JAK inhibitors: tofacitinib and baricitinib
JAK inhibitors such as tofacitinib and baricitinib are oral drugs that block Janus kinases (enzymes inside the cell), dampening signals from many cytokines (chemical messengers between immune cells).
Remember
JAK inhibitors block Janus kinases inside the cell and so dampen many cytokines at once, whereas biologics (protein drugs) each act on a single target. The MHRA (the UK medicines regulator) advises avoiding JAK inhibitors in people aged 65 or over unless there is no suitable alternative.
Tofacitinib and baricitinib are JAK inhibitors (JAK stands for Janus kinase). They are oral small molecules classed as targeted synthetic DMARDs. A DMARD is a disease-modifying anti-rheumatic drug, one that slows the disease itself rather than only easing symptoms. Targeted synthetic means made by chemical synthesis rather than grown from living cells, and aimed at a defined target. A biologic is a protein drug such as an antibody.
Janus kinases are enzymes inside the cell, attached to many cytokine receptors. A kinase is an enzyme that adds a phosphate group to another protein, which passes a signal on. In rheumatoid arthritis, several cytokines drive joint inflammation. A cytokine docks on its receptor, then the JAK relays the message to the nucleus through the JAK-STAT pathway (STAT stands for signal transducer and activator of transcription), and inflammatory genes are switched on.
One JAK serves many cytokine receptors, so blocking it dampens several cytokine signals at once. This is a broad cytokine blockade. A biologic acts on one target outside the cell, such as tumour necrosis factor alpha (TNF alpha).
That broad cytokine blockade is the likely link between the benefit and the harm of JAK inhibitors. The Medicines and Healthcare products Regulatory Agency (MHRA), the UK medicines regulator, reports that in trials in rheumatoid arthritis, patients with certain risk factors who took some JAK inhibitors, particularly tofacitinib, had more major adverse cardiovascular events (such as heart attack or stroke), malignancy (cancer), venous thromboembolism (blood clots in the deep veins or lungs), serious infection and death than those given TNF inhibitors (biologics that target TNF alpha). It advises avoiding a JAK inhibitor unless there are no suitable alternatives in people aged 65 or over, long-time smokers and those with other cardiovascular or malignancy risk factors.
Key facts
- Class
- oral targeted synthetic DMARDs, including tofacitinib, baricitinib and upadacitinib.
- Target
- JAK1, JAK2 and JAK3, to varying extents, inside the cell, attached to many cytokine receptors.
- Effect
- a broad cytokine blockade rather than the blockade of one cytokine.
- Contrast
- biologics are protein drugs that act outside the cell on a single target.
- Safety warnings
- in rheumatoid arthritis trials, the MHRA found more major adverse cardiovascular events, malignancy, venous thromboembolism, serious infection and death with JAK inhibitors than with TNF inhibitors in patients with certain risk factors.
- Higher-risk groups
- age 65 or over, current or past long-time smoking, and other cardiovascular or malignancy risk factors.
Exam traps
- Neutralising tumour necrosis factor alpha is how the anti-TNF biologics work, not tofacitinib. Those are protein drugs that target one cytokine, whereas tofacitinib is a small oral molecule that acts inside the cell on several cytokine pathways at once.
- Blocking the receptor for one cytokine, interleukin-6, from outside the cell is how tocilizumab works. JAK inhibitors also dampen interleukin-6 signalling, but they do so by acting on enzymes inside the cell, alongside many other cytokine pathways.
- Depleting B cells (the cells that make antibodies) is the action of rituximab, an antibody aimed at the CD20 surface antigen. It removes a cell type, whereas a JAK inhibitor is a small molecule that blocks cytokine signalling inside cells.
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