Atopic dermatitis (AD), also known as genetic atopic eczema and atopic dermatitis, is a common chronic recurrent, pruritic, inflammatory skin disease that often develops in infancy and childhood, with some patients continuing into adulthood. About 35% to 60% of children with AD may develop atopic diseases such as asthma, allergic rhinitis and allergic conjunctivitis as they grow older. However, the treatment of AD, especially the control of pruritus and the reduction of recurrence, is often a difficult clinical problem. Shi Chuankui, Department of Dermatology, Jinan Children’s Hospital Zhou Aiyan, Department of Dermatology, Jinan Children’s Hospital
1 Factors triggering the aggravation of AD
The onset of AD is the result of a combination of genetic and environmental factors. Patients with an atopic genetic background have a tendency to produce high immunoglobulin E (IgE), and the skin has increased sensitivity to a variety of stimulating allergic factors in the external environment. The common factors that trigger exacerbations are as follows.
(1) Irritating factors: wind, dry environment, sweating, excessive washing, rough clothing, woolen fabrics, etc. can cause skin irritation reactions in AD patients.
(2) Allergens: both ingested allergens and inhaled allergens can induce aggravation of AD lesions. Common ingested allergens include eggs, peanuts, milk, peas, wheat and fish, and common inhaled allergens include dust mites, animal dander, pollen and fungal spores.
(3) Microorganisms: Staphylococcus aureus colonization or infection is one of the main triggers of aggravation of AD. Staphylococcus aureus enterotoxin B (SEB) can activate and amplify the T-cell inflammatory response in a superantigenic manner; viral infections, especially herpes virus infections, often induce severe Kaposi varicella-like rash.
(4) Stress: work stress or mental tension can contribute to the aggravation of AD, possibly by inducing the brain to produce a variety of biopeptides that contribute to increased skin reactivity.
(5) Climate: winter and dry climate can contribute to the aggravation of AD lesions.
2 Treatment of AD
The principles of treatment for AD are to maintain the degree of skin hydration, restore the skin barrier, control pruritus and infection, use anti-inflammatory drugs appropriately, clarify and reduce various aggravation triggering factors, and reduce the recurrence of the disease.
2.1 Basic treatment
Finding and removing the cause and triggering factors, and educating patients and family members are the basis of drug treatment.
(1) Avoid excessive fatigue, emotional stress and anxiety.
(2) Pay attention to diet control Those who are allergic to seafood, milk, eggs, etc. should avoid eating such foods. Nursing mothers should also pay more attention to diet control.
(3) Keep the skin clean Use warm water to wash the skin, avoid excessive scrubbing, and use alkaline soap and shower gel as little as possible.
(4) Keep the environment clean Keep it clean by vacuuming daily to remove dust mites and pollen. Avoid stimulation by wool fibers. Avoid contact with organic solvents, detergents, paints and other chemicals.
2.2 Topical medication
(1) moisturizing emollient: moisturizing emollient can obviously improve the water content of the skin, have a hydrating effect on keratin-forming cells, improve the dry state of the skin, and also promote the repair of skin barrier function and reduce itching, which is the main means of adjuvant treatment for AD. 10% hydrophilic urea cream has good moisturizing properties, and moisturizing cream containing urea can improve skin barrier function and reduce sensitivity to external stimuli. Ceramide is a natural moisturizing factor present in the skin, which has good moisturizing effect and is very safe. Moisturizing emollients with ceramide are effective adjunctive therapeutic measures in the treatment of children with persistent AD. Others such as 2% sodium pyrrolidone hydroxylate (PCA), 5% lactic acid, and acetyl hyaluronic acid (AcHA) are all good moisturizers. The use of moisturizing emollients should be based on individual skin conditions, season or climatic conditions, etc. Different preparations should be selected. Generally, water-in-oil creams can be selected in winter and water-in-oil emulsions in summer, preparations containing urea can help strengthen skin hydration, preparations containing polyethanol monododecyl ether can help stop itching, and preparations with salicylic acid can be used for chronic hyperkeratotic lesions.
(2) Topical glucocorticosteroids: Topical glucocorticosteroids remain the main topical drug for controlling AD in the acute phase. To reduce the adverse reactions of topical glucocorticosteroids, topical glucocorticosteroid preparations with higher efficacy/risk such as 0.1% mometasone furoate cream, 0.05% fluticasone propionate cream, 0.25% methylprednisolone acetate, prednisolone, etc. can be selected; select topical glucocorticosteroids of different strengths according to different sites, avoid the use of strong hormones on the face, vulvar area and inter-rub areas, and avoid the use of strong hormones in children. Control the duration of continuous medication, reasonably adjust the intensity and dose of topical glucocorticoids according to the changes of skin lesions during treatment, and use intermittent therapy and rotation therapy during maintenance treatment to avoid rapid tolerance and rebound of glucocorticoids; recommend combined medication, during topical glucocorticoid treatment, combined topical moisturizers, calcium phosphatase inhibitors, anti-infective drugs, etc. can help reduce the amount of hormone, shorten the time of disease control and reduce recurrence.
(3) Calcium-regulated phosphatase inhibitors: mainly 0.03% and 0.1% tacrolimus ointment (tacrolimus, FK506), 1% pimecrolimus cream (pimecrolimus, SDZ, ASM981), are macrolide non-hormonal topical anti-inflammatory drugs. These drugs exert anti-inflammatory effects by inhibiting calcium-regulated phosphatase activity, a key molecule in signal transduction, and thus inhibiting nuclear factor of activated T cells (NFAT)-dependent gene transcription, including a variety of T cell activation-related cytokines such as IL-2, IL-3, IL-4, GM-CSF and TNF-? etc., exerting anti-inflammatory effects. Studies have demonstrated that the anti-inflammatory effect of 0.1% tacrolimus is equivalent to that of a medium-acting topical glucocorticoid, while the anti-inflammatory effect of 1% pimecrolimus is slightly weaker. Tacrolimus ointment is indicated for moderate to severe AD, pimecrolimus cream is indicated for mild to moderate AD, and 0.03% tacrolimus ointment and 1% pimecrolimus cream can be used in pediatric patients over 2 years of age. Evidence-based medical studies have confirmed that long-term topical application of these drugs does not cause adverse effects such as skin atrophy and is therefore a better choice for AD lesions on the face and inter-rub areas. Recent studies have found that intermittent topical tacrolimus ointment applied 3 times a week during the maintenance phase of treatment significantly prolongs the remission period with good safety and tolerability. The most common adverse reactions to tacrolimus and pimecrolimus during use are local skin burning sensation, tingling and other irritation reactions, most of which do not require special treatment or discontinuation of the drug.
(4) Topical antibacterial drugs: Mupirocin is a topical topical antibiotic that targets the isoleucine transfer ribonuclease on the bacterial cell wall, thereby inhibiting bacterial protein synthesis and playing a bactericidal role. Mupirocin ointment has good penetration, stable and long-lasting antibacterial activity, and low bacterial resistance. After topical application of mupirocin ointment, there was a significant reduction in the colonization of Aureus on the skin surface of AD patients. The combination of mupirocin and topical glucocorticoids resulted in significant improvement in lesions. For AD patients with persistent lesions on the face or chest and back in adults, topical combination of antifungal drugs targeting Malassezia such as ketoconazole can be used topically with good efficacy.
(5) Topical antihistamines: Topical 5% doxepin cream has antihistamine and antipruritic effects and can be used for the treatment of AD. doxepin ointment combined with topical glucocorticoids can significantly relieve pruritus and interrupt the vicious cycle of scratching-induced lesion aggravation, which helps the recovery of the disease. The main adverse effects of doxepin ointment are local irritation and drowsiness.
(6) Wet pack therapy Wet pack therapy is suitable for patients with acute exacerbation or chronic intractable AD. After the affected area is coated with topical anti-inflammatory drugs, moisturizers or anti-microbial drugs, the surface is wrapped with a layer of wet cotton cloth, and a tube bandage is rolled outside the cotton cloth, and the course of treatment is usually 3-5 days. Wet pack therapy helps to improve skin hydration, increase the efficacy of drugs, but also to prevent scratching the barrier, help the recovery of severe scratching lesions. It should be noted that wet pack time is too long or improper operation but will aggravate the lesions or secondary bacterial infection.
(7) Other topical drugs: phosphodiesterase (PDE) inhibitors can reduce cyclic adenosine monophosphate (cAMP) hydrolysis activity, reducing prostaglandin E2 synthesis, so the treatment of AD effective, its efficacy is worse than weak glucocorticoids, but better than moisturizers. Topical application of non-steroidal anti-inflammatory drug flufenamic acid butyl cream, in vivo can block arachidonic acid production of prostaglandins and leukotrienes and other inflammatory mediators, with anti-inflammatory, anti-itch effect.
2.3 Systemic treatment
Most AD patients can obtain relief of clinical symptoms with basic treatment and topical medication. When conventional treatment is ineffective or treatment resistant, systemic medication or UV therapy should be considered.
(1) Anti-infective drugs: Systemic antibiotics should be used for AD patients with more extensive bacterial (mainly Staphylococcus aureus) infections, usually choosing first- or second-generation cephalosporins or semi-synthetic penicillin, and the course of treatment is usually 7 to 10 days. Due to the increase in erythromycin-resistant strains, macrolide antibiotics are generally less commonly chosen. Clindamycin or fusidic acid may be chosen for penicillin allergy. Long-term antibiotics are generally not recommended after infection control to avoid the development of drug-resistant strains. patients with AD combined with herpes virus infection (Kaposi varicella-like rash) are usually more serious or even life-threatening, and antiviral drugs such as acyclovir and valacyclovir should be used systematically at an early stage.
(2) Antihistamines: Reducing pruritus and breaking the vicious cycle of itching-scratching are important aspects of AD treatment, and antihistamines are often used to control the pruritus symptoms of AD. In addition to antagonizing H1 receptors, the first-generation antihistamines also have the effect of anti-pruritic mediators (such as 5-hydroxytryptamine, acetylcholine, etc.), and the first-generation antihistamines have a more obvious central sedative effect, which helps to control the nocturnal itching and scratching of AD patients. The tricyclic antidepressant Doxepin has a better effect on patients with intense itching and severe sleep disturbance. Second-generation non-sedating antihistamines have increased affinity for H1 receptors and have little effect on other itch-causing mediators, so they have limited efficacy in controlling pruritus in AD patients; however, in vitro studies have found that second-generation antihistamines may inhibit the release of inflammatory mediators such as leukotrienes and prostaglandins from mast cells and basophils, or may block eosinophil chemotaxis, so they have an anti-allergic inflammatory effect.
(3) Glucocorticoids: Since serious rebound phenomenon often occurs after systemic use of glucocorticoids, dose reduction or discontinuation, and long-term use is prone to a variety of adverse effects such as growth arrest in children, osteoporosis, cataract, hypertension, diabetes, etc., systemic use should be avoided as much as possible. For patients with acute exacerbation of the disease and difficult to control by other drugs, they can take a short term oral medium dose of glucocorticoids and gradually reduce the dose after the disease is controlled, and long-term use should be avoided.
(4) Immunosuppressants: Cyclosporine: It exerts anti-inflammatory effects by inhibiting calcium-regulated phosphatase-dependent signaling pathways and reducing the synthesis of various cytokines and inflammatory factors. Several clinical studies have confirmed the efficacy of cyclosporine in both pediatric and adult AD patients, but rebound may also occur after discontinuation of the drug. Long-term application may cause hypertension or nephrotoxicity. It is suitable for refractory adult and pediatric AD patients and can be treated with a long course of treatment at a low dose of 2.5 mg/(kg?d) or a short course of treatment at a high dose [3-5 mg/(kg?d)] for a period of up to 6 months in children and up to 1 year in adults, with blood pressure, blood potassium, liver and kidney function and blood concentration tested regularly during the drug administration. In patients with AD receiving long-term treatment with cyclosporine, attention should also be paid to monitoring its possible carcinogenicity.
Azathioprine: It exerts immunosuppressive effects through anti-purine metabolism and inhibition of DNA synthesis, with a more significant inhibitory effect on T cells. The most common adverse effects are bone marrow suppression, gastrointestinal reactions and increased risk of infection.
Mycophenolate: A selective, reversible, non-competitive myrosinase inhibitor that inhibits purine ab initio synthesis and thus cell proliferation and is highly selective for lymphocytes, inhibiting T-cell activation and B-cell production of antibodies. It is indicated for recalcitrant adult AD patients at a starting dose of 1 g/d orally, increasing to 2 g/d after 1 week for 4 weeks, after which it may be changed to 1 g/d orally for up to 8 weeks. Common adverse reactions to mycophenolate are gastrointestinal reactions manifested as diarrhea or vomiting, neutropenia, and teratogenicity, with minor effects on liver and kidney function.
Methotrexate: Inhibits dihydrofolate dehydrogenase, affects pyrimidine/purine synthesis, inhibits DNA synthesis and cell proliferation, and also exerts anti-inflammatory effects by inhibiting monocyte chemotaxis, IL-1 and leukotriene B4 (LTB4) synthesis. The results of open clinical studies have shown that methotrexate is effective in the treatment of moderate to severe AD at doses of 10-15 mg once a week, with common adverse effects of gastrointestinal mucosal erosion/ulcer, bone marrow suppression, and hepatotoxicity.
(5) Anti-leukotriene drugs There are two classes of anti-leukotriene drugs, one exerts antagonistic effects on leukotriene receptors and blocks the biology of leukotrienes, such as montelukast and zalutostat, and the other is leukotriene synthesis inhibitors, such as zileuton. At present, leukotriene receptor antagonists have been initially applied in the treatment of AD, and clinical studies have shown that montelukast can be used as an adjuvant therapy for patients with moderate to severe AD.
(6) Traditional Chinese medicine: Traditional Chinese medicine is effective in the adjuvant treatment of AD. The Chinese medicine Leigongteng can suppress T-cell immunity and inhibit late metamorphosis, which can be applied to adult AD patients for a short period of time; the active ingredient of licorice, licorice sweetener preparation, has strong pro-adrenocorticotropic hormone, stable cell membrane and anti-metamorphosis inflammation effects, which can also be used clinically for mild to moderate AD patients. According to TCM diagnosis, if AD is wind-heat type, it should be given to cool blood and dispel wind; if it is damp-heat type, it should be given to benefit dampness and clear heat; if it is spleen-damp type, it should be given to strengthen spleen and benefit dampness; if it is yin-deficiency with dampness, it should be given to nourish yin and remove dampness; if it is wind-heat and blood-dry type, it should be given to nourish blood and moisten dryness.
(7) Intravenous immunoglobulin (IVIG): The therapeutic mechanism of IVIG may be related to the inhibition of immune cell proliferation and activation, regulation of immune cell apoptosis, regulation of cytokine synthesis and secretion, and inhibition of complement activation. Currently, IVIG is used for the treatment of AD mostly in small sample studies or case reports, and can be tried in patients with severe AD who are ineffective to other treatments. The usage is 2 g/kg per month, divided into 3 intravenous injections for 3-6 months, and the clinical symptoms can be significantly improved after treatment, and the serum IgE level and IL-4 level can be significantly decreased, and the remission period of some patients can be more than 6 months.
(8) Immunomodulatory therapy: The therapeutic mechanism of immunomodulators is not clear, and some clinical studies have shown that thymidine, BCG polysaccharide nucleic acid and levamisole can be used as adjuvant therapy for AD.
(9) Biological agents: recombinant human interferon-? (IFN-?) IFN-? can inhibit Th2-type cellular responses and reduce eosinophil infiltration in the skin. A few controlled clinical studies have shown that IFN-? is only effective in some AD patients, with high treatment costs and possible adverse effects such as flu-like symptoms, diarrhea and hair loss, and is only tried in patients with severe AD who are resistant to conventional treatment.
Other biologics: Other biologics that have been tried in AD treatment or are still in clinical trials include recombinant human specific anti-IgE monoclonal antibody (Omazo), monoclonal antibodies against cytokines such as IL-2, IL-4, IL-5, anti-lymphocyte function-associated antigen (LFA-1) monoclonal antibody, lymphocyte function-associated antigen (LFA-3)-CD2 fusion protein, etc. These biological agents provide new directions and good prospects for the future treatment of AD.
2.4 Ultraviolet therapy
The use of phototherapy and photochemotherapy in AD can achieve good efficacy and can be used as a very effective adjuvant therapy for AD, but mostly for patients with poor efficacy after conventional treatment. Phototherapy with high doses of long-wave ultraviolet 1 (UVA1) irradiation, narrow-spectrum medium-wave ultraviolet (NB-UVB) irradiation is more effective, and broad-spectrum medium-wave ultraviolet (BB-UVB) is also available. Photochemotherapy with photosensitizers mainly uses 8-methoxypsoralen (8-MOP), and 5-methoxypsoralen can also be used. Oral psoralen combined with UVA (PUVA), PUVA combined with UVB, water bath PUVA, topical 8-MOP solution or cream PUVA, etc. are used.
Phototherapy and photochemotherapy given for AD should be selective. Acute phase or severe AD is based on the application of high-dose UVA1, PUVA, or in vitro photochemotherapy, and hand and foot lesions with blisters can be PUVA with topical 8-MOP cream; chronic phase or moderate AD can be PUVA with NBUVB, medium-dose UVA1, BBUVB, and mossy lesions can be PUVA with topical 8-MOP.
The dose of irradiation for AD patients should be individualized. In clinical treatment, the initial dose can be determined according to the minimum erythema (MED) or the minimum phototoxicity (MPD), or according to the classification of the skin color type. The increase of radiation dose depends on the response to irradiation, and the total dose of irradiation should be controlled, and long-term maintenance is not advisable after the treatment becomes effective.
Patients with AD should pay attention to contraindications for phototherapy and photochemotherapy, such as varicella-like rash, associated photosensitive skin disease, skin tumors, severe cardiovascular disease, significant abnormalities in liver function (only in oral 8-MOP), and younger patients should not be performed. Short-term adverse reactions include gastrointestinal reactions after oral 8-MOP, erythema and edema due to excessive dose at the irradiated site, and dry, itchy skin after irradiation. Long-term adverse reactions include skin photoaging, cataract tendency and potential skin tumor development, while patients with skin types I and II have a higher chance of skin tumor development and patients with skin type IV have a much lower chance of skin tumor development.
2.5 Patient education
AD is a chronic disease and the condition is affected by many environmental factors, therefore, patients’ understanding of the disease and treatment compliance is one of the important factors to determine the treatment effect. The content of patient education includes disease-related knowledge, improving psychological awareness and tolerance, learning to control scratching behavior, topical medication techniques, allergen avoidance methods and general knowledge of daily skin care, etc. It can be done in the form of lectures and clubs to improve patients’ awareness to cooperate with medication, as well as to enhance confidence in overcoming the disease through communication and exchange among patients. In addition, education of patients’ family members or caregivers is also included.
2.6 Step therapy and combination of drugs for AD
The current recommendation for the treatment of AD is to adopt a stepwise treatment, with an upper or lower step depending on the severity of the disease, as shown in Figure 1.
Figure 1 Step therapy for AD
Note: CysA: cyclosporine A
Combination therapy refers to the combined use of 2 drugs with different mechanisms of action, which on the one hand increases the therapeutic effect and on the other hand is able to reduce the dose or course of one or two of the drugs, thus reducing the occurrence of adverse drug reactions. Combination therapy must be careful that there is no interaction between the two drugs and that they do not reduce each other’s efficacy or increase toxicity. The combination can be done in the form of concurrent therapy, sequential therapy or alternating therapy regimen. There are few evidence-based medical research data on combination therapy for AD. Some clinical studies have shown that the combination of topical anti-Galactobacillus antibiotics, topical emollients and topical glucocorticoids can significantly improve the efficacy of glucocorticoids, and the efficacy of combined topical glucocorticoids and topical immunomodulators is significantly better than monotherapy, while reducing the adverse effects of topical glucocorticoids. More combination therapies and strategies need to be validated in randomized controlled clinical studies.