2014
In Allergic Asthma:
Xolair has been listed in the Egyptian market for more than 6 years, and indicated for
adults and children (6 years of age and above) with moderate to severe persistent allergic
asthma whose symptoms are inadequately controlled with inhaled corticosteroids (ICS).
Xolair has been shown to decrease the incidence of asthma exacerbations in these
patients. Safety and efficacy have not been established in other allergic conditions.
96. Apart from reducing free IgE levels, the additional
mechanisms by which omalizumab works in patients with
CSU remains unclear.
Reports describe patients with CSU as having abnormal
basophil function, including:1
• Decreased responsiveness to stimuli acting through the IgE receptor (50% of
patients),
• Blood basopenia, and
• Recruitment of basophils into skin lesions.
With successful therapy, blood basopenia and FcεRI
function began to return to normal levels.1
102
1. Vonakis BM, Saini SS. New concepts in chronic urticaria. Curr Opin Immunol 2008;20:709-16.
Omalizumab Mode of Action:
97. In previous studies, omalizumab reduced free IgE levels
within hours after administration and down regulates
FcεRI on blood basophils within 2 weeks;
A study of human cutaneous mast cells indicates a down
regulatory effect in 3 to 4 weeks.1,2
However, in individual patients the time course of
symptom control does not necessarily follow these
parameters.
103
1. Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell FcεRI
expression and function. J Allergy Clin Immunol 2004;114:527-30.
2. Gomez G, Jogie-Brahim S, Shima M, Schwartz LB. Omalizumab reverses the phenotypic and functional
effects of IgE-enhanced FcεRI on human skin mast cells. J Immunol 2007;179:1353-61.
Omalizumab Mode of Action
98. Xolair® Clinical Trails
105
6 SC Xolair injections
over 24 weeks
ASTERIA I ASTERIA II GLACIAL
Xolair® 300 mg vs. Xolair® 150 mg vs.
Xolair® 75 mg vs. placebo (1:1:1:1)
Moderate-to-severe CSU
Follow-up period: 16 weeks
Xolair® 300 mg vs.
placebo (3:1)
318 patients 322 patients 335 patients
3 SC Xolair injections
over 12 weeks
6 SC Xolair injections
over 24 weeks
Patients continued to receive stable doses of their prerandomization
background therapy (therapies) throughout the treatment period
99. Patient baseline demographics (mITT population): ASTERIA II
and GLACIAL*
*Please refer to the manuscripts for a full list of patient baseline demographic data;
Data are means (SDs) unless otherwise stated;
†Measured in 78 patients in the placebo group.
CIU=chronic idiopathic urticaria; CSU=chronic spontaneous urticaria; DLQI=Dermatology Life
Quality Index; mITT=modified intention to treat; OMA=omalizumab; SD=standard deviation;
UAS=urticaria activity score; UAS7=weekly urticaria activity score.
1. Maurer M, et al. N Engl J Med 2013;
2. Kaplan A, et al. J Allergy Clin Immunol 2013.
Characteristic ASTERIA II1 GLACIAL2
Placebo
(n=79)
OMA 75 mg
(n=82)
OMA 150 mg
(n=82)
OMA 300 mg
(n=79)
Placebo
(n=83)
OMA 300 mg
(n=252)
Age, years 43.1 12.5 39.7 15.0 43.0 13.2 44.3 13.7 44.3 14.7 42.7 13.9
Female sex, no. (%) 55 (70) 61 (74) 65 (79) 63 (80) 55 (66.3) 186 (73.8)
Race (white), no. (%) 70 (89) 64 (78) 70 (85) 68 (86) 75 (90.4) 223 (88.5)
Body mass index (kg/m2) 30.0 7.7 30.2 7.7 30.0 7.3 29.0 6.3 31.0 9.6 29.4 7.1
Time since diagnosis of CSU,
years
Mean
Median
7.2 10.7
3.3
5.3 7.1
2.5
7.2 8.9
3.9
6.1 7.3
3.5
8.8 11.2
4.1
7.0 8.8
3.4
No. of previous CSU medications 4.4 2.9 4.1 2.1 4.5 3.2 4.3 2.5 6.4 2.9 5.9 2.5
In-clinic UAS 5.3 0.7 5.4 0.8 5.3 0.7 5.3 0.7 5.2 0.8 5.2 0.8
UAS7 31.0 6.6 30.7 6.9 31.4 7.0 29.5 6.9 30.2 6.7 31.2 6.6
Weekly itch severity score 14.0 3.4 14.0 3.7 14.2 4.1 13.7 3.5 13.8 3.6 14.0 3.6
Weekly no. of hives score 17.0 4.2 16.8 4.2 17.1 4.1 15.8 4.6 16.4 4.6 17.1 4.2
Overall DLQI score 12.6 5.9† 12.6 6.5 13.0 6.1 12.7 6.4
Presence of angioedema, no (%) 30 (38) 31 (38) 38 (46) 32 (41) 41 (49.4) 137 (54.4)
100. Objectives of the 3 clinical trials
107
− Evaluation of the efficacy
of Omalizumab compared
with placebo in patients
who remained
symptomatic despite H1-
antihistamine therapy (at
licensed doses.)
− Safety and tolerability were
evaluated as secondary
objectives.
GLACIAL ASTERIA I and ASTERIA II
− Evaluation of the safety of
Omalizumab compared with
placebo in CSU patients who
remained symptomatic despite
treatment with H1-
antihistamines at up to 4 times
the approved dose plus H2-
antihistamines, leukotriene
receptor antagonists, or both.
− Efficacy was assessed as a
secondary objective.
101. Primary and secondary endpoints
Asteria I
N=318
Asteria II
N=322
Glacial
N=335
Primary
endpoint
Change from baseline to Week 12 in weekly
Itch Severity Score (ISS)
Safety
Secondary
endpoints
At Week 12:
• Change from baseline in UAS7
• Change from baseline in weekly # of hives score
• Time to MID (≥5 points) response in weekly ISS
• Proportion of patients with UAS7 ≤6
• Proportion of weekly ISS MID responders
• Change from baseline in weekly size of largest
hive score
• Change from baseline in DLQI
• Proportion of angioedema-free days from Week 4
to Week 12 of therapy
• Proportion of Complete Responders (UAS7=0)*
Same as Asteria I
and Asteria II
primary and
secondary endpoints
*Exploratory endpoint in Asteria II. DLQI, Dermatology Life Quality Index, UAS7, urticaria activity score over 7 days.
MID: minimal important difference
102. Summary for results of
Omalizumab 300 mg vs Placebo in
Phase III Programme in CSU
103. 110
71% reduction in itch
with Omalizumab 300 mg vs baseline at 12 weeks1
Asteria II
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are
relative to the placebo group; data represent the modified intention-to-treat (mITT) population; ISS, itch severity score
1. Maurer M, et al. N Engl J Med 2013;368:924–35.
Omalizumab 300 mgPlacebo
71%
104. 111
Omalizumab 300 mgPlacebo
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are
relative to the placebo group; data represent the modified intention-to-treat (mITT) population; ISS, itch severity score
67% reduction in itch
with Omalizumab 300 mg vs baseline at 12 weeks1,2
Asteria I
1. Saini SS, et al. Ann Allergy Asthma Immunol 2013;111 (Suppl. 5):A18.
2. Rosén K, et al. Allergy 2013;68 (Suppl. 97):259.
67%
105. 62% reduction in itch
with Omalizumab 300 mg vs baseline at 12 weeks1
112
Glacial
Patients were receiving background treatment of non-sedating H1-antihistamines (up to 4x the approved dose)
plus H2-antihistamines and/or leukotriene-receptor antagonists; all p-values are relative to the placebo group;
data represent the modified intention-to-treat (mITT) population; ISS, itch severity score
1. Kaplan A, et al. J Allergy Clin Immunol 2013;132:101–9
29%
Omalizumab 300 mgPlacebo
62%
106. Rapid itch reduction after the 1st dose
with Omalizumab 300 mg1
113
Asteria I
1. Saini SS, et al. Ann Allergy Asthma Immunol 2013;111 (Suppl. 5):A18.
2. Rosén K, et al. Allergy 2013;68 (Suppl. 97):259.
3. Mathias SD, et al. Ann Allergy Asthma Immunol 2012;108:20–4
* Mean weekly ISS increased to values similar to those in the placebo group after Week 12, but did not return to baseline values. Itch
relief was defined by a reduction in weekly ISS by ≥5 points from baseline3
** Time to achieve minimally important difference in weekly itch severity score was 1 week with Omalizumab.
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from
Novartis/Genentech, data on file (Q4881g); data represent the modified intention-to-treat (mITT) population; ISS, itch severity score
P<0.0001 for the comparison with placebo at week 12
Denotes treatment
administration
107. 114
Asteria II
* Mean weekly ISS increased to values similar to those in the placebo group after Week 12, but did not return to baseline values. Itch
relief was defined by a reduction in weekly ISS by ≥5 points from baseline3
** Time to achieve minimally important difference in weekly itch severity score was 1 week with Omalizumab.
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from
Novartis/Genentech, data on file (Q4881g); data represent the modified intention-to-treat (mITT) population; ISS, itch severity score
P<0.0001 for the comparison with placebo at week 12
1. Maurer M, et al. N Engl J Med 2013;368:924–35.
Rapid itch reduction after the 1st dose
with Omalizumab 300 mg1
Rapid reduction**
Itch re-emerges after end
of treatment *
108. 115
Rapid itch reduction after the 1st dose
with Omalizumab 300 mg2
* Mean weekly ISS increased to values similar to those in the placebo group after Week 12, but did not return to baseline values. Itch relief was defined by a
reduction in weekly ISS by ≥5 points from baseline6
** Time to achieve minimally important difference in weekly itch severity score was 2 weeks with Omalizumab.2
Patients were receiving background treatment of non-sedating H1-antihistamines (up to 4x the approved dose) plus H2-antihistamines and/or leukotriene-
receptor antagonists. Data represent the modified intention-to-treat (mITT) population; ISS, itch severity score.
P <.001 for the comparison with placebo at week 12
Mean change from baseline in weekly ISS by study week (baseline observation carried forward
method, modified intention-to-treat population).
Itch re-emerges after end of
treatment *
Rapid reduction**
.................................
......Discontinuation of Omalizumab
adapted from Kaplan A, et al. 2013
109. Omalizumab increased the proportion of patients
who were itch-free and hive-free (UAS7=0) at
Week 12 vs. placebo*
The mean percentage of patients who were free of itch and hives (UAS7=0) was
significantly greater in the omalizumab 150 mg (ASTERIA II) and 300 mg groups
(ASTERIA II and GLACIAL) vs. placebo
ASTERIA II (mITT population)1
GLACIAL (mITT population)2
0
10
20
50
5.1 15.9 22.0 44.3 4.8 33.7
Proportion(%)ofpatients
withUAS7=0atWeek12
22.0
44.340
30
1. Maurer M, et al. N Engl J Med 2013;
2. Kaplan A, et al. J Allergy Clin Immunol 2013.
*Post hoc analysis in ASTERIA II / secondary endpoint in GLACIAL.
mITT=modified intention-to-treat; OMA=omalizumab;
UAS7=weekly urticaria activity score.
p<0.001
OMA
300 mg
PlaceboPlacebo OMA
75 mg
OMA
150 mg
OMA
300 mg
110. 44% of patients were itch- and hive-free
with Omalizumab 300 mg at 12 weeks1
117
Omalizumab 300 mgPlacebo
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from
Maurer M, et al. 2013; data represent the modified intention-to-treat (mITT) population; UAS7, urticaria activity score
over 7 days
1. Maurer M, et al. N Engl J Med 2013;368:924–35.
Asteria II
44%
111. Omalizumab significantly increased the proportion of
patients who were well controlled (UAS7≤6) at Week 12*
A significantly higher proportion of patients in the omalizumab 150 mg (ASTERIA II) and
300 mg groups (ASTERIA II and GLACIAL) had symptoms which were well-controlled
(UAS7≤6) vs. placebo
0
15
30
45
60
75
90
19 27 43 66 12.0 52.4
Proportion(%)ofpatientswith
UAS7≤6atWeek12
42.7
65.8
p<0.05
p<0.05
*Secondary endpoint in ASTERIA II and GLACIAL.
mITT=modified intention-to-treat; OMA=omalizumab;
UAS7=weekly urticaria activity score.
ASTERIA II (mITT population)1 GLACIAL (mITT population)2
1. Maurer M, et al. N Engl J Med 2013;
2. Kaplan A, et al. J Allergy Clin Immunol 2013.
p<0.001
OMA
300 mg
PlaceboPlacebo OMA
75 mg
OMA
150 mg
OMA
300 mg
112. 66% of patients achieved UAS7≤6
with Omalizumab 300 mg at 12 weeks1
119
Asteria II
1. Maurer M, et al. N Engl J Med 2013;368:924–35.
66%*
Omalizumab 300 mgPlacebo
* p<0.0001 relative to placebo group
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from
Maurer M, et al. 2013; data represent the modified intention-to-treat (mITT) population; UAS7, urticaria activity score over 7 days.
113. Omalizumab significantly improved QoL (DLQI)* at
Week 12 vs. placebo
*Secondary endpoint in ASTERIA II and GLACIAL.
DLQI=Dermatology Life Quality Index; mITT=modified intention-to-treat population;
OMA=omalizumab; QoL=quality-of-life.
1. Maurer M, et al. N Engl J Med 2013
2. Kaplan A, et al. J Allergy Clin Immunol 2013
–15
–10
–5
0
–8.3
–10.2
Changefrombaselinein
DLQIscoreatWeek12
p<0.001
p=0.02
ASTERIA II (mITT population)1 GLACIAL (mITT population)2
Significant improvements in QoL (measured using DLQI) seen with omalizumab 150 mg
(ASTERIA II) and 300 mg (ASTERIA II and GLACIAL) vs. placebo
Placebo
OMA
75 mg
OMA
150 mg
OMA
300 mg
OMA
300 mgPlacebo
–6.1 –7.5 –8.3 –10.2 –5.1 –9.7
p<0.001
114. 80% reduction in DLQI score
with Omalizumab 300 mg vs baseline at 12
weeks1
121
Omalizumab 300 mgPlacebo
48%
80%
Asteria II
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are
relative to the placebo group; data represent the modified intention-to-treat (mITT) population; DLQI, Dermatology Life
Quality Index.
1. Maurer M, et al. N Engl J Med 2013;368:924–35.
115. Omalizumab significantly improved angioedema-
free days during Weeks 4–12 vs. placebo*
Significantly greater proportion of angioedema-free days between Weeks 4–12 seen
with omalizumab 300 mg (ASTERIA II and GLACIAL) vs. placebo
1. Maurer M, et al. N Engl J Med 2013;
2. Kaplan A, et al. J Allergy Clin Immunol 2013.
ASTERIA II (mITT population)1
GLACIAL (mITT population)2
*Secondary endpoint in ASTERIA II and GLACIAL.
mITT=modified intention-to-treat population; OMA=omalizumab.
0
20
40
60
80
100
89.2 93.5 91.6 95.5 88.1 91.0
Proportion(%)ofangioedema-free
daysoverWeeks4–12
91.6
p<0.001
OMA
300 mg
PlaceboPlacebo OMA
75 mg
OMA
150 mg
OMA
300 mg
p<0.001
116. 76% reduction in weekly hives score
with Omalizumab 300 mg vs baseline at
12 weeks1
123
Omalizumab 300 mgPlacebo
76%
Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are relative to the placebo
group; adapted from Maurer M, et al. 2013; data represent the modified intention-to-treat(mITT) population
Asteria II
1. Maurer M, et al. N Engl J Med 2013;368:924–35.
117. Xolair® safety was investigated in over 700
patients in the CSU Phase III clinical program1
124
Overall incidences of adverse reactions were similar
between Omalizumab and placebo patients. 2
1. Xolair Basic Prescribing Information
2. Kaplan A, et al. J Allergy Clin Immunol 2013;132:101–9
118. Incidences of adverse reactions
between Omalizumab and placebo patients1
125
Adverse reactions* reported during Weeks 1–12
From the pooled CSU safety database (ASTERIA I, ASTERIA II, GLACIAL)
Adverse reactions (%) Placebo† Xolair® 300 mg†
Sinusitis 2.1 4.9
Headache 2.9 6.1
Arthralgia 0.4 2.9
Adverse reactions* reported during Weeks 1–24
From the pooled CSU safety database (ASTERIA I, GLACIAL)
Upper respiratory tract
infection
3.1 5.7
Injection site reaction** 0.8 2.7
1. Xolair basic prescribing information
*Events occurring in ≥1% of patients in any treatment group and ≥2% more frequently in any Xolair® treatment group than in the
placebo group
**Despite not showing a 2% difference to placebo, injection site reactions were included as all cases were assessed as related to
study treatment
†Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses (ASTERIA I/II) or non-sedating
H1-antihistamines (up to 4x the approved dose) plus H2-antihistamines and/or leukotriene-receptor antagonists (GLACIAL)
119. Xolair® has an established safety profile
based on long-term use in severe allergic asthma
126
Safety evaluated in >9,300 subjects receiving Omalizumab in clinical
programs.1
Omalizumab has >400,000 patient years’ experience, since US
approval in 2003, and EU approval in 2005.1
In the US, Xolair® is licensed for adults and adolescents (≥12 years of
age) with moderate to severe persistent allergic asthma.2
In the EU, Xolair® is licensed for adults and adolescents (≥6 years of
age) with severe persistent allergic asthma.3
Xolair® is now approved in >90 countries, including the EU.1
1. Sixteenth Periodic Safety Update Report (PSUR) dated 15.02.2013. Novartis data on file.
2. Xolair® US summary of product characteristics 2014.
3. Xolair® EU summary of product characteristics 2014.
121. Warnings and precautions 1
128
Allergic reactions:
• Anaphylactic reactions and other allergic reactions: Frequency rare. Medication for
the treatment of anaphylactic reactions should be available immediately.
• Patients should be informed that such reactions are possible and prompt medical
attention should be sought if allergic reactions occur.
Serum sickness and serum sickness-like reactions: Frequency rare.
Antihistamines and corticosteroids may be useful for preventing or treating
this disorder, and patients should be advised to report any suspected
symptom.
Parasitic infections:
• Patients with high risk of helminth infection show a slight increase in infection rate.
• If patients do not respond to recommended anti-helminth treatment, discontinuation of
Xolair® should be considered
Xolair® Basic Prescribing information
122. 129
Patients should be observed following administration of
Xolair® 300mg CSU:
• In more than 700 Omalizumab-treated patients enrolled in the Phase
III trials, there were no cases of Omalizumab-related
anaphylaxis1-4
Asthma1
• In patients with severe allergic asthma, anaphylaxis was rare
(≥1/10,000 to <1/1,000) in previous clinical trials. Onset was usually
within 2 hours of the first or subsequent injections, but may occur
later.
Patients should be informed that such reactions are
possible.1
1. Xolair basic prescribing information
2. Maurer M, et al. N Engl J Med 2013;368:924–35.
3. Kaplan A, et al. J Allergy Clin Immunol 2013;132:101–9
4. Saini SS, et al. Ann Allergy Asthma Immunol 2013;111 (Suppl. 5):A18.
Warnings and precautions 1
123. Omalizumab has a simple dosing schedule1
130
1. Xolair Basic Prescribing Information
2. Zuberbier T, et al. Allergy 2014 (in press).
The recommended dose is 300 mg(2x 150 mg) every
four weeks through subcutaneous administration.
– Clinical trial experience of long-term treatment beyond
6 months in this indication is limited.
– Prescribers are advised to periodically reassess the need for
continued therapy.
Recently updated international guidelines recommend
Omalizumab for patients inadequately controlled with
H1-antihistamines.2
124. With Omalizumab 300mg:
131
1
2
No need to determine baseline IgE levels.1
No need to calculate the dose based on patient’s
body weight. 1
1. Xolair Basic Prescribing Information
Xolair® provides improvement in itch severity independent of
patient’s weight or IgE levels1
There was no correlation between patients’ baseline IgE
levels/weight and response to Xolair®