Treatment of atopic dermatitis in children

Treatment of atopic dermatitis in children should be comprehensive and pathogenetic, including elimination measures, diet, hypoallergenic regimen, local and systemic pharmacotherapy, correction of concomitant pathology, patient education, rehabilitation. Treatment tactics are determined by the severity of clinical manifestations.

Treatment should be aimed at achieving the following goals:

• reduction of clinical manifestations of the disease:
• reduction in the frequency of exacerbations;
• improving the quality of life of patients;
• prevention of infectious complications.

Indications for consultation with other specialists

• Allergist: to establish a diagnosis, conduct an allergological examination, prescribe an elimination diet, establish causal allergens, select and correct therapy, diagnose concomitant allergic diseases, educate the patient and prevent the development of respiratory allergies.
• Dermatologist: to establish a diagnosis, conduct differential diagnostics with other skin diseases, select and correct local therapy, and educate the patient.
• A repeated consultation with a dermatologist and allergist is also necessary in case of a poor response to treatment with topical glucocorticoids (TGC) or antihistamines, the presence of complications, severe or persistent course of the disease | long-term or frequent use of strong TGC. extensive skin lesions (20% of the body area or 10% involving the skin of the eyelids, hands, perineum, the presence of recurrent infections, erythroderma or widespread exfoliative lesions in the patient).
• Nutritionist: to create and correct an individual diet.
• Otolaryngologist: detection and treatment of foci of chronic infection. Early detection of symptoms of allergic rhinitis.
• Psychoneurologist: for severe itching, behavioral disorders.
• Medical psychologist: to provide psychotherapeutic treatment, teach relaxation techniques, stress relief and behavior modification.

Drug treatment of atopic dermatitis in children

Local treatment of atopic dermatitis in children is a mandatory and important part of the complex treatment of atopic dermatitis. It should be carried out differentially, taking into account pathological changes in the skin.

The goal of local treatment of atopic dermatitis is not only to relieve inflammation and itching, but also to restore the hydrolipid layer and barrier function of the skin, as well as to ensure proper daily skin care.

Ointments and creams for atopic dermatitis in children based on glucocorticoids

Topical glucocorticoids are first-line agents for the treatment of exacerbations of atopic dermatitis, as well as initial therapy for moderate to severe forms of the disease. There are currently no precise data regarding the optimal frequency of applications, duration of treatment, amounts and concentrations of topical glucocorticoids used to treat atopic dermatitis.

There is no clear evidence of superiority of twice-daily application of topical glucocorticoids over single application; therefore, single application of topical glucocorticoids as a first step in therapy is justified for all patients with atopic dermatitis.

Administration of short courses (3 days) of potent topical glucocorticoids to children is as effective as long-term use (7 days) of weak topical glucocorticoids.

Dilution of officinal topical local glucocorticoids with indifferent ointments is not recommended for local treatment of atopic dermatitis, since such dilution does not reduce the incidence of side effects, as proven by randomized controlled trials, but is accompanied by a significant decrease in the therapeutic efficacy of local topical glucocorticoids.

With a significant reduction in the severity of clinical manifestations of the disease, local glucocorticoids can be used in an intermittent course (usually 2 times a week) in combination with nutritional agents to maintain remission of the disease, but only if long-term therapy with local glucocorticoids is justified by the undulating course of the disease. The use of local combination drugs of glucocorticoids and antibiotics has no advantages over local glucocorticoids (in the absence of infectious complications).

The risk of developing local side effects during therapy with topical glucocorticoids (striae, skin atrophy, telangiectasia), especially on sensitive skin areas (face, neck, folds), limits the possibility of long-term use of topical glucocorticoids in atopic dermatitis. Non-fluorinated MGCs with a predominantly extragenomic mechanism of action (mometasone - Elokom) and non-halogenated MGCs (methylprednisolone aceponate - Advantan) have minimal side effects. Of these, mometasone has a proven advantage in effectiveness compared to methylprednisolone.

The use of topical glucocorticoids on sensitive skin areas is limited.

Depending on the ability of local glucocorticoids to bind to cytosolic receptors, block the activity of phospholipase A ₂ and reduce the formation of inflammation mediators, taking into account the concentration of the active substance. MGCs by strength of action are usually divided into activity classes (in Europe, classes I-IV are distinguished), combined into 4 groups:

• very strong (class IV)
• strong (class III);
• medium (class II):
• weak (class I).

Classification of MHC by activity level (Miller&Munro)

Class (activity level)	Name of the drug
IV (very strong)	Clobetasol (Dermovate) 0.05% cream, ointment
III (strong)	Fluticasone (Flixotide)0.005% ointment Betamethasone (Celestoderm-B) 0.1% ointment, cream Mometasone (Elokom) 0.1% ointment, cream, lotion Methylprednisolone aceponate (Advantan) 0.1% fatty ointment, cream, emulsion Triamcinolone (Triamcinolone) 0.1% ointment
II (medium strength)	Alclomethasone (Afloderm) 0.05% ointment, cream Fluticasone (Flixotide) 0.05% cream Hydrocortisone (Locoid) 0.1% ointment, cream
1 (weak)	Hydrocortisone (Hydrocortisone) 1%, 2.5% cream, ointment Prednisolone

General recommendations for children on the use of ointments and creams containing glucocorticosteroids

• In severe exacerbations and localization of pathological skin lesions on the trunk and extremities, treatment begins with MHC class III. For treatment of the skin of the face and other sensitive areas of the skin (neck, folds), it is recommended to use calcineurin inhibitors.
• For routine use in cases of lesions localized on the trunk and limbs in children, MHC classes I or II are recommended.
• Class IV MHCs should not be used in children under 14 years of age.

Creams and ointments containing glucocorticosteroids, antibacterial and antifungal substances

In the presence or suspicion of an infectious complication, the administration of glucocorticoids in combination with antibiotics and antifungal drugs (betamethasone + gentamicin + clotrimazole) is indicated.

It has been established that atopic dermatitis is associated with a disruption of the skin barrier function. Recent studies have shown that disruption of the epidermis barrier function is observed not only during exacerbation of atopic dermatitis, but also during remission, as well as on skin areas not involved in the pathological process. During exacerbation of atopic dermatitis, as a rule, the integrity of the stratum corneum is disrupted, which is often accompanied by clinical manifestations of secondary infection. Skin infections in atopic dermatitis (often severe, torpid to the conducted etiotropic therapy, prone to recurrence. The most common infectious complication of atopic dermatitis is pyoderma, occurring in the form of impetigo, furuncles, folliculitis and ostiofolliculitis. In severe cases, even abscesses may develop. Moreover, up to 90% of cases of bacterial skin infection are caused by S. aureus. In case of addition or intensification of an existing secondary infection, combined external glucocorticosteroids are used, which contain antibacterial and/or antifungal components.

In recent years, drugs containing a broad-spectrum antibiotic have begun to be used in Russia as antibacterial agents. - Fusidic acid (FA). FA has bacteriostatic and, in very high doses, bactericidal activity primarily against gram-positive bacteria. FA has the greatest activity against S. aureus and S. epidermidis, including methicillin-resistant S. aureus (MRSA). In atopic dermatitis complicated by secondary infection. FA is used both systemically and locally, mainly as part of combined topical drugs. Combined topical therapy with FC in combination with betamethasone (Fucicort) or FC in combination with hydrocortisone (Fucidin G) allows achieving a rapid and lasting positive therapeutic effect in the treatment of complicated forms of atopic dermatitis, as well as a reduction in the colonization of the skin with S. aureus compared to monotherapy with glucocorticosteroids.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Calcineurin inhibitors

Topical calcineurin inhibitors (local immunomodulators) include pimecrolimus (1% cream) and tacrolimus. Pimecrolimus is a non-steroidal drug, a cell-selective inhibitor of proinflammatory cytokine production. It suppresses the synthesis of inflammatory cytokines by T-lymphocytes and mast cells (IL-2, IL-4, IL-10, y-IFN) by inhibiting the transcription of proinflammatory cytokine genes. It suppresses the release of inflammatory mediators by mast cells, which leads to the prevention of itching, redness and swelling. Provides long-term control over the disease when used at the beginning of the exacerbation period. The effectiveness of pimecrolimus in atopic dermatitis has been proven. It has been proven that the use of pimecrolimus is safe, effectively reduces the severity of atopic dermatitis symptoms in children with mild and moderate course of the disease. The drug prevents disease progression, reduces the frequency and severity of exacerbations, and reduces the need for MHC use. Pimecrolimus is characterized by low systemic absorption; it does not cause skin atrophy. It can be used in patients from 3 months on all areas of the body and especially on sensitive areas (face, neck, skin folds) without restrictions on the area of application.

Given the mechanism of action, the possibility of local immunosuppression cannot be excluded, but patients using pimecrolimus have a lower risk of developing secondary skin infections than patients receiving MHC. Patients using topical calcineurin inhibitors are advised to minimize exposure to natural sunlight and artificial radiation sources, and on sunny days to use sunscreens after applying the drug to the skin.

[ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ]

Tar preparations

They are used to treat atopic dermatitis in children, and in some cases they can serve as an alternative to MHC and calcineurin inhibitors. However, the slow development of their anti-inflammatory action and pronounced cosmetic defect limit their widespread use. It is necessary to take into account the data on the possible risk of carcinogenic effect of tar derivatives, which is based on studies of occupational diseases in people working with tar components.

Local agents with antibacterial and antifungal properties

Topical antibacterial and antifungal agents are effective in patients with atopic dermatitis complicated by bacterial or fungal skin infections. To prevent the spread of fungal infection during antibiotic therapy, it is justified to prescribe complex drugs containing both bacteriostatic and fungicidal components (e.g. mometasone + gentamicin, betamethasone + gentamicin + clotrimazole).

Antiseptics are used in the complex therapy of atopic dermatitis. However, there is no evidence of their effectiveness confirmed by randomized controlled trials.

Moisturizing (softening) agents of medicinal cosmetics

Moisturizing and emollient agents are included in the modern standard of therapy for atopic dermatitis, as they restore the integrity of the hydrolipid and horny layers of the epidermis, improve the barrier function of the skin (corneotherapy), have a GCS-sparing effect and are used to achieve and maintain control over the symptoms of the disease. These agents are applied to the skin regularly, daily, at least twice a day, including after each wash or bath, both against the background of the use of MHC and calcineurin inhibitors, and during the period of remission of atopic dermatitis, when there are no symptoms of the disease. These agents nourish and moisturize the skin, reduce dryness and reduce itching.

Ointments and creams restore the damaged hydro-lipid layer of the epidermis more effectively than lotions. The maximum duration of their action is 6 hours. Therefore, applications of nourishing and moisturizing agents should be frequent. Every 3-4 weeks, it is necessary to change nourishing and moisturizing agents to prevent tachyphylaxis.

Nourishing and moisturizing agents include traditional (indifferent) and modern medicinal dermatological cosmetics.

Dermatological cosmetics for dry and atopic skin care

Program	Hygiene	Moisturizing	Nutrition	Anti-sleep
Atoderm program (laboratory Bioderma)	Atoderm mousse, Atoderm Soap	Atoderm RR cream Hydrabio Cream	Atoderm cream Atoderm cream RR	Atoderm RO Zinc cream
Program for dry and atopic skin (Uriage laboratory)	Cu-Zn Soap Cu-Zn gel	Thermal water Uriage (spray) Hydrolipidic Cream	Cream Emollient Cream Emollient Extreme	Spray Cu-Zn Cu-Zn Cream Prurised Cream Prurised Gel
A-Derma program (Ducret laboratory)	Realba Oat Milk Soap, Realba Oat Milk Gel	Exomega Milk	Exomega Cream	Sitelium Lotion Elitelyal Cream
Mustella Program (Expansciece Lab)	Cleansing cream StelAtopia		Cream-Emulsion StelAtopia
Lipikar program (La Roche-Posay laboratory)	Soap Surgra Mousse Lipikar Sindet	La Roche-Posay thermal water (spray), Hydronorm cream, Toleran cream	Lipikar emulsion, Lipikar bath oil Ceralip lip cream
Friederm series of shampoos	Friederm Zinc Friederm PH balance			Friederm Zinc
Program for dry and atopic skin with Avene thermal water (Aven laboratory)	Cold Cream Soap. Cold Cream Gel	Thermal water Avene (spray) Cold Cream Body Emulsion Lotion for ultra-sensitive skin without rinsing	Trixera Cream Trixera Softening Bath Cold Cream Body Balm Cold Cream Lip Balm	Sikalfat lotion Cicalfate Cream

Traditional products, especially those based on lanolin or vegetable oils, have a number of disadvantages: they create a waterproof film and often cause allergic reactions. Therefore, modern products of medicinal dermatological cosmetics are considered more promising. The most common are the programs of several specialized dermatological laboratories: Bioderma (Atoderm program), the program of the Uriage laboratory, Ducret (A-Derma program), Avene (program for atopic skin).

The programs listed are based on the use of specific, balanced and carefully selected components.

Daily Skin Care for Atopic Dermatitis in Children

The third important task of local treatment of atopic dermatitis in children is proper daily skin care (cleansing, moisturizing), which helps reduce pathological changes in the epidermis, restore its functions and prevent exacerbations, which also increases the effectiveness of treatment and helps increase the duration of remission.

It is important to note that the old outdated dermatologist's advice to ban bathing children with atopic dermatitis, especially during an exacerbation of the disease, is incorrect. On the contrary, daily bathing (using baths is preferable to showers) actively hydrates and cleanses the skin, providing better access to medications and improving the functions of the epidermis.

To cleanse the skin, it is advisable to use daily short cool (32-35 °C) baths lasting 10 minutes with a mild washing base (pH 5.5) that does not contain alkali [for example, Friderm pH-balance series shampoo, which can also be used as a shower gel or bath foam (a 10-minute exposure is required)].

For the same purpose, it is recommended to use medicinal dermatological cosmetics - soaps, mousses, gels. They have a soft washing base without alkali, effectively cleanse and at the same time soften, nourish and moisturize the skin without irritating it.

When cleaning the skin, do not rub it. After bathing, it is recommended to only blot the surface of the skin without wiping it dry.

D-Panthenol can help improve skin condition, reduce irritation, and restore the structure and functions of damaged epithelium in atopic dermatitis.

D-Panthenol can be used from the first days of a child's life on any area of the skin. D-Panthenol helps to preserve the natural protective layer of the skin and promotes rapid healing of damaged skin.

D-Panthenol saturates the skin with dexpanthenol, a derivative of pantothenic acid (a water-soluble vitamin of group B), which is necessary for activating metabolism, which normalizes cellular metabolism, stimulates skin regeneration, and increases the strength of collagen fibers.

Optimal molecular weight, hydrophilicity and low polarity make it possible for D-Panthenol to penetrate into all layers of the skin.

Thus, D-Panthenol helps to normalize cellular metabolism, providing skin cells with energy and nutrients. has a regenerating, anti-inflammatory effect on the skin. reduces irritation, nourishes and softens the skin, helps eliminate dryness and flaking.

For external therapy of atopic dermatitis in children, daily skin care, D-Panthenol cream is more comfortable. It has a light texture, is quickly absorbed, leaving no traces.

To protect the delicate skin of the diaper area of babies, as well as to treat diaper rash that has already appeared, D-Panthenol ointment is more suitable, creating a reliable barrier against moisture.

[ 10 ], [ 11 ], [ 12 ], [ 13 ], [ 14 ]

Systemic treatment of atopic dermatitis in children

Antihistamines are the most commonly used group of drugs for the treatment of atopic dermatitis worldwide. Current recommendations for the use of this group of drugs are summarized in the following general provisions:

• Both sedative and non-sedative drugs (1st and 2nd generation) should be considered as basic therapy for atopic dermatitis in children;
• antihistamines should be used for atopic dermatitis as a means of combating itching (since itching in atopic dermatitis is one of the pathogenetic mechanisms that support inflammation);
• Antihistamines can be used either continuously throughout the day or only before bedtime, depending on the individual course of the disease in each patient.

Modern antihistamines

1st generation (sedatives)	2nd generation (non-sedative)
	Inactive metabolites	Active metabolites
Dimetinden (Fenistil)	Loratadine (Claritin)	Desloratadine (Erius)
Sequifenadine (Fenkarol)	Ebastine (Kestin)	Levocetirizine (Xyzal)
Clemastine (Tavegil)		Cetirizine (Zyrtec)
Chloropyramine (Suprastin)		Fexofenadine (Telfast)
Cyproheptadine (Peritol)

1st generation antihistamines

First-generation antihistamines block only 30% of H1 receptors. To achieve the desired antihistamine effect, high concentrations of these drugs in the blood are required, which requires their administration in large doses. It is important to note that these drugs have a pronounced sedative effect, since due to their high lipophilicity, they easily penetrate the blood-brain barrier and cause blockade of H1 receptors and central m-cholinergic receptors of the central nervous system (CNS), which causes their undesirable sedative effect. The use of these drugs can increase lethargy and drowsiness in patients, and worsen cognitive functions in children (concentration, memory, and learning ability). That is why they should not be used constantly and for a long time and can only be used in case of exacerbation of atopic dermatitis in short courses at night to reduce itching. In addition, due to the m-anticholinergic (atropine-like) effect, these drugs are not recommended for use in children with a combination of atopic dermatitis and bronchial asthma or allergic rhinitis.

[ 15 ], [ 16 ], [ 17 ], [ 18 ]

2nd generation antihistamines

These drugs selectively act on H1 receptors and do not have m-anticholinergic action. Their significant advantage is the absence of a sedative effect and influence on cognitive functions. Therefore, they are the drugs of choice in the treatment of atopic dermatitis, including in children with respiratory allergies (bronchial asthma and allergic rhinitis). They can be used for a long time to eliminate not only night but also daytime itching. A significant difference between 2nd generation antihistamines is that they have not only a selective H1 blocking effect, but also an anti-inflammatory effect.

The efficacy of ketotifen and oral cromoglicic acid in atopic dermatitis has not been proven in randomized controlled trials.

[ 19 ], [ 20 ]

Antibacterial treatment of atopic dermatitis in children

The skin of patients with atopic dermatitis is often colonized with Staphylococcus aureus in the foci of the pathological process and outside of them. Local and systemic use of antibacterial drugs temporarily reduces the degree of colonization. In the absence of clinical symptoms of infection, systemic use of antibacterial drugs has a minimal effect on the course of atopic dermatitis. Systemic administration of antibiotics may be justified in patients with confirmed severe bacterial skin infection accompanied by high fever, intoxication, deterioration of the general condition and poor health of the patient. Long-term use of antibiotics for other purposes (for example, for the treatment of forms of the disease resistant to standard therapy) is not recommended.

[ 21 ], [ 22 ], [ 23 ], [ 24 ]

Immunosuppressive therapy

It is used in cases of particularly severe atopic dermatitis and insufficient effectiveness of all other treatment methods. The question of prescribing immunosuppressive therapy is decided by an allergist-immunologist.

Cyclosporine and azathioprine

These drugs are effective in treating severe forms of atopic dermatitis, but high toxicity and numerous side effects limit their use. Short courses of cyclosporine have a significantly lower cumulative effect compared to long-term therapy (taking the drug for 1 year). The initial dose of cyclosporine 2.5 mg / kg is divided into 2 doses per day and taken orally. In order to reduce the likelihood of side effects, the daily dose should not exceed 5 mg / kg per day.

[ 25 ], [ 26 ], [ 27 ], [ 28 ]

Systemic glucocorticoids

Systemic glucocorticoids are used to relieve severe exacerbations of atopic dermatitis in short courses. However, side effects limit the use of this treatment in children, so systemic glucocorticoids cannot be recommended for routine use. There are no randomized controlled trials confirming the effectiveness of this treatment, despite its long-term use.

Allergen-specific immunotherapy

This treatment method is not used for atopic dermatitis, but it can be effective for concomitant bronchial asthma and allergic rhinoconjunctivitis.

[ 29 ], [ 30 ], [ 31 ], [ 32 ], [ 33 ]

Alternative Treatments for Atopic Dermatitis

There is no evidence from randomized controlled trials to support the effectiveness of homeopathy, reflexology, herbal medicine, dietary supplements, etc. in the treatment of atopic dermatitis.

[ 34 ], [ 35 ], [ 36 ], [ 37 ], [ 38 ], [ 39 ]

Non-drug treatment of atopic dermatitis in children

Diet for atopic dermatitis in children

Diet for atopic dermatitis in children plays a key role in the treatment and primary prevention of atopic dermatitis, especially in infants and young children. Elimination of causative food allergens from the diet can significantly improve the condition and quality of life of children, the prognosis and outcome of the disease.

The most common cause of atopic dermatitis in children in their first year of life is an allergy to cow's milk proteins (79-89%). Breastfeeding provides optimal conditions for normal growth and development of the child, but even 10-15% of children who are breastfed have a "milk" allergy. In such situations, soy formulas are used: Alsoy (Nestle, Switzerland), Nutrilak soya (Nutritek, Russia), Frisosoy (Friesland, Holland), etc.

In the case of allergies to soy proteins, as well as severe forms of food allergies, hypoallergenic mixtures with a high degree of protein hydrolysis are recommended: Alfare (Nestle), Nutramigen and Pregestimil (Mead Johnson), etc.

In case of allergy to gluten - a protein of cereal products (wheat, rye, oats), which occurs in 20-25% of children with atopic dermatitis, it is recommended to use gluten-free hypoallergenic cereals of industrial production based on buckwheat, rice, corn (manufacturers: Istra-Nutricia, Remedia, Heinz, Humana, etc.).

It is not recommended to use products with high allergenic activity in the diet of children with atopic dermatitis (especially in the first years of life). The introduction of each new product should be carried out under the strict supervision of a pediatrician.

Products containing food colorings, preservatives, emulsifiers; spicy, salty and fried foods, broths, mayonnaise are excluded from the diet of sick children; products with high sensitizing activity are limited.

NB! Exclusion of any product from the diet of children should be carried out if its intolerance is proven. When determining the tolerance of food products and drugs, it is advisable to take into account the likelihood of cross-allergy. Thus, children with an allergy to cow's milk proteins may have an allergy to beef and some enzyme preparations made from the mucous membrane of the stomach, pancreas of cattle; with an allergy to mold fungi, hypersensitivity to yeast-containing food products is often observed: kefir, baked goods, kvass, moldy cheeses (Roquefort, Brie, Dor Blue, etc.), penicillin antibiotics, etc.

[ 40 ], [ 41 ], [ 42 ], [ 43 ], [ 44 ], [ 45 ]

Phototherapy

UV irradiation is used in patients aged 12 years and older with widespread skin manifestations that are resistant to standard treatment.

Bioresonance therapy

Randomized controlled trials of the effectiveness of this intervention have not been conducted.

[ 46 ], [ 47 ], [ 48 ]

Psychotherapy

Treatment of atopic dermatitis in children can be carried out using group psychotherapeutic interventions, where training in relaxation techniques, stress relief and behavior modification is provided.

Indications for hospitalization

• Exacerbation of atopic dermatitis, accompanied by a deterioration in the general condition.
• A common skin process accompanied by secondary infection.
• Recurrent skin infections.

Patient education

The patient should be taught:

• skin care rules;
• correct use of nutritional and moisturizing agents, local glucocorticosteroids and other drugs;
• limiting contact with unfavorable environmental factors.

General recommendations for patients with atopic dermatitis:

• Hypoallergenic regimen, diet.
• Limit as much as possible contact with environmental factors that cause an exacerbation of the disease.
• Ensure optimal indoor air humidity (50-60%).
• Maintain a comfortable air temperature.
• Use air conditioning indoors in hot weather.
• Avoid using synthetic fabrics and woolen clothing; give preference to cotton fabrics, silk, and linen.
• Provide a calm environment at school and at home.
• Cut your nails short.
• During periods of exacerbation, sleep in cotton socks and gloves.
• Do not prohibit bathing, do not use hot water for showers and/or baths; water procedures should be short-term (5-10 minutes) using warm water.
• Take a shower and apply moisturizer after swimming in the pool.
• Use special skin care products for atopic dermatitis.
• Use liquid detergents for washing, not powder detergents.
• Minimize contact with allergens that cause exacerbation of the disease, as well as with irritants.
• Use sunscreens that do not cause contact irritation of the skin in sunny weather.
• Completely follow the instructions of your doctor.

Patients should not:

• use alcohol-containing hygiene products;
• use products with antimicrobial components without the recommendation of a doctor;
• participate in sports competitions, as this causes intense sweating and is accompanied by close contact of the skin with clothing;
• take water treatments too often;
• When washing, rub the skin vigorously and use tools for washing that are harder than a terry cloth washcloth.

Atopic dermatitis has a significant impact on the quality of life of children. In terms of the degree of negative impact on the quality of life, atopic dermatitis surpasses psoriasis and is comparable to such serious conditions as the onset of diabetes mellitus.