Drug Category: Immunomodulators

Background

Atopic dermatitis (AD) is a pruritic disease of unknown origin that usually starts in early infancy (an adult-onset variant is recognized); it is characterized by pruritus, eczematous lesions, xerosis (dry skin), and lichenification (thickening of the skin and an increase in skin markings). AD may be associated with other atopic (immunoglobulin E [IgE]) diseases (eg, asthma, allergic rhinitis, urticaria, acute allergic reactions to foods). AD has enormous morbidity, and the incidence and prevalence appear to be increasing. Other conditions with different etiologies and prognoses are often grouped under the umbrella of a diagnosis of AD.

Pathophysiology

Good evidence indicates that genetic factors are important in the development of atopic dermatitis (AD), but the pathophysiology is still poorly understood. Two main hypotheses have been proposed regarding the development of the inflammatory lesions. The first suggests an immune dysfunction resulting in IgE sensitization and a secondary epithelial-barrier disturbance. The second proposes a defect in epithelial cells leading to the defective barrier problem, with the immunological aspects being epiphenomena.

In healthy individuals, balance exists between 2 important subdivisions of T cells (ie, TH1, TH2). The immune hypothesis invokes an imbalance in the T lymphocytes, with TH2 cells predominating; this results in cytokine production of interleukins 4, 5, 12, and 13 and granulocyte macrophage colony-stimulating factor, causing an increase in IgE and lowered interferon gamma levels. Later, in persons with chronic AD, the TH1-type cells predominate. Other cell types are also involved in the process, including eosinophils, Langerhans cells, keratinocytes, and B cells.

The second hypothesis involves defective barrier function in the stratum corneum of AD patients, leading to the entry of antigens that result in the production of inflammatory cytokines. Some authors question whether the antigens can also be absorbed from the gut (eg, from food) and the lungs (eg, from house dust mites). Xerosis is known to be an associated sign in many AD patients. Evidence has shown multiple loss-of-function mutations in the filaggrin gene (FLG) on band 1q21.3 in patients with AD in Europe and other filaggrin mutations in Japanese patients. This gene is mutated in persons with ichthyosis vulgaris; it is associated with early-onset AD and with airway disease in the setting of AD. These changes are only found in 30% of European patients, begging the question of whether other genetic variants may also be responsible for some of the findings in the pathogenesis of AD.

In AD, transepidermal water loss is increased. Defective lamellar bodies may be caused by abnormalities of ceramide production. Whether the inflammation causes primary or secondary epidermal barrier breakdown is not known, but with the knowledge that filaggrin is involved in epithelial disruption, it is now thought that this finding leads to increased transepidermal penetration of environmental allergens, increasing inflammation and sensitivity.

Frequency

United States

The prevalence rate is 10-12% in children and 0.9% in adults. More recent information examining physician visits for AD in the United States from 1997-2004 estimates a large increase in office visits for AD occurred. In addition, blacks and Asians visit more frequently for AD than whites. Note that this increase involves all disease under the umbrella of AD and it has not been possible to allocate which type has increased so rapidly.

International

The prevalence rate is rising, and AD affects 15-30% of children and 2-10% of adults. In China and Iran, the prevalence rate is approximately 2-3%. The frequency is increased in patients who immigrate to developed countries from underdeveloped countries.

Mortality/Morbidity

Incessant itch and work loss in adult life is a great financial burden. A number of studies have reported that the financial burden to families and government is similar to that of asthma, arthritis, and diabetes mellitus. In children, the disease causes enormous psychological burden to families and loss of school days. Mortality due to AD is unusual.

Kaposi varicelliform eruption (eczema herpeticum) is a well-recognized complication of AD.

· It usually occurs with a primary herpes simplex infection, but it may also be seen with recurrent infection. Vesicular lesions usually begin in areas of eczema and spread rapidly to involve all eczematous areas and healthy skin. Lesions may become secondarily infected. Timely treatment with acyclovir ensures a relative lack of severe morbidity or mortality.

· Another cause of Kaposi varicelliform eruption is vaccination with vaccinia for the prevention of small pox, but because this is no longer mandatory, patients with AD do not develop the sequelae of eczema vaccinatum that has been seen in the past. It was usually contracted by the patient from the vaccination of themselves or their close relatives. This condition had a high mortality rate (up to 25%). In the current climate of threats of bioterrorism, vaccination may once again become necessary, and physicians should be aware of eczema vaccinatum in this setting.

· Note that chickenpox vaccine does not carry the same risk as herpes simplex and vaccinia.

· Bacterial infection with Staphylococcus aureus or Streptococcus pyogenesis is not infrequent in the setting of AD. The skin of patients with AD is colonized by S aureus. Colonization does not imply clinical infection, and physicians should only treat patients with clinical infection. The emergence of methicillin-resistant S aureus (MRSA) may prove to be a problem in the future in these patients. Eczematous and bullous lesions on the palms and soles are often infected with beta-hemolytic group A Streptococcus.

· Urticaria and acute anaphylactic reactions to food occur with increased frequency in patients with AD. The food groups most commonly implicated include peanuts, eggs, milk, soya, fish, and seafood. In studies in peanut-allergic children, the vast majority were atopic.

· Latex allergy is more common in patients with AD than in the general population.

· Of AD patients, 30% develop asthma and 35% have nasal allergies.

Race

AD affects persons of all races. Immigrants from developing countries living in developed countries have a higher incidence of AD than the indigenous population, and the incidence is rapidly rising in developed countries

Sex

The male-to-female ratio is 1:1.4.

Age

In 85% of cases, AD occurs in the first year of life; in 95% of cases, it occurs before age 5 years. The incidence of AD is highest in early infancy and childhood. The disease may have periods of complete remission, particularly in adolescence, and may then recur in early adult life.

In the adult population, the rate of AD frequency is 0.9%, but onset may be delayed until adulthood.

CLINICAL

History

Incessant pruritus is the only symptom of atopic dermatitis (AD); children often scratch themselves uncontrollably. Although pruritus may be present in the first few weeks of life, parents become more aware of the itch as the itch-scratch cycle matures when the patient is aged approximately 3 months. The disease typically has an intermittent course with flares and remissions occurring, often for unexplained reasons.

Physical

Primary findings of atopic dermatitis (AD) include xerosis, lichenification, and eczematous lesions. Excoriations and crusting are common. The eczematous changes and its morphology are seen in different locations depending on the age of the patient.

Infancy

· AD is usually noticed soon after birth. Xerosis occurs early and often involves the whole body; the diaper area is usually spared.

· The earliest lesions affect the creases (antecubital and popliteal fossae), with erythema and exudation. Over the following few weeks, lesions usually localize to the cheeks, the forehead and scalp, and the extensors of the lower legs; however, they may occur in any location on the body, usually sparing the diaper area. Lesions are ill-defined, erythematous, scaly, and crusted (eczematous) patches and plaques.

· Lichenification is seldom seen in infancy.

Childhood

· Xerosis is often generalized. The skin is flaky and rough.

· Lichenification is characteristic of childhood AD. It signifies repeated rubbing of the skin and is seen mostly over the folds, bony protuberances, and forehead.

· Lesions are eczematous and exudative. Pallor of the face is common; erythema and scaling occur around the eyes. Dennie-Morgan folds (ie, increased folds below the eye) are often seen. Flexural creases, particularly the antecubital and popliteal fossae, and buttock-thigh creases are often affected.

· Excoriations and crusting are common. The crusting with AD should not be confused with infection because both may manifest oozing and crusting.

Adulthood

· Lesions become more diffuse with an underlying background of erythema. The face is commonly involved and is dry and scaly. Xerosis is prominent.

· Lichenification may be present.

· A brown macular ring around the neck is typical but not always present. It represents localized deposition of amyloid.

Until Hanifin and Rajka developed diagnostic criteria for the diagnosis of AD in 1980, no standardized methods were available to make the diagnosis. Since then, numerous other experts have developed different criteria suitable for their own environment, and varying with age. The original criteria of Hanifin and Rajka have been modified many times. Efforts to develop practical clinical criteria have not been successful, and those available are not suitable for all geographic areas and age groups. The lack of a good chemical marker for diagnosing the disease is an enormous obstacle to the study of AD.

The following is a constellation of criteria commonly used for the diagnosis of AD:

Major and Minor Features of Atopic Dermatitis

Major Features

· Intense itching

· Characteristic rash in locations typical of the disease

· Chronic or repeatedly occurring symptoms

· Personal or family history of atopic disorders (eczema, hay fever, asthma)

Some Minor Features

· Early age of onset

· Dry skin that may also have patchy scales or rough bumps

· High levels of immunoglobulin E (IgE), an antibody, in the blood

· Numerous skin creases on the palms

· Hand or foot involvement

· Inflammation around the lips

· Nipple eczema

· Susceptibility to skin infection

· Positive allergy skin tests

A firm diagnosis of AD depends on excluding conditions such as scabies, allergic contact dermatitis, seborrheic dermatitis (SD), cutaneous lymphoma, ichthyosis, psoriasis, immunodeficiency, and other primary disease entities.

Causes

Genetics8, 9: A family history of AD is common. Genome-wide scans have highlighted several atopic dermatitis (AD) related loci on 3q21, 1q21, 16q, 17q25, 20p, and 3p26. Several candidate genes have been identified (5q31-33); they all encode cytokines involved in the regulation of IgE synthesis.

Infection: The skin of patients with AD is colonized by S aureus. Clinical infection with S aureus often causes a flare of AD, and S aureus has been proposed as a cause of AD by acting as a superantigen.

Hygiene: The hygiene hypothesis is touted as a cause for the increase in AD. This attributes the rise in AD to reduced exposure to various childhood infections and bacterial endotoxins.10, 11

Climate: AD flares occur in extremes of climate. Heat is poorly tolerated, as is extreme cold. A dry atmosphere increases xerosis. Sun exposure improves lesions, but sweating increases pruritus. These external factors act as irritants or allergens, ultimately setting up an inflammatory cascade.

Food antigens: The role of food antigens in the pathogenesis of AD is controversial, both in the prevention of AD and by the withdrawal of foods in persons with established AD. Most reported studies have methodologic flaws. Because of the controversy regarding the role of food in AD, most physicians do not withdraw food from the diet. Nevertheless, acute food reactions (urticaria and anaphylaxis) are commonly encountered in children with AD.

Probiotics12: The role of probiotics in the diet of patients with AD remains controversial

Aeroallergens: A role for aeroallergens and house dust mites has been proposed, but this await s further corroboration.

DIFFERENTIALS

Other Problems to be Considered

Atopic dermatitis (AD) is indistinguishable from other causes of dermatitis. In infancy, the most common difficulty is distinguishing it from SD. This entity is not seen with the same frequency as a decade ago. Both AD and SD are associated with cradle cap (a retention hyperkeratosis) found on the vertex of the scalp, which is greasy and yellow in individuals with SD and dry and crusted in individuals with AD. Other areas of involvement in SD are the intertriginous areas and diaper area; erythema and a greasy scale can be seen over the eyebrows and the sides of the nose. In AD, xerosis of the skin and pruritus occur, which are not usually features of SD. Both conditions should be distinguished from psoriasis.

Scabies manifests in infancy or childhood as a pruritic eruption. Other members of the family are usually itchy, and the primary sites of involvement are moist, warm areas. The eruption is polymorphic with a dermatitis, nodules, urticaria, and 6-10 burrows. Pustules on the hands and feet are almost diagnostic of scabies in infancy. Facial involvement is rare, and xerosis does not occur.

Allergic contact dermatitis from nickel in infants and children is sometimes difficult to distinguish from AD. A central area of dermatitis on the chest from nickel snaps in undershirts or around the umbilicus from snaps in jeans is helpful for making the diagnosis, although a dermatitic eruption may occur as an id reaction in other areas, particularly the antecubital fossae. Xerosis and facial involvement are absent. AD usually starts earlier than contact dermatitis.

Infants with a severe itch and generalized dermatitis in the setting of recurrent infections should be investigated for evidence of an immunodeficiency. Failure to thrive and repeated infections help distinguish the eruption from AD. In Wiskott-Aldrich syndrome, bleeding may be prominent with the dermatitis, because of the associated thrombocytopenia. In older children, mycosis fungoides (a form of T-cell lymphoma) often presents with hypopigmented patches associated with a dermatitis. This entity is being recognized with increased frequency as physicians become more aware of the disease, and it is sometimes difficult to distinguish between the 2 entities.

Tinea corporis usually manifests as a single lesion, but inappropriate treatment with steroids may cause a widespread dermatitis. Facial involvement, the presence of xerosis, the age of appearance, and an early onset (in AD) help distinguish between the 2 conditions.

WORKUP

Lab Studies

• No chemical marker for the diagnosis of AD is known.
• Laboratory testing is seldom necessary. A swab of infected skin may help with the isolation of a specific organism and antibiotic sensitivity.
• Allergy and radioallergosorbent testing is of little value.
• A platelet count for thrombocytopenia helps exclude Wiskott-Aldrich syndrome, and testing to rule out other immunodeficiencies may be helpful.
• Scraping to exclude tinea corporis is occasionally helpful.

Histologic Findings

Biopsy shows an acute, subacute, or chronic dermatitis, but no specific findings are demonstrated.

Medical Care

Patients with atopic dermatitis (AD) do not usually require emergency therapy, but they may visit the emergency department for treatment of acute flares caused by eczema herpeticum and bacterial infections. For further information on treatment, see the NICE Guidelines Issued for Treating Atopic Eczema in Children.

Moisturization. Depending on the climate, patients usually benefit from 5-minute, lukewarm baths followed by the application of a moisturizer such as white petrolatum. Frequent baths with the addition of emulsifying oils (1 capful added to lukewarm bath water) for 5-10 minutes hydrate the skin. The oil keeps the water on the skin and prevents evaporation to the outside environment. In infants, 3 times a day is not a great burden; in adults, once or twice a day is usually all that can be achieved. Leave the body wet after bathing.

Advise patients to apply an emollient such as petrolatum or Aquaphor all over the body while wet, to seal in moisture and allow water to be absorbed through the stratum corneum. The ointment spreads well on wet skin. The active ingredient should be applied before the emollient. Newer emollients such as Atopiclair and Mimyx have been advocated as having superior results, but they are expensive and need further evaluation.

Topical steroids

• Topical steroids are currently the mainstay of treatment. In association with moisturization, responses have been excellent.
• Ointment bases are preferred, particularly in dry environments.
• Initial therapy consists of hydrocortisone 1% powder in an ointment base applied 3 times daily to lesions on the face and in the folds.
• A midstrength steroid ointment (triamcinolone or betamethasone valerate) is applied 2-3 times daily to lesions on the trunk until the eczematous lesions clear.
• Steroids are discontinued when lesions disappear and are resumed when new patches arise.
• Flares may be associated with seasonal changes, stress, activity, staphylococcal infection, or contact allergy.
• Contact allergy is rare but accounts for increasing numbers of flares. These are seen mostly with hydrocortisone.

Immunomodulators

· Tacrolimus (topical FK506) is an immunomodulator that acts as a calcineurin inhibitor. Studies have shown excellent results compared with placebo and hydrocortisone 1%. Little absorption occurs. A stinging sensation may occur following application, but this can be minimized by applying the medication only when the skin is dry. The burning usually disappears within 2-3 days. Tacrolimus is available in 2 strengths, 0.1% for adults and 0.03% for children, although some authorities routinely use the 0.1% preparation in children. Tacrolimus is an ointment and is indicated for moderate-to-severe AD. It is indicated for children older than 2 years.

· Pimecrolimus 1% is also an immunomodulator and calcineurin inhibitor. It is more effective than placebo. Pimecrolimus is produced in a cream base for use twice a day; it is indicated for mild AD in persons older than 2 years and is particularly useful on the face.

A 2006 black box warning has been issued in the United States based on research that has shown an increase in malignancy in association with the calcineurin inhibitors. While these claims are being investigated further, the medication should likely only be used as indicated (ie, for AD in persons older than 2 y and only when first-line therapy has failed).

· These agents are much more expensive than corticosteroids and should only be used as second-line therapy.

Other treatments, effective and ineffective

• Probiotics have been explored as a therapeutic option for the treatment of AD. The rationale for their use is that bacterial products may induce an immune response of the TH1 series instead of TH2 and could therefore inhibit the development of allergic IgE antibody production. This research has yet to be proven.
• UV-A, UV-B, a combination of both, psoralen plus UV-A (PUVA), or UV-B1 (narrow-band UV-B) therapy may be used. Long-term adverse effects of skin malignancies in fair-skinned individuals should be weighed against the benefits.
• In patients with eczema herpeticum, acyclovir is effective.
• In patients with severe disease, and particularly in adults, phototherapy, methotrexate (MTX), azathioprine, cyclosporine, and mycophenolate mofetil1 have been used with success.
• Both hydroxyzine and diphenhydramine hydrochloride provide a certain degree of relief from itching but are not effective without other treatments.
• Ketotifen (a calcium channel blocker) may be effective.
• Oil of evening primrose was believed to be effective, but in a randomized controlled study, it showed no benefit in children and little improvement in adults.
• Results with many other medications, such as thymopentin, gamma interferon, and Chinese herbs, have been disappointing. Many medications are not practical to use, and they can be expensive. Some Chinese herbal preparations contain prescription medications, including prednisone, and have been associated with cardiac and liver problems.
• Antibiotics are used for the treatment of clinical infection caused by S aureus or flares of disease. They have no effect on stable disease in the absence of infection. Laboratory evidence of S aureus colonization is not evidence of clinical infection because staphylococcal organisms commonly colonize the skin of patients with AD.

Nonmedical efforts

• Clothing should be soft next to the skin. Cotton is comfortable and can be layered in the winter.
• Cool temperatures, particularly at night, are helpful because sweating causes irritation and itch.
• A humidifier (cool mist) prevents excess drying and should be used in both winter, when the heating dries the atmosphere, and in the summer, when air conditioning absorbs the moisture from the air.
• Clothes should be washed in a mild detergent with no bleach or fabric softener.
• Food avoidance is discussed in Diet, below, and in Causes.

Diet

• Avoid foods that provoke acute allergic reactions (hives, anaphylaxis). Most frequently, allergic reactions occur to peanuts (peanut butter), eggs, seafood, milk, soya, and chocolate. Additionally, advise patients to apply a barrier of petroleum jelly around the mouth prior to eating to prevent irritation from tomatoes, oranges, and other irritating foods.

Activity

Advise patients to avoid activities that cause excessive sweating. Also, swimming in an outdoor pool (or wading pool for babies) in summer provides therapeutic benefit by exposing the person to the sun but avoiding the heat.

MEDICATION

The basis of treatment for atopic dermatitis (AD) is to provide moisturization for dryness, allay pruritus, and manage inflammation of the eczematous lesions.

Drug Category: Anti-inflammatory agents

Provide relief of inflammation of eczematous lesions. Ointment base provides moisturization. White petrolatum is useful to avoid potential sensitization to preservatives in water-based moisturizers.

1) Drug Name Hydrocortisone ointment 1% (Cortaid)

Description Mild topical corticosteroid mixed in petrolatum. Has mineralocorticoid and glucocorticoid effects and anti-inflammatory activity.

Use 1% ointment 2-3 times daily.

Adult Dose Apply sparingly to affected areas bid/tid; discontinue when cleared

Pediatric Dose Apply as in adults

Contraindications Documented hypersensitivity; clinical viral, fungal, and bacterial skin infections

Interactions None reported

Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Caution around eyes, prolonged use, and application over large surface areas; occlusive dressings may increase systemic absorption of corticosteroids

2) Drug Name Betamethasone valerate (Beta-Val)

Description Medium-strength topical corticosteroid for body areas. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.

Use 0.05-0.1% ointment in adults and 0.05% ointment in pediatrics.

Adult Dose Apply topically bid/tid until response; discontinue when cleared

Pediatric Dose Administer as in adults

Contraindications Documented hypersensitivity; skin infections

Interactions None reported

Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Can cause atrophy of groin, face, and axillae; may cause striae distensae in teenagers or rosacealike eruption; may increase skin fragility; rarely, may suppress HPA axis; if infection is present, discontinue use until infection is under control

Drug Category: Antihistamines

Provide symptomatic relief of pruritus.

1) Drug Name Hydroxyzine hydrochloride (Atarax)

Description Antihistamine with antipruritic, anxiolytic, and mild sedative effects. Antagonizes H1 receptors in periphery. May suppress histamine activity in subcortical region of CNS.

Syr available as 10 mg/5 mL.

Adult Dose 25-50 mg PO tid/qid prn

Pediatric Dose <6 years: 30-50 mg/d PO (2 mg/kg/d) in divided doses

>6 years: 50-100 mg/d PO in divided doses

Contraindications Documented hypersensitivity

Interactions CNS depression may increase with alcohol or other CNS depressants

Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Associated with clinical exacerbations of porphyria (may not be safe for patients with porphyria); ECG abnormalities (alterations in T waves) may occur; may cause drowsiness; caution operating automobiles and other dangerous machinery; anticholinergic effects (ie, dry mouth) may occur

2) Drug Name Diphenhydramine (Benadryl)

Description Antihistamine used for pruritus and allergic reactions.

Adult Dose Cap: 25-50 mg tid/qid prn

Elix: 10-20 mL (12.5 mg/5 mL) q4-6h; not to exceed 4 doses/d

Pediatric Dose Cap

<10 years: Not recommended

>10 years: 25 mg PO tid/qid prn

Elix (12.5 mg/5 mL)

6-12 years: 12.5-25 mg every 4-6 hours

>12 years: Administer as in adults

Children's liquid (6.25 mg/5 mL)

<2 years: 2.5 mL q6h prn

2-6 years: 5 mL q6h prn

6-12 years: 10-20 mL q6h prn; not to exceed 4 doses/d or 5 mg/kg/d

Contraindications Documented hypersensitivity; children with chronic lung disease; glaucoma

Interactions Potentiates effect of CNS depressants; as a result of alcohol content, do not administer elix to patient taking medications that can cause disulfiramlike reactions

Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur; caution operating automobiles and other dangerous machinery because of possible sedation; as a result of atropinelike action, caution in history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension

Drug Category: Immunomodulators

For treatment of patients with severe disease in whom conventional therapy is ineffective. In more severe cases and particularly in adults, consider using both MTX and cyclosporine. The latter is more efficacious, but lesions recur when it is stopped.

1) Drug Name Cyclosporine (Neoral, Sandimmune)

Description Demonstrated to be helpful in a variety of skin disorders, especially psoriasis. Acts by inhibiting T-cell production of cytokines and ILs. Like tacrolimus and pimecrolimus (ascomycin), cyclosporine binds to macrophilin and then inhibits calcineurin, a calcium-dependent enzyme, which, in turn, inhibits phosphorylation of nuclear factor of activated T cells and inhibits transcription of cytokines, particularly IL-4. Discontinue treatment if no response within 6 wk.

Adult Dose 2 mg/kg/d PO divided bid; if no improvement within 1 mo, may be increased gradually; not to exceed 5 mg/kg/d

As skin lesions improve, reduce dose by 0.5-1 mg/kg/d/mo; lowest effective dose for maintenance

Pediatric Dose 5 mg/kg/d PO for 6 wk (see note in Contraindications)

Contraindications Absolute: Significantly decreased renal function, uncontrolled hypertension, hypersensitivity to cyclosporine, clinically cured or persistent malignancy (except nonmelanoma skin cancer)

Relative: Age <18 y or >64 y (however, cyclosporine A at 5 mg/kg/d for 6 wk has been shown to be effective and well tolerated in children aged 2-16 y with severe AD), controlled hypertension, planning to receive a live-attenuated vaccine, active infection or evidence of immunodeficiency, concurrent phototherapy, coal tar, MTX (or other immunosuppressive agents), pregnancy or lactation, unreliable patient, severe hepatic dysfunction

Interactions Erythromycin, clarithromycin, azithromycin, norfloxacin ciprofloxacin, cephalosporins, doxycycline, ketoconazole, itraconazole, fluconazole, ritonavir, indinavir, saquinavir, nelfinavir, diltiazem, verapamil, nicardipine, cimetidine, methylprednisolone, dexamethasone, thiazides, furosemide, allopurinol, bromocriptine, danazol, amphotericin B, metoclopramide, oral contraceptive pills, warfarin, and grapefruit juice increase levels

Rifampin, rifabutin, nafcillin, carbamazepine, phenobarbital, phenytoin, valproate, octreotide, and ticlopidine decrease levels

Tobramycin, gentamicin, ketoconazole, azapropazone, TMP-SMZ, vancomycin, sulindac, amphotericin B, indomethacin, naproxen, cimetidine, ranitidine, diclofenac, tacrolimus, and melphalan potentiate renal toxicity

Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Evaluate renal and liver function often by measuring BUN, serum creatinine, serum bilirubin, and liver enzyme levels; may increase risk of infection and lymphoma; reserve IV use only for patients who cannot take PO; development of malignancies (particularly skin) has been reported; perform biopsy on skin suggestive of malignancy or premalignancy and, if malignant, discontinue use

2) Drug Name Methotrexate (Folex PFS, Rheumatrex)

Description Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction. Satisfactory response seen 3-6 wk following administration.

Adjust dose gradually to attain satisfactory response.

Adult Dose 10-25 mg/wk PO/IM or 2.5-7.5 mg PO q12h for 3 doses/wk

Pediatric Dose Not established

Contraindications Absolute: Pregnancy or desire to become pregnant, active peptic ulcer, alcoholism, primary/secondary immunodeficiency, blood dyscrasias, active hepatitis, cirrhosis, chronic renal failure, active infections

Relative: History of excessive alcohol intake or substance abuse, increased LFT results, recent hepatitis, diabetes, obesity, family history of heritable liver disease, unreliable patient, CrCl <50 mL/min, male contemplating conception (must not take for 3 mo)

Interactions Salicylates, NSAIDS, dipyridamole, probenecid, retinoids, ethanol, triamterene, pyrimethamine, sulfonamides, tetracycline, chloramphenicol, penicillin or other broad-spectrum antibiotics, trimethoprim, dapsone, theophylline, phenytoin, phenothiazines, barbiturates and nitrofurantoin (impair folic acid absorption), ascorbic acid, phenylbutazone, cyclosporin, and aminoglycosides

Pregnancy X - Contraindicated; benefit does not outweigh risk

Precautions Monitor CBC count, renal panel, urinalysis, and LFTs at 1 wk initially and after dose increases, and monitor liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood cell counts occurs; fatal reactions reported when administered concurrently with NSAIDs

3) Drug Name Tacrolimus (Protopic) ointment 0.03% or 0.1%

Description Immunomodulator that suppresses humoral immunity (T-lymphocyte) activity. Used for refractory disease.

Adult Dose Apply a thin layer to affected areas bid; continue for 1 wk after symptoms clear

Pediatric Dose <2 years: Not established

2-15 years: Only the 0.03% ointment is indicated

Contraindications Documented hypersensitivity

Interactions Topical tacrolimus is minimally absorbed; however, levels may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, or clarithromycin; levels may reduce with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine

Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions Do not use with occlusive dressings; may be associated with an increased risk of folliculitis in adults; may cause local burning sensation, stinging, soreness, or pruritus (typically improve as lesions heal); for external use only; minimize exposure to natural or artificial sunlight (eg, tanning beds or UVA/B treatment); be sure skin is completely dry before application; product insert for tacrolimus revised in January 2006 and contains a black box warning stating the long-term safety of calcineurin inhibitors has not been established; although a causal relationship has not been established, rare cases of malignancy (eg, skin, lymphoma) reported; only 0.03% ointment is indicated for use in children aged 2-15 y

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