A 57-year-old woman comes to the emergency department due to cough and hemoptysis. The patient also reports several months of fatigue and joint pain. Physical examination is notable for crusting of the nasal mucosa, lung crackles, and scattered palpable purpura over the lower extremities. Chest x-ray reveals bilateral, diffuse alveolar infiltrates. Laboratory studies show normocytic anemia, red blood cell casts and protein in the urine, and positive c-ANCA. After a confirmatory biopsy, treatment with rituximab infusion is planned. This medication is most likely to improve this patient's condition via which of the following mechanisms?
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This patient's clinical picture is consistent with granulomatosis with polyangiitis (GPA), a c-ANCA–positive inflammatory vasculitis that primarily attacks the upper/lower respiratory tract, kidneys, and skin. Molecular and immunologic advances have led to a dramatic expansion in treatments for chronic systemic inflammatory diseases such as GPA; treatments are generally classified as follows:
Cytokine inhibitors: These bind free inflammatory cytokines or block cytokine receptors on cell surfaces; they target tumor necrosis factor (eg, infliximab, etanercept), IL-1, IL-6, IL-17, or IL-12/23 (Choice E).
T-cell costimulation inhibitors: Two steps are required to activate cytotoxic T cells. The T cell must bind a specific antigen on the major histocompatibility complex type 1 of an antigen-presenting cell, and then the T cell must be costimulated by the interaction between the T-cell surface receptor CD28 and the antigen-presenting cell surface ligand CD80/86. T-cell costimulatory inhibitors (eg, abatacept) block the CD28 receptor on the cytotoxic T cell, which prevents T-cell costimulation and causes T-cell anergy (Choice A).
B-cell depletion or inhibition: Because B cells generate inflammatory cytokines, promote T-cell activation, and differentiate into plasma cells that generate autoantibodies, medications that inhibit B-cell activation (eg, belimumab) or deplete B-cell populations (eg, rituximab) are highly effective in many systemic inflammatory disorders.
Rituximab is an IgG monoclonal antibody against CD20, a surface molecule present on developing and mature B cells. Binding of rituximab to CD20 results in Fc receptor–mediated B-cell cytotoxicity and antibody-dependent B-cell phagocytosis, which significantly reduces the B-cell population. Although existing plasma cells are unaffected (they do not express CD20), the reduction in total B-cell population significantly improves inflammatory symptoms. However, depletion of B cells also increases the risk for severe and recurrent bacterial infections, a major adverse effect of therapy.
(Choice C) Natalizumab is a monoclonal antibody against integrin, an adhesion molecule that mediates leukocyte interaction with the endothelium and subsequent leukocyte attachment/migration into tissue. Natalizumab is used in relapsing-remitting multiple sclerosis.
(Choice D) Cytoplasmic kinases (eg, Janus kinase) transmit inflammatory cytokine receptor binding to the nucleus. Rituximab does not operate via this mechanism, but new therapies that target these intracellular signaling pathways are under development.
Educational objective:
Rituximab is a monoclonal antibody directed against CD20, a cell surface receptor on developing and mature B cells. Binding of rituximab to CD20 results in B-cell cytotoxicity and phagocytosis, which reduces the B-cell population. This reduces inflammatory symptoms in a wide range of rheumatologic diseases.