New therapies for RA Flashcards
What is important when choosing a treatment for particular patient?
- Certain therapies work better for patients positive for rheumatoid factor or ACPA and some for patients negative for these
- Some people when given biologic drug will develop antibody against the drug which may stop the drug from working
- Some patients with RA have more lymphoid cell infiltration, some myeloid cell and some have high expansion of tissue resident fibroblasts (Choy 2013)
- For example patients with high B cell infiltration respond better to rituximab so it is important to try personalise treatments towards patients (Humby 2021)
What are new therapeutic approaches being explored in RA?
- JAK inhibitors
- Melanocortins agonists
- Targeting fibroblasts using CDK4/6 inhibitors
- Otilimab - anti-GM-CSF
- Peresolimab - PD-1 agonist
- Neonatal Fc Receptor (FcRn)
- Inhibiting PAD enzymes
- Antibody drug conjugates
JAK inhibitors?
They inhibit JAK/STAT signalling which leads to inhibition of expression of pro-inflammatory mediators. There are 4 JAKs
- Tofacitinib is a JAK1 and 3 inhibitor
- Baricitinib is JAK1 and 2 inhibitor
JAK inhibitors lead to increased rate of infections, especially viral reactivation. They also increase risk of cancer (Harigai 2019)
Melanocortins agonists?
They stimulate body own production of steroids. There are different types of melanocortins. For example MC3 activation gives inflammation resolution without an increase in steroid production. MC3 leads to increased phagocytosis and efferocytosis of macrophages for better debris clean up. It also switched NF-kB off in macrophages which leads to decreased production of pro-inflammatory cytokines (Patel 2011). For treatment are used MC3 agonists which activate MC3.
Targeting fibroblasts using CDK4/CDK6 inhibitors?
To stop fibroblasts proliferation and differentiation of pro-inflammatory subtypes. CDK4/6 inhibitors are being explored in cancer treatment but cause neutropenia which is a very dangerous side effect. TCK-276 is being currently explored in clinical trials for RA but it does not trigger neutropenia (Tasaki 2024)
Otilimab anti-GM-CSF?
It stops proliferation of neutrophils and macrophages. The drug worked but is not as big difference than other therapies already available so it was not licences to use
Peresolimab PD-1 agonist?
Leads to suppression of T cells, particularly T peripheral helper cells (Tph) which is a subtype of T cells largely present in RA patients. PD-1 agonist can lead to increased occurrence of malignancies (Tuttle 2023)
Neonatal Fc Receptor (FcRn) blockade?
It is a receptor which allows antibodies to cross the placenta but also endothelial cells, macrophages and monocytes have these receptors and when IgG will be engulfed, within the endosome there is the neonatal Fc receptor, IgG will be recycled back to the surface. If you give antibody blocking neonatal Fc receptor it blocks IgG recycling (Pyzik 2023). One antibody blocking FcRn was tried in RA and showed efficacy (Taylor 2025)
This leads to decreased number of rheumatoid factor and ACPA antibodies
Inhibiting PAD enzymes?
PAD enzymes are associated with citrullination. Antibodies blocking PAD2 and PAD4 have been developed and showed efficacy in murine RA models
Antibody-drug conjugates?
For example anti-TNF antibody conjugated with glucocorticoid receptor modulator is currently being explored in RA treatment (Buttgereit 2023)
What is a bit different new approach to treatment of RA?
Activation of vagus nerve leads to decreased cytokine production (Koopman 2017). People try to produce vagus nerve stimulants e.g. implants which can be controlled using an app. There is not a lot of data on this but it showed some improvement in RA patients (Genovese 2020)
