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Hepatotoxicity
13%
37/275
Hyperglycemia
7%
20/275
Nephrotoxicity
61%
169/275
Osteoporosis
4%
10/275
Pancytopenia
18/275
Select Answer to see Preferred Response
This woman’s presentation of symmetric pain, swelling, and morning stiffness that improves with use is characteristic of rheumatoid arthritis, which can be treated with highly nephrotoxic calcineurin inhibitors. Calcineurin inhibitors, which include cyclosporine and tacrolimus (FK506), are immunosuppressant drugs that block T-lymphocyte activation by preventing transcription of IL-2. Cyclosporine binds cyclophilin while tacrolimus binds FK506 binding protein (FKBP) to form a complex that inhibits calcineurin, a protein phosphatase, when activated, upregulates IL-2 gene transcription to enhance the growth and differentiation of T-lymphocytes. When calcineurin is inhibited, it prevents the dephosphorylation of NFAT which remains inactive and cannot upregulate IL-2 transcription. The major adverse effect of calcineurin inhibitors is nephrotoxicity; other adverse effects include hypertension, hyperlipidemia, hyperglycemia, and neurotoxicity. Calcineurin inhibitors are also commonly used clinically for the treatment of psoriasis. Incorrect Answers: Answer 1: Hepatotoxicity is a potential adverse effect of azathioprine and 6-mercaptopurine, antimetabolite drugs that are also used in the treatment of rheumatoid arthritis. Answer 2: Hyperglycemia is a potential adverse effect of glucocorticoids and mycophenolate mofetil, an immunosuppressant drug that reversibly inhibits IMP dehydrogenase to prevent purine synthesis in B- and T-lymphocytes. Hyperglycemia can also be a result of tacrolimus administration, but this is not the most concerning toxicity associated with calcineurin inhibitors. Answer 4: Osteoporosis is a potential adverse effect of glucocorticoids, which have an immunosuppressant mechanism of inhibiting NF-kB to suppress lymphocyte function by decreasing the transcription of many cytokines. Answer 5: Pancytopenia is a potential adverse effect of azathioprine, mycophenolate mofetil, and sirolimus, an immunosuppressant drug that blocks T-lymphocyte activation and B-lymphocyte differentiation by preventing a response to IL-2. Bullet Summary: Calcineurin blocks production of IL-2 and can cause nephrotoxicity.
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