1. Pruritus in Atopic Dermatitis
Martín Bozzola, MD
Pediatric Allergy and Immunology
Dept. of Pediatrics
British Hospital – Buenos Aires

2. Disclosure
No conflict of interest for this conference

3. Bieber, T. Atopic dermatitis. Global Atlas of Allergy. EAACI 2014
We have been listening about the immunological and pathophysiology mechanims in AD.
I’d like to highlight a very important concept. Genetics is a neccesary condition, but it is not sufficient to cause any allergic disease. The environment trigger the genetical predisposition to provoke the atopic dermatitis or any allergic disease. In other words, genetics and environment interact between them to generate an allergic disease
Bieber, T. Atopic dermatitis. Global Atlas of Allergy. EAACI 2014

4. AD – Diagnostic criteria
Chronic relapsing inflammatory skin disease
Xerosis – Epidermal barrier dysfunction
IgE reactivity
Increased prevalence
15%-20% in children
1-10% in adults
The diagnostic criteria are known from many years ago. It is a chronic relapsing inflammatory skin disease, with xerosis, and a dysfunction of the epidermal barrier. It could be an IgE reactivitiy, and its prevalence have been increasing in the last 30 years. Nowadays, the prevalence rise 15-20% in children, and 1-10% in adults

5. Cardinal Symptom
PRURITUS
But the cardinal symtom in AD is pruritus

6. Pruritus - Definition
Itch (or pruritus) has been defined as an unpleasant sensation that provokes the desire to scratch.
And the definition of pruritus is: “pruritus (or itch) has been defined as an unpleasent sensation that provokes the desire to scratch. This is a simple definition that hides many aspects that we are going to talk in the next minutes

7. Modify of AAAAI Mechanical Trauma
Nerve Elongation Factors
Sweat
Enviromental factors
Irregular habits
Mechanical Trauma
Production of proinflammatory cytokines and chemoquines
Leukocyte recruitment
Leukocyte activation
Atopic skin inflammation
Pruritus
IL-31
Histamine
Proteases
Neuropeptides
Stress
IL-31
IFN-g, IL-12, IgE, IL-4, IL-13, TSLP
IL-1, IL-18, TNF-a, GM-CSF, TSLP, CCL17, CCL22, CCL27, CCL1, CCL18, CCL26, IL-16
TH-1
This is the cycle of AD. Many years ago it began with the production of proinflamatory mediators like cytokines and chemokines. The expression of these mediators induce the leukocyte recruitment to the site of inflammation. At this point the leukocytes became in an activated and express another profile of mediators that increase the recruitment of inflammatory cells. The TH2 cells induce a suppression of anti-microbial peptides that induce the bacterial colonization of the skin and the amplification of leukocyte recruitment. Il-31 appears close to another cytokynes that cause the atopic skin inflamation, and then the releasing of histamine, proteases, neuropeptides induce pruritus.
But today the concept is different. The process of the cycle begin with pruritus. Itch is the key of the whole cycle. Nowadays, we should consider that AD is an inflammatory skin disease caused by pruritus. Itch is the first symptom in AD, and preceed the inflammation itself. Many environment factors trigger the pruritus in an hyperinnervated skin, causing the inflammation as a reflex
TH-2
Allergens
Bacterial products
Suppression of anti-microbial peptides
Bacterial colonization of the skin
Modify of AAAAI

8. The nerve ending in skin has many receptors for the mediators of inflammation. The signal goes to the spinal cord and bring back a reflex that induced scratch, the mechanical trauma, and the inflammatory process in the skin.

9. Tominaga M. Biol. Pharm. Bull. 36(8) 1241–1247 (2013)
These nerve endings penetrate the epidermal layer in the AD patients. There is an imbalance between the nerve elongation factors and nerve repulsion factors. As we can see in the upper picture, the nerves are in direct contact with the skin surface. This hyperinnervation could be the cause of the hypersensitivity in these patients
Tominaga M. Biol. Pharm. Bull. 36(8) 1241–1247 (2013)

10. Itch increases at night
From evening to night
Itch increases at night Tº
Sweat contains components that help on honeostasis skin. On the other hand we known that sweat is an aggraviating factor in AD. There are three mechanisms that could explain this. 1) the alterated components of sweat in allergic patients, 2) an abnormal perspiration and 3) leaving the excess of sweat without rising out could be a csuse of worsening of AD.
The other point to stop is the increase of deep boby temperature. In patients with AD the temperature increase from evening to night and the icth follow this pattern.
The strategies in treatment should be into account those characteristics in order to give the best comfort to patient.
Leaving excess without rising out
Alterated components
Abnormal perspiration
Modify from Allergology International  , 8-13DOI: ( /j.alit )
Copyright © 2016 Japanese Society of Allergology

11. Measuring the itch Not easy Decrease the Quality of Life
QoL questionnaires are not adecuated in every circumstance
Scratch monitors in wirsts do not correlate the subjective complaints with the objective measures
Decrease the Quality of Life
Could I measure the itch?
It is not easy, because que QoL questionnaires are not adecuated to measure a subjective symptom
And the scratch monitors in wirsts do not correlate the complaints with de objective measures.
But all we known that pruritus decrease the QoL
Yarbrough, KB et al. Dermatol Ther 2013;26:

12. Effective Treatment in AD
Skin hydratation
Identification and elimination of exacerbating factors
Pharmacological therapy
Ameliorate subjective symptoms
Pruritus
Insomnia
An effective treatment of AD is based in four pillars
Sher, LG et al. Acta Derm Venereol 2012;92:
Yarbrough, KB et al. Dermatol Ther 2013;26:

13. Pharmacological treatment - Meta analysis
Group of drugs
Effect
95% Ci P
Pruritus decrease
Calcineurin inhibitors (topical)
0.64
<0.001
36%
Corticosteroids (topical)
0.66
34%
Antihistamines (topical)
0.73
27%
Immunosuppressants
0.88
=0.037
12%
Antihistamines (oral)
0.71
=0.058 NS
Placebo
0.55
24%
The pharmacological treatment has been study by many meta-analysis. At the top of the chart are the calcineurin inhibitors with a pruritus decrease of 36%
Topical corticosteroids could decrease the itch by 34%, but not all the corticosteroids have the same effect over pruritus.
The oral antihistamines are not useful in the treatment of pruritus in AD. So, we should to consider that is not a good option in the treatment of AD patients.
Since 1964 we known that placebo could release the itch. The result of a recent meta-analysis indicate that the placebo can reduce pruritus in a 24% in all skin disease with itch
Sher, LG et al. Acta Derm Venereol 2012;92:
van Laarhoven, AIM et al. Journal of Investigative Dermatology 2015;135:1234–1243

14. Pharmacological Treatment Other immunosuppressors
Cyclosporine
Azathioprine
Methotrexate
Mycofenalate
Systemic Corticosteroids
Other drugs are demonstrated that could decrease the itch. Cicloporine can reduce the pruritus by 70%, but we should consider the adverse effects of this drugs.
So, the indication is reserved to special situations.
New drugs are actually in process of development. Anti IL-31, Anti-alfa IL-4 receptor, and phosphodiesterase-4 inhibitor. The last one has been approved recently, but it is not available in our country and we have not experience with it.

15. Key messages about Pruritus in AD
Is the cardinal symptom in AD
Is the first step in the inflammation cycle of AD
Epidermal hyperinnervation could be responsible for itch sensitization
Many inflammatory mediators worse pruritus (histaminergic and no- histaminergic)
Avoid pruritus could be the first step in the treatment of AD
Many pharmacological agents improve the pruritus, including placebo
The key messages about pruritus could be summurize in this way,
It is the cardinal symptom in AD
Actually is consider as first step in the inflammation cycle of AD
The epidermal hyperinnervation could be responsible for itch sensitization
Many inflammatory mediators worse pruritus
Avoid and prevent pruritus could be the first step in the treatment of AD
6) Many pharmacological agents improve the pruritus, including placebo