A 22-year-old man comes to the physician for a follow-up evaluation for chronic lower back pain. He has back stiffness that lasts all morning and slowly improves throughout the day. He has tried multiple over-the-counter medications, including ibuprofen, without any improvement in his symptoms. Physical examination shows tenderness over the iliac crest bilaterally and limited range of motion of the lumbar spine with forward flexion. The results of HLA-B27 testing are positive. An x-ray of the lumbar spine shows fusion of the lumbar vertebrae and sacroiliac joints. The physician plans to prescribe a new medication but first orders a tuberculin skin test to assess for the risk of latent tuberculosis reactivation. Inhibition of which of the following is the most likely primary mechanism of action of this drug?

Inosine monophosphate dehydrogenase

A 62-year-old man, a retired oil pipeline engineer, presents to his primary care physician with complaints of headaches, fatigue, and constant ringing in his ears. Recurrently he has developed pruritus, usually after a hot shower. He also noted a constant burning sensation in his fingers and toes, independent of physical activity. On examination, he has a red face and his blood pressure levels are 147/89 mm Hg. A CBC revealed that his Hb is 19.0 g/dL and Hct is 59%. Because of his condition, his physician prescribes him 81 mg of aspirin to be taken daily in addition to therapeutic phlebotomy. Which of the statements below is true about this patient’s condition?

Mutation of the JAK2 gene is commonly seen in this condition.

Warfarin and phlebotomy are the preferred course of treatment.

The patient has a decreased risk of developing myelofibrosis.

Serum erythropoietin is expected to be high.

Arterial oxygen saturation is usually higher than normal values in this condition.

A 46-year-old male presents to his dermatologist for routine follow-up of his psoriasis. He was last seen in the office six months prior, at which time he started undergoing ultraviolet light therapy. He reports that he initially noticed an improvement in his symptoms but the effects were transient. He has also started noticing pain and stiffness in his fingers. His past medical history is notable for obesity and diabetes mellitus. He takes metformin. His temperature is 99°F (37.2°C), blood pressure is 130/80 mmHg, pulse is 80/min, and respirations are 16/min. Multiple plaques with scaling are noted on the extensor surfaces of the upper and lower extremities. The patient’s physician suggests stopping the ultraviolet light therapy and starting an injectable medication that acts as a decoy receptor for a pro-inflammatory cytokine. Which of the following is an adverse effect associated with the use of this medication?

Reactivation of latent tuberculosis

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

A 53-year-old man with hyperlipidemia comes to the physician for a follow-up examination. His home medications include acetaminophen and atorvastatin. Serum studies show elevated total cholesterol and triglyceride concentrations. A drug that activates the peroxisome proliferator-activated receptor alpha is added to his existing therapy. This patient is at highest risk for developing which of the following drug-related adverse effects?

Reddish-brown discoloration of urine

Acutely swollen and painful joint

Pruritus and flushing of the skin

A 49-year-old woman presents to her primary care doctor in late December with malaise. She reports worsening fatigue, myalgias, headache, and malaise that started 1 day ago. She works as a lunch lady at an elementary school. Her past medical history is notable for a distal radius fracture after a fall 2 years ago, but she is otherwise healthy and takes no medications. She does not smoke or drink alcohol. She is married and has 3 adult children who are healthy. Her temperature is 102.9°F (39.4°C), blood pressure is 101/61 mmHg, pulse is 112/min, and respirations are 21/min. On exam, she appears lethargic and uncomfortable but is able to answer questions appropriately. Breath sounds are normal bilaterally. She is started on intravenous fluids and a pharmacologic agent for treatment. Which of the following is the most likely mechanism of action of the drug being used to treat this patient?

Reverse transcriptase inhibitor

RNA-dependent polymerase inhibitor

JAK inhibitors for USMLE Step 1: High-Yield Pharmacology Lessons

Mechanism of Action - Nipping Cytokines in the Bud

JAK-STAT pathway and JAK inhibitor mechanism

JAK inhibitors are small molecules that block the intracellular Janus Kinase (JAK) family of tyrosine kinases, preventing the phosphorylation and activation of Signal Transducer and Activator of Transcription (STAT) proteins.
This blockade disrupts the signaling cascade from numerous cytokine receptors on the cell surface to the nucleus.
Net Effect: ↓ transcription of key pro-inflammatory cytokines (e.g., IL-2, IL-6, IL-12, IL-23, IFN-γ).

⭐ Unlike biologic DMARDs (e.g., monoclonal antibodies) that target extracellular cytokines or receptors, JAK inhibitors work intracellularly, blocking the final common pathway for numerous cytokines.

The '-citinibs' - Rogues' Gallery

📌 Mnemonic: Think of the "-citinib" (sit-in-ib) crew that 'sits on' and inhibits the JAK-STAT pathway.

Drug Name	JAK Specificity	Key FDA-Approved Indications	Unique/Notable Feature
Tofacitinib	JAK1/JAK3 > JAK2	RA, PsA, UC, JIA	First-in-class oral JAK inhibitor.
Baricitinib	JAK1/JAK2	RA, Alopecia Areata, COVID-19	Also approved for hospitalized COVID-19 patients.
Upadacitinib	Selective JAK1	RA, PsA, UC, Atopic Derm	Higher selectivity for JAK1 aims to reduce off-target effects.

Adverse Effects - The JAK Side

Pre-Screening: Before initiation, screen for latent TB (IGRA/TST) and viral hepatitis (HBV, HCV). Establish baseline CBC, LFTs, and a lipid panel.
⚠️ BLACK BOX WARNINGS
- Serious Infections: High risk for bacterial, fungal, and viral infections. Herpes Zoster reactivation is particularly notable.
- Malignancy: Increased risk of lymphomas and other cancers.
- Thrombosis: ↑ risk of Pulmonary Embolism (PE), Deep Vein Thrombosis (DVT), and arterial thrombosis.
- MACE: Major Adverse Cardiovascular Events (e.g., MI, stroke).
- Mortality: ↑ all-cause mortality (seen with tofacitinib).
Lab Monitoring:
- CBC: Neutropenia, anemia.
- Lipids: Hyperlipidemia (↑ LDL, ↑ HDL).
- LFTs: Elevated liver enzymes.

⭐ The risk of Herpes Zoster reactivation is a hallmark adverse effect, significantly more pronounced with JAK inhibitors than with biologics like TNF-α inhibitors.

Herpes Zoster Rash on Torso

High‑Yield Points - ⚡ Biggest Takeaways

JAK inhibitors like Tofacitinib work by blocking the JAK-STAT signaling pathway, which is crucial for the action of numerous pro-inflammatory cytokines.

Primarily used for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis, especially in patients who have failed TNF-α inhibitors.

A key advantage is their oral administration.

BLACK BOX WARNINGS include increased risk of serious infections (tuberculosis), malignancy (lymphoma), and thrombosis (pulmonary embolism, DVT).

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JAK inhibitors