Sjögren's syndrome: Current therapies Flashcards
Current Sjogrens syndrome treatments?
- Eye drops (artificial tears)
- Saliva substitutes (gels)
- Pilocarpine (mimics neurological signal to stimulate saliva flow)
- Hydroxychloroquine (inhibits TLRs so decreases type 1 interferons production)
Why did anti-TNF not work in sjogrens?
Because in Sjogrens there is high amount of TNF but that TNF is good as it actually stops type 1 interferon.
What is the problem about hydrochloroquine?
It does not really make patients feel better. They don’t report symptoms improvement. Patients treated with it or placebo still reported similar symptoms (Gottenberg 2014)
Why did rituximab not work in Sjogerns?
Because rituximab is good at depleting B cells from blood and not infiltrated B cells. Rituximab is effective but the effect is not strong. Certain patients who benefit have high B cell infiltration.
What are approaches for B cells inhibition?
- anti-BAFF (Belimumab)
- combination of anti-BAFF and anti-CD20
- anti-BAFF receptor (Ianalumab) shows promise in Sjogrens syndrome
- CD-22 agonist (Epratuzumab)
- Telitacicept - binds both BAFF and APRIL (Shi 2021)
- Remibrutinib - inhibits Bruton’s tyrosine kinase, it showed clinical improvement but did not improve symptoms (Dorner 2022)
- Nipocalimab - anti-FcRn - showed efficacy in lowering anti-Ro (Gothenburg 2024)
What is APRIL?
It is a cytokine which is important for supporting plasma cell survival
What is Bruton’s tyrosine kinase?
It sits below B cell receptor and it leads to B cell proliferation, survival and cytokine survival
What are approaches for blocking type 1 interferons?
- TLR antagonists
- anti-IFNa
- anti-IFN receptor
- induce host immunity against IFN
- Block downstream IFN receptor signalling (JAK/STAT inhibitors)
- anti-BDCA2
Anti-BDCA2?
BDCA2 is on pDCs and antibody when binds to it, it inhibits type 1 interferon production. It was tested in Lupus but not Sjogrens (Werth 2022)
Risk genes in Sjogrens?
Sjogren’s was not very researched, comparing to other autoimmune conditions and because of that we don’t know many risk genes. Polymorphism of TYK2 was identified as risk for Sjogren’s (Khatri 2022). Drugs inhibiting TYK2 like Devcravacitinib was tested in SLE (Morands 2023)
What is CD40?
CD40 is expressed on B cells, DCs, macrophages and epithelial cells. CD40 binds to CD40L.
What is CD40L?
CD40L is expressed on activated T cells, activated B cells and activated platelets. It is also known as CD154.
CD40/CD40L?
It is a co-stimulatory signal. CD40 activation leads to up regulation of CD80/86. If DC take up apoptotic cell it will not up regulate CD40 or CD80/86 only if DC take up necrotic cell with danger signals on it so they are blocking CD40/40L to stop T cell activation. CD40/40L is important for germinal centre formation and B cell function and survival.
Is blocking CD40/40L safe?
No, when blocking CD40/40L was explored in RA and SLE, it lead to dangerous adverse events. This is because CD40 is expressed on activated platelets and it led to thrombosis.
Is blocking CD40/40L potential in Sjogren’s?
Yes because in Sjögren’s syndrome we can see B cell hyperactivity which is enabled by T cells and contributes to destruction. There is increased expression of CD40/40L in Sjögren’s syndrome also shows increased expression of CD40/40L on T and B cells. CD40 block mice in Sjogren’s showed decreased disease progression (Wieczorek 2019). Trial on Iscalimab showed efficacy in Sjögren’s syndrome (Fisher 2023). It leads to decrease in dryness and fatigue and increased saliva flow. However, in patients after transplantation this drug showed high infection rate which means that it will probably not be approved in Sjögren’s syndrome. However, there is another drug Dazodalibab which also showed improvement in Sjögren’s syndrome patients (St Clair 2024). This drug also blocks CD40L and it can improve dryness, fatigue and pain. Dazodalibab is a non-antibody fusion protein.
