A 35-year-old woman is admitted to the medical unit for worsening renal failure. Prior to admission, she was seen by her rheumatologist for a follow-up visit and was found to have significant proteinuria and hematuria on urinalysis and an elevated serum creatinine. She reports feeling ill and has noticed blood in her urine. She was diagnosed with systemic lupus erythematosus at the age of 22, and she is currently being treated with ibuprofen for joint pain and prednisone for acute flare-ups. Her blood pressure is 165/105 mmHg. Laboratory testing is remarkable for hypocomplementemia and an elevated anti-DNA antibody. A renal biopsy is performed, which demonstrates 65% glomerular involvement along with the affected glomeruli demonstrating endocapillary and extracapillary glomerulonephritis. In addition to glucocorticoid therapy, the medical team will add mycophenolate mofetil to her treatment regimen. Which of the following is the mechanism of action of mycophenolate mofetil?

Inosine monophosphate dehydrogenase inhibitor

Interleukin-2 receptor complex inhibitor

mTOR inhibitor via FKBP binding

Calcineurin inhibitor via cyclophilin binding

A 44-year-old man, with a history of intravenous (IV) drug use, presented to the emergency department due to worsening non-productive cough, exertional dyspnea, and night sweats. His cough started 3 weeks ago and progressively worsened. He is homeless and well-known by the hospital staff. He was previously admitted to the hospital after an overdose of opioids. He takes no medication. At the hospital, the vital signs included: blood pressure 101/68 mm Hg, heart rate 99/min, respiratory rate 20/min, oxygen saturation of 91% on room air, and oral temperature of 37.4°C (99.3°F). His chest X-ray showed left perihilar shadowing. The laboratory results included: WBC count 8,800/mm3 Arterial pH 7.39 Rapid HIV testing positive with an elevated viral load PaCO2 41 mm Hg PaO2 76 mm Hg He was admitted for the treatment of presumed sepsis and pneumonia, and he was immediately started on IV ceftriaxone. An induced sputum specimen shows multiple kidney bean-shaped cysts that are approximately 5 um. These cysts stain positive with methenamine silver. What is the preferred antibiotic therapeutic regimen for this condition?

Intravenous liposomal amphotericin B with flucytosine

Isoniazid, rifabutin, pyrazinamide and ethambutol

Clindamycin and primaquine, with adjunctive prednisone

A 38-year-old woman comes to the physician for a follow-up examination. Two years ago, she was diagnosed with multiple sclerosis. Three weeks ago, she was admitted and treated for right lower leg weakness with high-dose methylprednisone for 5 days. She has had 4 exacerbations over the past 6 months. Current medications include interferon beta and a multivitamin. Her temperature is 37°C (98.6°F), pulse is 90/min, and blood pressure is 116/74 mm Hg. Examination shows pallor of the right optic disk. Neurologic examination shows no focal findings. She is anxious about the number of exacerbations and repeated hospitalizations. She is counseled about the second-line treatment options available to her. She consents to treatment with natalizumab. However, she has read online about its adverse effects and is concerned. This patient is at increased risk for which of the following complications?

Progressive multifocal leukoencephalopathy

Syndrome of inappropriate antidiuretic hormone

Costimulation blockers for USMLE Step 2 CK: High-Yield Pharmacology Lessons

Costimulation Blockade - T-Cell Handshake Denied

Full T-cell activation requires two distinct signals. Blocking the second signal prevents the immune response, inducing a state of T-cell anergy (inactivation).

Signal 1 (Antigen Recognition): T-cell receptor (TCR) on the T-cell binds to the Major Histocompatibility Complex (MHC) on an Antigen-Presenting Cell (APC).
Signal 2 (Costimulation): The CD28 protein on the T-cell must bind to a B7 protein (CD80 or CD86) on the APC.

T-cell costimulation: anergy, activation, and CTLA-4

Mechanism of Action: Costimulation blockers are fusion proteins that act as high-affinity decoys for the B7 protein, preventing it from binding to CD28 and thus denying the crucial "go" signal for T-cell activation.

⭐ Belatacept binds B7 proteins with higher avidity than Abatacept but carries a black box warning for increased risk of Post-Transplant Lymphoproliferative Disorder (PTLD), especially in patients who are Epstein-Barr Virus (EBV) seronegative.

The Drugs - Meet the Blockers

Both are CTLA-4-Ig fusion proteins that bind to CD80/86 on antigen-presenting cells, preventing T-cell activation by blocking the CD28 costimulatory signal.

Feature	Belatacept	Abatacept
Binding	Higher affinity & avidity	Lower affinity & avidity
Primary Use	Kidney transplant rejection prophylaxis	Rheumatoid & psoriatic arthritis

⭐ Exam Favorite: Belatacept carries a black box warning for an increased risk of post-transplant lymphoproliferative disorder (PTLD), especially in patients who are Epstein-Barr Virus (EBV) seronegative.

Adverse Effects - The Dark Side

Black Box Warning for PTLD: Increased risk of Post-Transplant Lymphoproliferative Disorder, a type of lymphoma, particularly involving the central nervous system.
- Risk is highest in EBV-seronegative patients, as they lack immunity to Epstein-Barr virus.
- Screening for EBV serostatus is mandatory before starting therapy.
Infections & Malignancy:
- Increased risk of opportunistic infections, including tuberculosis and cytomegalovirus (CMV).
- Progressive Multifocal Leukoencephalopathy (PML) due to JC virus reactivation.
- Higher incidence of skin cancer; advise sun protection.
Other Side Effects:
- Infusion-related reactions.
- Anemia, leukopenia.
- Hypertension, peripheral edema.

⭐ Exam Favorite: Belatacept is contraindicated in EBV-seronegative patients due to the prohibitively high risk of PTLD. This is a major safety checkpoint on board exams.

High‑Yield Points - ⚡ Biggest Takeaways

Abatacept and Belatacept are fusion proteins (CTLA4-Ig) that function as costimulation blockers.

They bind to CD80/86 on antigen-presenting cells, preventing interaction with CD28 on T-cells.

This blockade of the second signal of T-cell activation induces anergy.

Belatacept has higher avidity and is used in kidney transplant rejection prophylaxis.

Major side effects include ↑ risk of infections and PTLD, especially in EBV-seronegative patients.

Unlike calcineurin inhibitors, they are not nephrotoxic.

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