Atopic Dermatitis Position Paper SLaai

ATOPIC DERMATITIS
Position Paper

• Revista Alergia México
2014; 61: 178-211
• Jorge Sánchez, Bruno Páez,
A Macías, C Olmos, A de
Falco
• http://www.revistasmedic
asmexicanas.com.mx/niet
o/Alergia/2014/jul-
sep/pisition.paper_atopic.
pdf

Atopic dermatitis (AD)
• Atopic dermatitis affects a large part of the
population, particularly children under 5 years.
• It usually precedes the development of other allergic
diseases such as:
– Food allergy
– Asthma,
– Rhinitis and/or conjunctivitis
 It is considered an important risk factor for these diseases.

Evaluation and management of AD
• Should be comprehensive and must include all
participants in the process of health care
– Patients
– Families
– Health care system

• The environmental characteristics of
the tropics and subtropics make it
necessary to create a guideline
addressed to the particularities of
atopic dermatitis in Latin America.

Methodology I
• The committee of atopic dermatitis of the Latin American
Society of Allergy Asthma and Immunology (SLAAI) developed
this guideline.
• The committee organized a table of contents that was divided
into sections, reviewed by at least two committee members.
• The points regarding the diagnosis and management were
defined by vote using the Delphi method.
• This guideline had a process of external validation to assess
the clarity of the concepts and their applicability.

Methodology II
• Each management section concludes with a summary of the
topic, which includes the strength of the recommendation
and a statement of the group based on current evidence in
Latin America.
• To facilitate understanding by health care staff and patients,
recommendations on the diagnosis and treatment were
divided into “strong”, “moderate” or “weak” according to the
GRADE system (Grading of Recommendations Assessment,
Development and Evaluation).

Strength of recommendation GRADE

Definitions I
• We use the nomenclature proposed by the World
• Allergy Organization (WAO) in 2004.
• According to the recommendation of the WAO, the
general term for a local inflammation of the skin should
be “dermatitis”.
• While proposing the term “eczema” to replace the term
previously used as “syndrome eczema/dermatitis”.
Johansson SG et al. J Allergy Clin. Immunol. 2004; 113:832-836

Definitions II
• They also recommend limiting the use of the term
“atopic eczema” when a mediation IgE is
demonstrated in the pathophysiology of the disease,
and “nonatopic eczema” when it is discarded.
• While confirmatory immunological studies are done,
they recommend only using the term eczema.

However, in many countries of Latin America
the term “dermatitis” is used as equivalent
to “eczema”, so in this guideline they are
used a common term

Epidemiology – AD
• The most common skin allergic disease.
• Affecting 1% to 20% of population.
• It has an onset in 80% of cases in children under 2
years of age.
• No significant differences between genders in the
first years of life.
• It is most frequent in women (60%) than in men
(40%) after 6 years.

Atopic dermatitis
• Usually tends to remission symptoms before 5 years
in 40% to 80% of patients, and in 60% to 90% at 15
years of age.
• This disease has been recognized as an important
risk factor for the development of other allergic
diseases such as food allergy, rhinitis and asthma.
Barnetson RS, Rogers M. BMJ 2002; 324:1376-1379

Atopic dermatitis
• Kemp et al observed that stress and psychiatric
• problems in patients with moderate to severe
• dermatitis were higher than those in patients with
diabetes mellitus.
Kemp AS Pharmacoeconomics 2003;21:105-113

Prevalence and incidence studies in Latin
America (LA)
• The ISAAC study (International Study of Asthma and
Allergies in Childhood) observed that among children
aged 6-7 years, the presence of “actual eczema”
varied from 0.9% in Jodhpur (India) to 22.5% in Quito
(Ecuador).
• Among children between 13-14 years, the prevalence
ranged from 0.2% in Tibet (China) to 24.6% in
Barranquilla (Colombia).
Odhiambo JA et al J Allergy Clin Immunol 2009;124(6):1251-1258

Causes of increased prevalence of AD in LA
• Multiple causes…
• Latin American factors as high exposure to mites, and
the high genetic heterogeneity.

Pathophisiology I
• Complex and multifactorial disease.
• It is currently known that not only Th2 and IgE-
mediated hypersensitivity are involved.
• Also the Th1 and even an autoimmune response.
• Multiple genes may be involved in its development,
conferring risk or protection between populations.
Several genes from the immune system has been
involved (STAT-6, RANTES, TGF-beta);20-22 Filaggrin
gene is located in the locus 1q21.

Pathophisiology II
• Two main points are present in all phenotypes:
1) An alteration of the integrity of the skin barrier
2) An immune inflammatory process.

Alteration of the skin barrier I
• The skin is a physical barrier that prevents the entry
of multiple agents as organic and inorganic
contaminants.
• Alterations in proteins or cells involved in the barrier
function carry the entry of microorganisms, irritants
and allergens, leading to a neuroimmune-
inflammatory response with the consequent
development of symptoms such as ITCHING.

Alteration of the skin barrier II
• Dermatitis : Substance P
Nerve growth factor (NGF)
Vasoactive intestinal polypeptid (VIP)
Exposure and stimulation of
Malpighian receptors
Accelerated apoptosis of keratinocytes
 colonization of bacteria (S Aureus)

Immunological alterations in AD
• Langerhans cells
• Myeloid dendritic cells
• Inflammatory dendritic epidermal cells
• Favor an inflammatory response and present allergens
to immature T lymphocytes (both CD4 + and CD8 +)
which are activated and become mature T cells specific
for the allergen that generated activation.

Risk factors according ISAAC in Europe
• Family history of atopy
• Personal development of asthma
• Urban environment
• Early sensitization to food and aeroallergens
• High socioeconomic strata
• Few family members

Study FRAAT (Risk factors for asthma and
atopy in the tropics)
• Birth cohort consists of 326 children from the lowest
socioeconomic strata (lower income of $200 per
month) of Cartagena (Colombia), and who have
strong African ancestry.
• None of the children at age of three had developed
atopic dermatitis
• Protective factors:
– Genetic inheritance
– Low sanitary conditions
– Greater exposure to endotoxin
Acevedo N et al. BMC Pulm Med 2012; 12:13

ISAAC in Latin America
• The frequency of dermatitis in Barranquilla is one of
the highest in Latin America.
• One possibility is that in some cities in Latin America,
the onset of dermatitis is later (> 3 years) similar to
that found in some European countries
Dei-Cas I et al. Clin Exp Dermatol 2009;34:299-303

The concept of “atopic march” and the “hygiene
hypothesis” in Latin America
Favoring the development of allergic diseases:
- Rapid urbanization in Latin American countries
- Economic development
- Improvement of water quality
- Health coverage
- Increasing adoption of Western lifestyle with
consequent changes in diet
Number of infections  Th1 Th2

Helminthes infection in LA
• Appears to have an important role in sensitization
and some respiratory allergies.
• Has been demonstrated in some cohorts in Brazil,
Colombia and Ecuador.
Figueiredo CA et al J Allergy Clin Immunol 2013;131:1064-1068
Figueiredo CA et al Clin Immunol 2011; 139:57-64

Diagnosis
• There is not a definitive diagnostic test.
• Based on a set of clinical symptoms and signs:
- Pruritus
- Eczematous lesions with periods of exacerbation
and control. The distribution of eczema can change
with time. In children under 2 years the involvement
of the face and the extensor regions is usually more
common that in the elderly, where the involvement
of the folds becomes more relevant.

Williams criteria are based in original
Hanifin and Rafka criteria
1) Pruritus
2) Distribution and typical morphology (facial
involvement and extension areas in children, and in
the areas of flexion in adults)
3) Chronic or recurrent symptoms and
4) Personal or family history of asthma, rhinitis and/or
dermatitis
• For diagnosis, it is essential the presence of pruritus
and at least two of the other criteria.

Diagnosis
Hanifin and Rafka proposed to support the diagnosis
in the presence of at least three “minor criteria”:
• Xerosis
• Pityriasis alba
• Cheilitis
• Follicular hyperkeratosis
• White dermatographism
• Ichthyosis
• High total IgE
• Conjunctivitis
• Tendency to skin infections
• Facial erythema
• Dennie Morgan bifold
• Sensitization to food
• Contact dermatitis
• Seborrheic dermatitis

Severity
• Among the most frequently used are:
– SCORAD (Severity Scoring of Atopic Dermatitis)
– EASI (Eczema Area and Severity Index
– POEM (Patient-Oriented Eczema Measure).

SCORAD
• The scale goes from 0 to 104 points, and ranks as
“mild”, “moderate”, and “severe”
• Scale: Mild < 15 puntos
Moderate 16-40
Severe > 40

• Dermatitis classification divides patients in:
Intrinsic Extrinsic
Normal IgE
Phenotypes
High levels of total IgE (generally
accepted > 200 kU/L), or a
demonstrated sensitization to
aeroallergens or food allergens.

Population characteristics in Latin America
• A big part of the NON-ALLERGIC population in Latin
American cities seem to have total IgE levels above
200 kU/L, so this cutoff would not serve as a criterion
for classifying dermatitis as intrinsic or extrinsic.
• This higher concentration of total IgE in the tropical
population seems to be due to the high frequency of
helminthes infections.

Phenotypes according to immunological
changes.
• Parallel to the better understanding of the
pathophysiology of AD, a more accurate classification
has been developed to allow, through the use of
multiple biomarkers, a greater certainty in the
prediction of the evolution of dermatitis, and also to
define a more effective treatment for each patient.

Phenotype I
Th1 Response  Expression of cytokines:
IL-1
IL-6
TNF-beta
Dendritic cells with few exilon
receptors in the membrane
Predominates in patients classified with intrinsic
dermatitis and in patients with extrinsic dermatitis during
inter-critical periods

Phenotype II
• Predominance of Th2 response
•  Airborne and food allergen sensitization
This process: - associated with asthma
- lower remission rate
- greater severity
- associated with defects in filaggrin gene
May be suspected: palmar hiperlineality
eczema herpeticum

Phenotype III
• Presence of an autoimmune response mediated by
IgE.
• It is suggested that this may be due to the homology
between human proteins and allergens from other
species
• Represent the most serious phase in a patient with
dermatitis as a result of the persistent exposure to
intrinsic allergens

• These three processes represent different “endo-
phenotypes” of the dermatitis
• Their identification would predict the likelihood of
remission and the treatment required (whether or
not avoidance of allergenic sources, treatment with
topical or systemic immunomodulators, etc.).

These processes may occur separately,
can also be different stages of a single process
Process 1 Th1 response
Process 2 Th2 response
Process 3 Sensitization to auto-
allergens

Classification according to age of presentation
80% of the cases begin before
age 2
• 43.2% had a complete remission
between 2 and 7 years
• 18.7% persisted with symptoms
• 38.3% had a intermittent pattern
Illi S et al, JACI,2004
Factors related to persistence
early onset (before the 1er year of life)
AD severity
lower respiratory symptoms

Classification according to age of presentation
20% of the cases begin >14 years
Only few studies about adult AD
45% of the adult AD begin before age
6
18% of the adult AD begin after 20
years
Higher sensitization and total IgE level
Higher persistence
Garmhausen et al. Allergy, 2013

Laboratory test
Total IgE
•Higher level in AD patients
•Biomarker associated with
• Persistence (Kawamoto N et al; Lui FT et al)
• Severity (Antunez C et al, Laske N et al)
• Rate of sensitization (Laske N et al)
• Topical and systemic treatment response
•It may persist elevated even with a AD improvement
•Other causes of elevated total IgE should be considered

Laboratory test
Total IgE
Indication:
•Evaluation and monitoring of the patients with extrinsic and intrinsic AD
Committee recommendation:
•Weak
•May be used in children < 6 months with severe symptoms
and children >5 years with persistent symptoms
Particular considerations in Latin America:
•It is necessary to know normal total IgE
in different regions of Latin America before performing this test routinely

Laboratory test
Allergen sensitization
•AD patients are sensitized to a large number of sources than patients
with asthma or rhinitis
(Johnke H, Pediatr Allergy Immunol 2006)
•Sensitization to food occurs in the first years of life and then it is replaced
by sensitization to aeroallergens (Acevedo N, BMC Pulm Med 2012)
In tropical zones, mites sensitization could start early in life
(before the first year)
(Acevedo N, BMC Pulm Med 2012, López N, Eur resp J, 2002)
•Specific IgE (mites and cat dander) in Europa:
has been related with AD severity
(Schöfer T, JACI 1999)
•High specific IgE in AD patients has been associated with
an increased risk of food allergic reactions
(Hill DJ, Pediatr Allergy Immunol 2008; Wahn U Pediatr Allergy Immunol 2008)

Laboratory test
•Colombian study:
Correlation between the pattern of sensitization to aeroallergens
and the development of AD and asthma
•Other allergen sources must be consered in Latin America: corn,
tomato and pork
A right interpretation of the test result is neccessary
in order to increased the patient adherence to therapy
and the quality of life
Sánchez J, Revista Alergia México 2012
Sánchez J, Allergol Immunopathol 2013

Laboratory test
•Microbial proteins: 50-80% sensitization to the AD patients
It has been correlated with the AD severety
•A greater sensitization to Malazzasia fufur has been observed
in the AD patients; a clear correlation with severity is not demostrated
•Response against autoallergens (Hom s) appears to be specific
of AD severe which could be important in predicting the prognosis

Laboratory test
Indication:
•Diagnosis and monitoring of AD patients
•Identification of environmental sources exacerbating symptoms
Committee recommendation:
•Aeroallergens: strong. All patients with dermatitis
•Food allergens: strong. Only when a clinical suspicion or AD severe
or persistente.
The test battery should be consistent with the geographical area
Particular considerations in Latin America:
•There are many studies about aeroallergens but only a few
about food allergens in specific regions

Laboratory test
Patch tests with food and/or aeroallergens
• Food
• Tests have been carried out with milk, egg, soy, wheat…
•Drawback.
•Wide range in predictive values and lack of standardization
•Adventages
•Easy to perform
•It can reduce the requeriment for provocation tests and avoid
unnecessary restriction diets
•Aeroallergens
•The main experience with mites patch tests
•Lack of standardizations so the routinely use is not recommended
•
(Isolauri E, JACI 1996; Niggemann B, Allergy 2000; Vanto T, Allergy 1999;
Niggemann B, JACI 1999; Majamaa H, Allergy 1999; Darsow U, Allergy 2004

Laboratory test
Patch tests with food and/or aeroallergens
Indication:
•Evaluation and monitoring of AD patients
•When delayed reactions with food or aerollergens are
suspected
Committee recommendation :
•Food: moderate.
Useful in patients with negative IgE response or late-onset
symptoms
•Aeroallergens: weak.
Few controled studies. Specific batteries of allergens should be used
Particular considerations in Latin America :
Only a few studies but in favor of its use
Standardization of the technique is necessary

Laboratory test
Patch with standard battery and other types of patch
15-30% of AD patients suffer from contact dermatitis
This test is very useful in patients with strong suspition of exacerbation by contac
allergens or persistent symptoms without response to treatment
Considered a false positive result in AD
In some occasions a photo-pach test must be performed
It is important to know that if non standarizated contacts are used,
pacth tests in 10 healthy controls must be performed
White JM, Clin Exp Allergy 2012; Spiewak R, Curr Opin Allergy Immunol 2012

Laboratory test
Patch with standard battery and other types of patch
Indication:
•Patients with suspicion of AD
•Patients with severe and persistent AD refractory to medical treatment
•Standard battery: strong
•Other types of patch: moderate
Useful as diagnosis support in AD
Rodrigues DF, An Bras Dermatol 2012; Blancas-Espinosa R, Contact Dermatitis
2006; Rivas A, Revista Asociación Colombiana Dermatologia 2011)

Laboratory test
Provocation and food elimination diets
The provocation test with food is considered the gold standard
for identifying if a suspected food is the cause of the patient´s symptoms
Due to the potential risk of this test, it is carried out when skin prick test
and laboratory test cannot clarify the diagnosis
In many cases are carried out elimination diets for 4-6 weeks
to assess the AD evolution; if doubt persists then a challenge test
could be performed

Laboratory test
Provocation and food elimination diets
Indication:
When skin prick test and laboratory test
cannot clarify the diagnosis
•Strong
•After elimination diet, if doubt persists, a provocation must be
performed
•There are few studies about this subject.
•It is necessary to establish protocols with native foods
Madrigal BI, Rev Aler Mex 1996)

Laboratory test
Complementary studies
-CSC, electrolytes determination,
liver function or kidney function…. :
•They are not inicated as routined exams
•They could be indicated as part of the follow up when
immunosupressants or sistemic steroids are been administrated
-Skin biopsia: useful for differencial diagnosis

Active management
FIRST LINE MANAGEMENT
Skin care and hydratation
Dry skin is one of the main signs of AD due to
-filaggrin defects
-lack of intercell lipids and other
stratum corneum alterations
In consequence, a lack of continuity of SKIN
BARRIER occurs in AD
Briot A, J Exp Med 2009

Active management
Bathing:
• Removes debris of the skin that could stimulate the bacterial
growth
• It is recommended very short bath (about 5 minutes) with
slightly cold water to reduce xerosis and mechanical irritation
• Add sodium hypochlorite into bath water in patients with
history of skin infection or risk of skin infection) aprox. 1 or 2
drops/liter of water prevent balterial growth
• Using bath salts or oils in final two minutes of the bath could
improve skin hydratation and skin cleansing
• Avoid soaps and use neutral cleansing
Huang JT, Pediatrics 2009

Active management
• If a chielitis exits, moisturizing lipsticks are recommended
• Keep nails short to prevent stcraching during sleep
• Baggy clothing made of cotton is the best in order to avoid irritation and heat
There are a few controlled studies in relation to
adjuvant treatment (moisturizing, general
recommendatios, cleansing products …)
Méndez-Cabeza J. MEDIFAM 2003

Active management
Moisturizers appear to reduce
• Severity of AD exacerbations (Breternitz M, Skin Pharmacol Physiol 2008)
• Bacterial infections (Verallo-Rovell VM, Dermatitis 2008)
• Steroid requirement (Grimalt R, Dermatology 2007;
Szczepanowska J Pediatr Allergy Immunol 2008)
It is recommended to apply twice a day; one of them after bathing or shower
(Chiang C, Pediatr Dermatol 2009)
Choosing the best depend on
• AD extension
• AD severity
• patient´s tolerance
(Varothai S, Asian Pac j Allergy Immunol 2013

Active management
Moisturizers
• It’s considered a pillar in the treatment of AD
• Another important factor in a good adherence is the
cost of the product
• Explain to the patient how to use moisturizers and apply
the right amount
Rule of the fingers could be used: The amount of cream
that covers a thumb must be cover the palm of hand),

Active management
Moisturizers
• Vaseline is considered a AD moisturizers with a excellent
cost/efficacy relation
•Disadventages: it has an oily consistency and it produce a sense
of heat and sweat retention
• Urea products impprove the skin renewal but tend to be less
tolerated than others, specially in areas with open lesions
• Urea is recommended on skin with lichenification.
Some creams contain natural ingredients (nuts, oats…) with a
small risk of sensitization
Lodén M, Acta Derm Venereol 2002
Lack G, N Engl J Med 2003

Active management
Moisturizers
Indication
• In all AD patients
• The frecuency and the amount depend on the severity
Committe recomendation
• Strong
• Choose the product that facilitate the better adherence
•At the moment, these products are not covered by the health systems in
the most countries.
•Factors such as cost/benefit must be considered to ensure a good
adherence and a better response

"For anti-inflammatory
treatment, topical steroids
remain the cornerstone in the
management of dermatitis"
Topical steroids
First line management

Topical steroids
•Reduce the risk of infection by S. aureus
•Lower frequency of systemic side effects
•Few controlled studies supporting their
uses or how to use them
•Different schemes have been proposed in
the use of steroids
Active management

• Schemes proposed in the use
of steroids:
–Potency and regions
Active management
Topical steroids

•Schemes proposed in the use of steroids:
–Minimum possible time
–Switch to medium or low power steroids
according to the control of the patient.
–Prolonged periods in wide body extensions
(even mild steroids) can have similar risk of
adverse effects than oral or intravenous
steroids.
–Intermittent treatment appears to reduce this
risk even with high potency steroids
Active management
Topical steroids

•Schemes proposed in the use of steroids:
–High potency steroids:
•Should be used only in patients with
moderate to severe AD
•Should be avoided in the facial, folds
and perennial regions
•Should be used with caution in
children under two years
?
Active management
Topical steroids

• Schemes proposed in the use of steroids:
–Steroid use with moisturizer seems to
improve the power of the steroid and
increase the time of its effect on the
skin
+
Topical steroids
Active management

•Recommendation of the Committee.
Strong.
•Particular considerations in Latin America.
–Latin America has a wide variety of
steroids
•It must be taken into account the
characteristics of the tropics and
subtropics regions when choosing the
consistency (cream, ointment, etc.) to
improve patient adherence.
Active management
Topical steroids

•In practice, they can be used for
the same indications as a steroid
of medium (tacrolimus 1%) or
low power (tacrolimus 0.03%,
pimecrolimus 1%)
• Advantages:
•Lower risk of adverse effects
•Not cause skin atrophy in
continuous treatment
Calcineurin inhibtors
Active management

•Recommendation of the
Committee. Strong
•Particular considerations in Latin
America.
• Currently in most Latin
American countries both
tacrolimus and
pimecrolimus are available.
Active management
Calcineurin inhibtors

“In the last two decades several controlled
studies showing that a significant percentage
of patients with atopic dermatitis can benefit
from this therapy"
Allergen-specific immunotherapy

• ACTIONS
• Significant reduction in
symptoms compared to
placebo (by SCORAD)
• Significant increase in IgG4
Active management

• Indication. Patients with persistent moderate or severe
atopic dermatitis who have a clear relationship of
exacerbation with aeroallergens.
• Recommendation of the Committee. Moderate.
• Particular considerations in Latin America.
• Studies support the efficacy and safety of using the
specific allergen immunotherapy with
Dermatophagoides farinae and Dermatophagoides
pteronyssinus
• Studies using other common allergen sources in the
region, as Blomia tropicalis, Dermatophagoides siboney
and some pollen grains are needed.
Active management

“Since the skin of patients with dermatitis is very
sensitive, many agents can act as irritants
increasing the inflammatory process and therefore
should be avoided"
Enviromental and dietary control

Environmental control
• Irritants substances:
• Soap, detergent, some creams, polluted air
• Control the temperature and humidity is
necessary
• Allergenic sources witch patients are
sensitized must be avoided
• Prophylactic restrictions without clinical
relevance are not recommended
• Removal of pets: unless there is clear clinical
relationship and sensitization is
demonstrated

•Dietary control
• Top Ten allergenic foods
• Restricted diet should be very careful
• High prevalence of irrelevant
sensitizations
• Nutritional problems

“Have been used for many years…
but controlled studies show
minimal or no effect"
Second line management
Antihistamines

•NO EFFECT?
• Other mechanisms? IL-33?
• First-generation:
• Sedative effect
• Risk of side effects: drowsiness; low
concentration
• Second-generation:
• Loratadine, cetirizine, fexofenadine:
some impact on pruritus
Antihistamines
Active management
SECOND LINE MANAGEMENT

Active management
Antihistamines

“Because the high risk of adverse effects
(cataracts, osteoporosis, height), is not
recommended for prolonged use”
Systemic steroids

• High relapse rate after
suspension, compared with
other immunosuppressants,
like cyclosporine
• Adjust the dose according the
weight
• Reduce the dose as soon as
possible
• No standard way to do this
Systemic steroids
Active management

Active management
Systemic steroids

“Mild to moderate AD had a significant
improvement over the summer, with
relapses in the other seasons”
Sun exposure and phototherapy

Sun exposure:
• 15 a 20 minutes (7:00-8:00 am; 3:00 -
4:00 pm) – beneficial effect
• High temperature and humidity in tropics
can exacerbate pruritus

Phototherapy:
• Controlled environments - 40 to 50% of
substancial improvements
• Mechanisms (not clear):
• Antimicrobial effect
• Inhibiting the Langehans cells activity
• Production of Vitamin D
• Wavelengths types:
• UVA1, UVB, UVB broadband
• UVB can use in children
• Side effects:
• Burns, hyper pigmentation, fatigue,
nausea, headache

“This therapy is clinically effective,
but with high relapse rate”
Cyclosporine A

Cyclosporine A:
• Mechanisms:
• Potent inhibitors of T lymphocytes immune
responses
• Clinical response is observed after 2 weeks,
reaching great effect at 2 to 3 months
• Risks:
• Nephrotoxicity and hypertension
• Side effects:
• Nausea, paresthesias, abdominal pain
Active management

Active management
Cyclosporine A

“Although there are numerous report
showing its positive effect in patients
with AD, there are few controlled studies”
Third line management
Mycophenolate mofetil

Mycophenolate mofetil:
• Mechanisms:
• Inhibitors of purine synthesis;
• Stop the division of diverse cell lines,
including lymphocytes
• Side effects:
• Nausea, vomiting, herpes and retinitis
Active management
THIRD LINE MANAGEMENT

Active management
Mycophenolate mofetil:

“Several controlled studies supported it,
use especially in severe cases in
population over 6 years of age”
Azathioprine

Azathioprine:
• Mechanisms:
• Not know
• High incidence of adverse effects
• Nausea, vomiting and abdominal pain
• Clinical response: 4 to 8 weeks
Active management

Active management
Azathioprine:

“There are few controlled studies
for AD treatment. Therefore the
appropriate dose and frequency
of adverses effects is limited”
Methrotrexate

Methrotrexate:
• Mechanisms:
• Inhibitor of dihydrofolatereductase, it
prevents the activity of thymidilate
synthetase necessary for the
incorporation of nucleotide dTMP into
DNA
• Efficacy similar to Azathioprine
• 10 to 25 mg/week
Active management

Active management
Methrotrexate:

Probiotics and prebiotics
Pro Contra
• Kalliomäki et al: Lactobacillus
rhamnosus
• Dotterud et al: Lactobacillus sp
• Osborn, Cochrane Review 2007:
reduction in eczema, but not enough
to recommend
• Williams et al
• Bath-Hextal, Cochrane Review 2012
• Osborn, Cochrane Review 2013: more
studies are needed
Kalliomäki, Lancet 2003. Osborn, Cochrane Database Syst Rev. 2007
Dotterud, Br J Dermatol 2010. Williams, Clin Exp Dermatol 2010
Bath-Hextal, Cochrane Database Syst Rev 2012, Osborn, Cochrane Database Syst Rev. 2013
Active management
FOURTH LINE MANAGEMENT

Omalizumab
• Conflicting evidence: studies with promising results and some
without clinical effect.
• Some reports suggest good results even with high levels of IgE
Caruso, Allergy 2010. Park, Ann Dermatol 2010. Lane, J Am Acad Dermatol 2006.
Belloni, JACI 2007. Sheinkopf, Allergy Asthma Proc 2008.
Heil, J Dtsch Dermatol Ges 2010. Iyengar, Int Arch Allergy Immunol 2013
Active management

Interferon gamma
• One study compared high dose, low dose and placebo, with good
results in the 2 groups treated with interferon gamma.
• Adverse effects: transient fever, myalgias, respiratory distress, elevated
transaminases and lipid profile.
Jang, J Am Acad Dermatol 2004.
Active management

Others therapies:
• Contradictory results: rituximab, efalizumab, aterizumab, alafacept,
mepolizumb and etanercept; can not be recommended to all
patients.
• Satisfactory results but not standardized: intravenous
immunoglobulin, autologous serum, some herbal products; can not
be recommend.
Simon, JACI 2008. Sedivá, JACI 2008. Ponte, J Am Acad Dermatol 2010.
Ibler, J Eur Acad Dermatol Venereol 2010. Bremmer, J Am Acad Dermatol 2009.
Jee, Allergy Asthma Immunol Res 2011. Pittler, Br J Dermatol 2003.
DiNicola, Clin Rev Allergy Immunol 2013. Zhang, Cochrane Database Syst Rev 2005.
Active management

Hospital management
• Should be avoided because high risk of complications.
• Should be consider when:
– Involvement >50% of skin surface with moist lesions or erythrodermia
– Sepsis or severe cutaneus infection, disseminated or extensive
– Involvement of other systems: renal, respiratory, etc.
– Limitation to perform daily activities
– Failure to follow established treatment
– Rapid deterioration
Buhles, J Dtsch Dermatol Ges 2011. Holling, J Eval Clin Pract 2010
Active management

Primary prevention:
• Vitamin D supplementation during pregnancy has contradictory results
• Some foods (fruits, vegetables, unsaturated fatty acids) may have a
preventive effect
• Polyunsaturated fatty acid supplementation during pregnancy appears to
reduce the risk, but further studies are needed
• In a meta-analysis, the presence of dogs in the house reduced the risk by
25%
Reinholz, clin Exp Allergy 2012. Bäck, Acta Derm Venereol 2009
Hyppönen, Ann N Y Acad Sci 2004. Nwaru, Pediatr Allergy Immunol 2010
Foolad, JAMA Dermatol 2013. Palmer, BMJ 2012. Pelucchi, JACI 2013

Secondary prevention
• The goal is to prevent common complications such as exacerbations and
bacterial superinfection.
• Topical antibiotics one week per month, although they appear to prevent
infection, no statistically significant changes and exists the risk of antimicrobial
resistance.
Boguniewicz, JACI 2010. Bath-Hextall, Br J Dermatol 2010

Pregnancy:
• During second half of pregnancy, 66% of patients present exacerbation
• Treatment is almost like non-pregnancy, but try to use small doses of topical
steroids (Category C)
• Only in extreme cases: calcineurin inhibitors, oral steroids, azathioprine and
cyclosporine
• Avoid: methotrexate, mycophenolate mofetil, psolarens and PUVA therapy
• First-generation antihistamines (Category B): chlorpheniramine, cyproheptadine
and diphenhydramine
• Second-generation antihistamines: loratadine seems to be a safe option, there few
studies
Babalola, Dermatol Ther 2013. Cho, Ann Dermatol 2010
Koutroulis, Obstet Gynecol Surv 2011. Kar, J Pharmacol Pharmacother 2012
Special situations

Breastfeeding:
• Elimination diet in the mother for food to which the child is allergic
• Breastfeeding seems to have a beneficial effect
• If the mother takes immunosuppressive drugs for dermatitis:
– Steroids can pass into breast milk
– Ideally cyclosporine should be discontinued
– Second-generation antihistamines approved after the sixth month of life
Orru, Int J Immunopathol Pharmacol 2013. Paveglio, Clin Exp Allergy 2012. Verhasselt, Nat Med 2008
Special situations

Adult dermatitis:
• Onset after 14 years: 5-15%
• Tendency to have more non-allergic comorbidities
• It may be necessary skin biopsy and / or patch tests
Garmhausen, Allergy 2013. De Bruin Weller, Clin Exp Allergy 2013
Special situations

Interdisciplinary management
Allergist
Dermatologist
Ophtalmologist
Pulmonologist
Pediatrician
Dentistry
Psychiatrist /
Psychologist
Otolaryngologist
Silverberg, Pediatr Allergy Immunol 2013. Yaghmaie, JACI 2013. Kemp, Pharmacoeconomics 2003

Table 2. Immunosuppressive drugs

Committee of Atopic Dermatitis
Dra. Ana María Agar, Chile
Dra. Milagros Lázaro, España
Dr. Bruno Paes Barreto, Brasil
Dra. Alejandra Macías Weinmann, México

Atopic Dermatitis Position Paper SLaai

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