Novel Therapies in RA

Question 1

What are the 4 types of JAKs?

Answer 1

JAK 1, JAK 2, JAK 3 and TYK 2

Question 2

How do JAK STAT pathway.

Answer 2

Protein tyrosine kinases constitutively bound to cytokine/growth factor receptor

Phosphorylates tyrosine residue on receptor

Conformational change allows STAT binding

STAT phosphorylation allows dimerisation

Translocation of STATs to nucleus

Question 3

What is a specific JAK1 inhibitor in development?

Answer 3

JAK1 – GLPG0634 (filgotinib) – specific JAK1 inhibitor

¥ 28-fold selectivity for JAK1 over JAK2
¥ Inhibition of leukocyte activation by IFNα (through pSTAT1) but lack of effect on
¥ GM-CSF (activates pSTAT5 through JAK2)
¥ JAK1 the only JAK to mediate effects of IL-6 on pSTAT1

Question 4

JAK 3 inhibitors

Answer 4

¥ JAK3 maintains IL-10 feedback suppression following LPS
¥ Preserves M2a differentiation/functions

If you take a lot of cells and give them Lipopolysaccharide - it will upregulate Il6 and IL10. IL10 has a feedback loop to control the extent of inflammation.
When you block IL10, you get higher level of IL6. When you don’t block IL10, you get lower levels of IL6 as you have IL6 mediating negative feedback low.
Higher doses – losing the IL10 effect

With JAK 3 inhibitor alone – preserving IL6

JAK 3 mediates signalling of pro-inflammtory cytokines but not anti-inflammatory cytokines.
If you only block JAK 3 you won’t inhibit the function of these anti-inflammatory cytokines such as IL10,27 and 35.
In an inflammatory state, JAK 3 inhibitor you inhibit the pro-inflammatory cytokines but you don’t block the anti-inflammatory negative feedback loop so don’t block IL10

Question 5

IRAK-4 Inhibitors

Answer 5

Inhibition of IRAK-4 blocks production of type I interferons, IL-6, TNF, IL-1 and IL-12 when you’ve stimulated via these two receptors

Question 6

Drugs that target IL17

Answer 6

– Psoriatic arthritis
– Ankylosing spondylitis
– Psoriasis

• Ixekizumab (Lilly)
– Psoriatic arthritis

• Bimekizumab (IL-17A/F; UCB)
– Psoriatic arthritis

Question 7

What is GM-CSF

Answer 7

Granulocyte-macrophage colony-stimulating factor (GM-CSF),

Stimulates macrophages, macrophages produces Il6 and IL23 which helps stimulate th17 cell production. Also activates neutrophils, dendritic cells

Question 8

Sirukumab and depression

Answer 8

¥ Serum IL-6 elevated in depression
¥ 26% phase 2 patients reported baseline anhedonia, independent of disease activity but related to increased depression and fatigue
¥ Sirukumab improved depression and fatigue in these patients, independent of joint improvement
¥ High levels of sIL-6R predicted effect on depression score