The PETITE study changed the approach to atopic dermatitis
"If I don't sleep, nobody sleeps"
This is how the famous lecturer from Münster (Germany), Prof. Thomas Luger, vividly began his presentation on one of the most common inflammatory skin diseases - atopic dermatitis, characterized by skin rashes (itchy erythematous patches and plaques). Indeed, atopic dermatitis is a disease that affects daily life. The impact of the disease on quality of life is not straightforward and depends on the severity of the disease. Childhood atopic dermatitis often becomes a burden for the family, requiring patience and long-term care.
Working extensively in the field of atopic dermatitis, neurodermatitis, and neurodermatology, Prof. T. Luger examined the causes of the disease and its relationship with other forms of allergies: "Atopic dermatitis can be the beginning of other allergic diseases such as asthma and allergic rhinitis, known as the atopic march. By properly treating atopic dermatitis, we can help prevent other mentioned allergic diseases."
The pathogenesis of atopic dermatitis is not fully understood, but genetic predisposition, environment, and skin microbiota play a significant role.
"There are a lot of bacteria on the skin - about 2 kg. Microorganisms are very diverse, they control each other's existence, regulate the development of the immune system. It has been proven that the severity of atopic dermatitis depends on the relationship of certain bacteria living on the skin. I believe that in the future, skin microbiota will become an interesting subject of research," noted the guest from Germany. "In normal skin, there is infiltration of inflammatory cells. If the disease is more severe, an inflammatory reaction begins, with the production of IL-4 and IL-8. Later, as the disease becomes chronic, IL-7 and various active cells are activated. It is important to start treatment in time. ILC2 are not classical but immature lymphocytes. They also release their mediators. Therefore, to stop a severe disease, it is important to start controlling the inflammatory mechanism precisely at this point - the site of ILC2 production."
How should we treat atopic dermatitis today?
In patients with atopic dermatitis, inflammation develops, skin barrier function is disrupted, both the internal and external skin barriers are compromised. The disease is characterized not only by skin itching, rashes, but also by a recurring course of the disease.
The main goals of atopic dermatitis treatment are to suppress inflammation, itching, and increased release of inflammatory mediators, restore the epidermal barrier function, moisturize the skin, and reduce bacteria on the skin surface. The treatment strategy depends on the severity of the disease.
Thus, the treatment regimen for atopic dermatitis may include:
● emollients (an integral part of basic therapy);
● topical glucocorticosteroids;
● topical calcineurin inhibitors;
● antiseptics (in case of signs of infection);
● phototherapy, using ultraviolet (UVA and UVB) rays for treatment (monotherapy or in combination with medications);
● PUVA photochemotherapy - phototherapy combined with oral or topical psoralen (a substance that increases sensitivity to UV rays);
● in cases of very severe disease - systemic immunosuppressants (e.g., cyclosporine).
Successful disease management also requires symptomatic treatment, avoidance of allergy triggers, and education of the patient and family.
"Treatment should start as soon as possible, when the disease is just beginning, while it is still mild. Even infants are recommended to start treatment early," says Prof. T. Luger.
How do calcineurin inhibitors work?
For many years, the only medications used to treat atopic dermatitis were topical glucocorticosteroids. However, the situation changed 15 years ago when the arsenal of drugs was supplemented by 2 topically acting agents - calcineurin inhibitors (tacrolimus and pimecrolimus). Currently, only pimecrolimus is registered in Lithuania.
Pimecrolimus is a lipophilic derivative of the inflammation-suppressing substance ascomycin macrolactam. It selectively inhibits the synthesis and release of inflammation-promoting cytokines in cells. Pimecrolimus mainly binds to macrophilin-12 and inhibits the calcium-dependent phosphatase
calcineurin. This action blocks the synthesis of inflammatory cytokines in T cells. As known, T cells play a key role in the immunopathogenesis of atopic dermatitis.
The PETITE study changing the treatment of atopic dermatitis
"Calcineurin inhibitors (pimecrolimus) were known before, but their use was limited, believing that they were not as effective as hormones, i.e., glucocorticosteroids. Therefore, a study was decided to be conducted to compare their effectiveness. Researchers also aimed to prove whether the drug is safe for infants, and most importantly, whether infants treated with this drug can be treated for a long time. It was sought to clarify other important aspects, such as whether the use of the drug does not promote the development of lymphoma or whether it is safe enough," - presented the objectives of the PETITE study by Prof. T. Lugeris.
The PETITE study - the largest and longest (5 years) comparative, randomized controlled trial involving 28 countries, 191 treatment centers. In the study, pimecrolimus cream was compared with topical corticosteroids (low-potency hydrocortisone acetate, medium-potency fluticasone propionate).
The study included 2,418 infants aged 3 to 12 months (but over the 5 years of the study, they became older than 2 years), with mild and moderate (rated 2 or 3 points) atopic dermatitis. One group (1,205 infants) was treated with 1% pimecrolimus cream, the other (1,213 infants) - with topical glucocorticosteroids. In both groups, the disease affected more than 5% of the total body surface area. Written consent of parents or guardians was also obtained. Children who, in addition to atopic dermatitis, suffered from other serious immunosuppressive diseases were not included in the study. The study simulated treatment "in real life" because patients in the pimecrolimus group, if necessary or in case of disease exacerbation, could be treated with short courses of topical glucocorticosteroids. Infants and children in the glucocorticosteroid group were monitored for bacterial, fungal, or viral complications.
It was found that when treating atopic dermatitis with 1% pimecrolimus cream, the effectiveness is the same as that of topical glucocorticosteroids. Both groups of drugs showed rapid onset of action. After 3 weeks, more than 60% of patients in both groups noted improvement
in facial skin condition, more than 50% indicated improvement in overall skin condition. At the end of the study, i.e., after 5 years, more than 95% of the subjects had disappeared or almost disappeared the symptoms of atopic dermatitis on the face, more than 85% had disappeared or almost disappeared all symptoms of the disease.
The study demonstrated the clear effectiveness of pimecrolimus: after 3 weeks of treatment with this drug, the total affected surface area of atopic dermatitis decreased to less than 5%.
The study also revealed another important aspect - the use of pimecrolimus reduced the need for glucocorticosteroids. 36% of patients in the pimecrolimus group did not require topical glucocorticosteroids over 5 years, in the pimecrolimus group, glucocorticosteroids were used only for 7 days throughout the treatment course, i.e., 5 years, compared to 178 days in the topical glucocorticosteroid group.
Use of Pimecrolimus: Practical Experience
Prof. T. Lugeris noted that numerous clinical trials have been conducted with pimecrolimus, involving over 55 thousand people (infants, children, adolescents, adults). "Pimecrolimus has been well studied in various age groups. Research shows that it is an effective preparation and can be used for a long time," emphasized the lecturer.
It has already been mentioned that atopic dermatitis is associated with a disturbance in the skin's barrier function, making it easier for allergens to penetrate the skin and cause irritation and inflammation. Atopic skin is characterized by a lack of the protein filaggrin, which increases transepidermal water loss, leading to the formation of microcracks in the epidermis. It is important to know that when using pimecrolimus, filaggrin levels do not decrease. Therefore, this medication, unlike long-term use of glucocorticosteroids, does not cause skin atrophy.
"With parental consent, I treated an infant with pimecrolimus cream. A significant improvement was observed after 2 weeks. Another one of my young patients started treatment with pimecrolimus cream at 7 months old (with parental consent, of course). He is now over 4 years old. This means he was treated for more than 4 years. The treatment of atopic dermatitis is always intermittent, unstable, i.e., as needed. Therefore, 1% pimecrolimus cream is effective, saving on hormone use, and safe to use for a long time. It does not damage the skin barrier, does not enter the systemic circulation. A 10-year-old boy was treated with pimecrolimus cream twice a day. A significant improvement was observed after 2 weeks. After 4 weeks of treatment, pimecrolimus was not detected in the plasma. This means the substance does not enter the systemic circulation, it is not absorbed into the blood," shared the professor based on practical treatment experience.
Safety confirmed by studies
It is known that long-term use of glucocorticosteroids can lead to adverse effects such as skin atrophy, worsening of dermatitis, growth suppression, as well as an increased risk of various respiratory diseases (bronchitis, etc.), otitis, or other infections, etc.
"The PETITE study found that the pimecrolimus group did not show suppression of adrenal function, growth or maturation delay, or other unwanted effects typical of hormones," noted Prof. T. Lugeris. According to the professor, the PETITE study examined the response of B cells, i.e., whether treatment with pimecrolimus does not suppress the response to vaccines.
"It was found that the administration of vaccines to children - hepatitis B, measles, chickenpox, etc. - is not affected by pimecrolimus cream, i.e., it does not block the immune response. CD3 lymphocytes were counted. It was determined that T lymphocytes slightly decreased in the pimecrolimus group, but this is normal. Cytokines were also examined: there was practically no significant difference between the groups (pimecrolimus and glucocorticosteroids). Therefore, the studies confirmed that pimecrolimus is a completely safe drug, having no impact on a child's development, growth, and when used, the normal development of the immune system is maintained. The drug, when used for a long time, does not affect development, maturation, and the immune system," stated the speaker.
A lot of attention was paid to studying the drug's influence on oncological diseases, lymphoma, melanoma. "There is an eczema registry that includes 8 thousand children. They were monitored for 10 years, and only 4 cases of lymphoma were identified. In another safety study, only 2 cases of lymphoma and 8 tumors were found. When evaluating the prevalence of cancerous diseases in percentages, we will see that it is very low: in 2012 - 0.0091%, in 2013 - 0.0038%. Just fractions of a hundredth, thousandth percent. Patients who were treated with pimecrolimus after transplants did not develop any lymphomas. Therefore, there is no proven link between pimecrolimus and the development of skin cancer, lymphoma. Therefore, this topic should not be touched upon further. Pimecrolimus is a safe first-choice drug for treating both small and large children, as well as adults with mild to moderate atopic dermatitis," Prof. T. Lugeris concluded.
New algorithm presented
"I present a new treatment scheme for atopic dermatitis. I hope that pimecrolimus will be available for use and its prescription will be approved for the easy form of treatment in children practically from birth," the speaker hopes. The new algorithm was necessary due to the findings of the PETITE study. It states that pimecrolimus is as effective in treating mild and moderate atopic dermatitis in the short and long term as low or moderate potency topical glucocorticosteroids, but it has advantages because it does not cause the undesirable effects typical of hormones and reduces the need for glucocorticosteroid use."
The new guidelines for the treatment of atopic dermatitis slightly change the assessment of the disease. It is proposed to assess the severity of atopic dermatitis according to the SCORAD system: severe form of the disease - more than 40 points, moderate severity - 15-40 points, mild - less than 15 points.
"The new algorithm for the treatment of atopic dermatitis states that pimecrolimus is the first-choice drug for treating mild or moderate atopic dermatitis. In the case of acute mild and moderate atopic dermatitis, it is recommended to initially use topical glucocorticosteroids 2 times a day, then - topically apply pimecrolimus 2 times a day until the condition improves. In the case of mild persistent atopic dermatitis, the first-choice drug is pimecrolimus 2 times a day. In the case of infected atopic dermatitis, antibiotics or antifungal drugs are prescribed along with topical glucocorticosteroids. In the absence of exacerbation in mild form of the disease, pimecrolimus is prescribed 2 times a day. For maintenance therapy to prevent exacerbations, it is planned to administer pimecrolimus 1 time a day for up to 3 months. It was suggested to administer it up to 1 year, but evidence was lacking for this recommendation. Treating for up to 3 months when symptoms disappear, the skin looks healthy, is necessary because the inflammatory process in the skin still continues."
In summary, I want to emphasize that it is recommended to apply pimecrolimus 2 times a day for the treatment of the disease, and for maintenance therapy - 1 time a day," - the new treatment recommendations, approved in Europe, were presented by Prof. T. Lugeris.
The Professor informed our country's doctors about the conclusions of the European allergists and pediatricians meeting held in January: "The conclusions are based on literature data. It is stated that pimecrolimus and tacrolimus are safe for treating infants from the age of 3 months. It was also decided at the meeting to lift the restrictions on the use of pimecrolimus related to lymphoma, melanoma, as it has been proven that there is no such connection, so this is an indisputable issue."
Lithuanian recommendations for the treatment of atopic dermatitis
According to Professor Brigita Šitkauskienė, Head of the Clinical Immunology and Allergology Sector at the Clinic of Clinical Immunology and Allergology at the Lithuanian University of Health Sciences (LSMU) Medical Academy, the stepwise treatment scheme presented in the approved Atopic Dermatitis Diagnosis and Treatment Algorithm for Children in Lithuania is based on the 2007 NICE recommendations. In these recommendations, according to the professor, regardless of the severity of atopic dermatitis, alongside emollients, topical glucocorticoids of various strengths are indicated as first-line drugs, and topical calcineurin inhibitors, as a second step after glucocorticoids, are recommended only in cases of moderate to severe atopic dermatitis. In cases of mild atopic dermatitis, only weakly acting topical glucocorticoids are recommended, which are also suggested for maintenance therapy.
Based on the latest clinical trial data and the latest European expert consensus recommendations for the treatment of atopic dermatitis, topical calcineurin inhibitors (due to their effectiveness and especially safety characteristics compared to glucocorticoids) are recommended as first-line agents for treating mild atopic dermatitis and for long-term disease control. In cases of acute mild or moderate-severity atopic dermatitis, topical glucocorticoids should only be used for a short period (3-4 days), after which, according to the new recommendations, treatment should be continued with topical calcineurin inhibitors. Due to these reasons, there was a need to update the diagnostic and treatment recommendations for atopic dermatitis in Lithuania. Professor Matilda Bylaitė-Bučinskienė mentioned at the conference about the established working group to develop recommendations for atopic dermatitis," noted Prof. B. Šitkauskienė.