Mechanism of Action of Tofacitinib (Xeljanz)

Introduction

Tofacitinib is an oral Janus kinase (JAK) inhibitor, primarily targeting JAK1 and JAK3. It blocks intracellular signaling of multiple inflammatory cytokines and is approved for rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC), and other immune-mediated diseases.

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Step-by-Step Mechanism of Action

1. Inhibition of JAK1 and JAK3
   Tofacitinib competitively blocks ATP-binding sites of JAK1 and JAK3, thus preventing their phosphorylation and activation.
2. Disruption of STAT phosphorylation
   Without activated JAKs, STAT transcription factors can’t be phosphorylated and fail to translocate to the nucleus.
3. Downregulation of cytokine gene expression
   Inhibition of STAT signaling leads to reduced transcription of genes encoding inflammatory cytokines like IL‑2, IL‑4, IL‑6, IL‑7, IL‑9, IL‑15, and IL‑21.
4. Dampening of immune cell activation
   The result is reduced T-cell, B-cell, and natural killer (NK) cell activity, and decreased production of inflammatory mediators.
5. Clinical anti-inflammatory and immunomodulatory effects
   These molecular actions translate to improved symptoms and reduced tissue damage in various autoimmune and inflammatory conditions.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral
Bioavailability	~74%
Time to Peak (Tmax)	~1 hour
Protein Binding	~40%
Metabolism	Hepatic via CYP3A4 (primary) and CYP2C19 (minor)
Half-life	~3 hours
Excretion	~70% via urine (mostly metabolites), ~30% feces

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Clinical Uses

• Moderate to severe rheumatoid arthritis (alone or with methotrexate)
• Active psoriatic arthritis
• Moderate to severe ulcerative colitis
• Off-label uses: alopecia areata, ankylosing spondylitis

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Adverse Effects

• Increased risk of serious infections (e.g., herpes zoster, tuberculosis)
• Elevated LDL and total cholesterol levels
• Cytopenias (lymphopenia, neutropenia, anemia)
• Mild elevation in liver enzymes
• Rare pulmonary embolism and venous thromboembolism—especially at higher doses

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Comparative Analysis

Drug	JAK Target	Dosing	Primary Indications
Tofacitinib	JAK1/3	5 mg twice daily	RA, PsA, UC
Baricitinib	JAK1/2	4 mg once daily	RA
Upadacitinib	JAK1-selective	15 mg once daily	RA, PsA

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MCQs

1. Tofacitinib primarily inhibits which kinases?
   a) JAK2/3 b) JAK1/3 c) SYK d) mTOR
   Answer: b) JAK1/3
2. Its effect on STAT signaling is:
   a) Enhanced phosphorylation b) Blocked phosphorylation c) No effect d) Increased degradation
   Answer: b) Blocked phosphorylation
3. Which cytokine signaling is reduced?
   a) IL‑2 b) IL‑1β c) TNF‑α d) IFN‑γ
   Answer: a) IL‑2
4. Main route of elimination is:
   a) Renal unchanged b) Hepatic excretion c) Metabolite elimination via urine and feces d) Pulmonary
   Answer: c) Metabolite elimination via urine and feces
5. Common adverse effect includes:
   a) Hypoglycemia b) Increased infections c) Hyperthyroidism d) Hypotension
   Answer: b) Increased infections
6. Compared to baricitinib, tofacitinib is:
   a) JAK1/2 selective b) JAK1/3 selective c) Non-selective kinase inhibitor d) A biologic
   Answer: b) JAK1/3 selective
7. It can cause elevation in:
   a) LDL cholesterol b) Sodium c) Bilirubin d) Magnesium
   Answer: a) LDL cholesterol
8. Half-life of tofacitinib is approximately:
   a) 1 hour b) 3 hours c) 8 hours d) 24 hours
   Answer: b) 3 hours
9. Serious but rare risk is:
   a) Myocardial infarction b) Pulmonary embolism c) Hyperkalemia d) Diabetes
   Answer: b) Pulmonary embolism
10. A typical dose for RA is:
    a) 5 mg once daily b) 5 mg twice daily c) 15 mg once daily d) 30 mg weekly
    Answer: b) 5 mg twice daily

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FAQs

1. Are vaccinations required before initiation?
Yes—varicella and zoster vaccines should be updated prior to starting.

2. Should lipids be monitored?
Yes; LDL and total cholesterol typically rise and require monitoring.

3. Can tofacitinib be used with biologics like TNF inhibitors?
No—combining with biologics increases infection risk and is contraindicated.

4. Is dose adjustment needed in renal impairment?
Yes—lower doses are necessary in moderate to severe renal dysfunction.

5. What monitoring is recommended?
Regular CBC, liver enzymes, lipids, and infection screening are advised.

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References

• FDA Label: Tofacitinib (Xeljanz)
• DrugBank: Tofacitinib Summary
• StatPearls: Tofacitinib in Rheumatoid Arthritis and Ulcerative Colitis
• PubMed Review: JAK inhibitors in autoimmune disease