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C1 esterase inhibitor
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C3a
C5b
C6
CD55
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This patient presenting with a fever and pruritic, urticarial rash on her torso and extremities 1 week after starting rituximab therapy has serum sickness. Serum sickness is an immune complex disease that is characterized by complement activation, of which C3a causes mast cell degranulation leading to a pruritic urticarial rash. Serum sickness is a type III, or immune complex-mediated, hypersensitivity reaction. Upon exposure to a heterologous antigen, IgM and IgG antibodies form against that antigen, leading to immune complex formation and deposition. These immune complexes then activate the complement pathway, which leads to the formation of the C1 complex. C4 and C2 also bind to the immune complex, leading to the formation of the C3 convertase. This cleaves C3 into C3a and C3b. C3a is a potent anaphylatoxin that causes mast cell degranulation, leading to increased vascular permeability and a pruritic, urticarial skin rash. C3b then cleaves C5 into C5a and C5b. C5a serves to attract neutrophils, further potentiating the inflammatory response, and is also an anaphylatoxin. C5b is combined with C6, C7, C8, and C9 to form the membrane attack complex (MAC). Serum sickness presents with a fever, malaise, polyarthralgias, and a skin rash within 1-2 weeks after exposure to a heterologous antigen. Common foreign proteins that cause this reaction include equine anti-botulinum toxin, equine anti-diphtheria, rituximab (murine/human chimeric antibody), and infliximab (murine/human chimeric antibody). The diagnosis is clinical and treatment is with discontinuation of the offending agent. Antihistamines can be used to treat pruritic rashes. Karmacharya et al. performed a review of rituximab-induced serum sickness. The authors found that the majority of patients studied had an underlying rheumatologic condition such as Sjogren syndrome and the classic triad of symptoms (fever, rash, arthralgia) were present in 49% of cases. They recommended that further infusions of rituximab be avoided in these patients, as it may cause more severe symptoms. Incorrect Answers: Answer 1: C1 esterase inhibitor is a protease inhibitor present in the plasma that normally functions to inhibit activation of the complement cascade at baseline. C1 esterase inhibitor deficiency causes hereditary angioedema. Patients with hereditary angioedema present with recurrent non-urticarial angioedema affecting the skin, upper respiratory tract, or gastrointestinal system. Answers 3 and 4: C5b is created after C5 is split into C5a and C5b. C6, C7, C8, and C9 then attach to C5b, forming the MAC. The MAC inserts into bacterial cell membranes, leading to lysis. Patients who are deficient in C5 or C6 have an increased susceptibility to Neisseria infections (e.g., meningitis) due to inability to form the MAC, which is critical for the destruction of this bacteria. Neisseria meningitis presents with fever, nuchal rigidity, altered mental status, and a maculopapular rash. Answer 5: CD55, also known as decay accelerating factor, regulates the classical and alternative complement pathways. Deficiency of CD55 causes paroxysmal nocturnal hemoglobinuria, which presents with fatigue, jaundice, and hemolytic anemia. Hemolytic episodes are caused by unregulated activation of the complement pathway on red blood cells, leading to lysis. These episodes increase at night. A rash would be unexpected. Bullet Summary: Serum sickness is a type III hypersensitivity reaction that is mediated by immune complex formation and activation of complement including C3a, which causes vascular permeability and a pruritic, urticarial rash.
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