A 6-year-old girl is brought to the clinic due to an itchy rash on her face. The patient's mother says the rash began approximately 3 weeks ago as dry skin on both of her cheeks. Over the past few days, it has progressed with areas of weeping and increased redness, and the patient has had to wear mittens to limit irritation from constant scratching. The patient has a history of similar rashs involving the flexural areas of her elbows and knees that resolved following treatment with topical corticosteroids. Vital signs are normal. Physical examination shows erythema of the bilateral cheeks and chin with crusting and oozing. The patient is prescribed a course of topical tacrolimus. Which of the following is the most likely mechanism of action of this drug?

Question

A 6-year-old girl is brought to the clinic due to an itchy rash on her face.  The patient's mother says the rash began approximately 3 weeks ago as dry skin on both of her cheeks.  Over the past few days, it has progressed with areas of weeping and increased redness, and the patient has had to wear mittens to limit irritation from constant scratching.  The patient has a history of similar rashs involving the flexural areas of her elbows and knees that resolved following treatment with topical corticosteroids.  Vital signs are normal.  Physical examination shows erythema of the bilateral cheeks and chin with crusting and oozing.  The patient is prescribed a course of topical tacrolimus.  Which of the following is the most likely mechanism of action of this drug?

Quizplus · Accepted Answer

11ec160b_3ba5_4212_9249_fb2058439497_MD0001_00 This patient most likely has atopic dermatitis (eczema), an inflammatory condition that begins in infancy or early childhood. Pathogenesis involves genetically mediated skin barrier dysfunction (eg, filaggrin mutation) and a dysregulated immune response that favors IgE production, mast cell and eosinophil activation, and overproduction of Th2 cytokines. Loss of epidermal water content, increased permeability to allergens/irritants, and inflammation result in dry skin, intense pruritus, erythema, and, sometimes, weeping and crusting (as seen in this patient). Distribution typically includes the face and the flexural areas of the elbows and knees in children. First-line treatment of atopic dermatitis is topical corticosteroids. However, due to concerns for corticosteroid-induced atrophy in areas with thin skin (eg, face, neck, axilla, groin), second-line therapy with calcineurin inhibitors (eg, tacrolimus, pimecrolimus) can be used instead. Through the inhibition of calcineurin, a lymphocyte-specific phosphatase, these medications inhibit T-cell signaling that would normally lead to transcription of the proinflammatory cytokine IL-2. Reduced IL-2 leads to decreased T-cell activation and proliferation, and, in turn, inflammation. (Choices A and C) Cromolyn is a mast cell stabilizer that inhibits histamine granule release from mast cells and can be used to treat allergic rhinitis or systemic mastocytosis. Omalizumab, a monoclonal anti-IgE antibody, prevents binding of IgE to mast cells and basophils and is most commonly used to treat persistent, severe asthma. (Choice D) IL-4 stimulates IgE production and the differentiation of naïve CD4 T cells to Th2 cells, which exacerbate the inflammatory response in atopic dermatitis. Dupilumab is a human monoclonal antibody that inhibits IL-4 action by antagonizing the IL-4 receptor. It can be considered for severe atopic dermatitis refractory to topical therapies. (Choice E) Rituximab is a monoclonal antibody against the CD20 antigen on B lymphocytes. Once bound, rituximab initiates complement and cell-mediated B-cell cytotoxicity. It is used to treat hematologic malignancies (eg, chronic lymphocytic leukemia) and rheumatologic diseases (eg, rheumatoid arthritis). Educational objective: Atopic dermatitis is an inflammatory condition that can be treated with calcineurin inhibitors (eg, pimecrolimus, tacrolimus) as second-line therapy after topical corticosteroids. Calcineurin inhibitors work by inhibiting T-cell signaling needed to transcribe the proinflammatory cytokine IL-2, thereby decreasing inflammation.

A 6-Year-Old Girl Is Brought to the Clinic Due to an Itchy