Small molecules in management of SLE

Question 1

What are small molecules?

Answer 1

These drugs target broad mechanisms not a single cytokine for example

Question 2

What small molecules are used for SLE treatment?

Answer 2

• Hydroxychloroquine (HCO)
• Cyclophosphamide
• MMF
• Azathioprine
• Calcineurin inhibitors

Question 3

Hydroxychloroquine?

Answer 3

• Anti-malarial drug
• Helpful for skin and joint disease and thrombosis
• Treatment with it reduces rate of organ damage and death
  (Fesslet 2005)

Question 4

What is the mechanism of action of hydroxychloroquine?

Answer 4

• it is lysosomotropic - it gets accumulated within lysosomes and endosomes
• it modifies effect of lysosomal enzymes
• it reduces antigen presentation via lysosomal pathway and this way it reduces autoantigens presentation on cell surface
• also within lysosomes it interferes with TLR 7, 8 and 9 by changing eadosomal pH and directly binding to RNA or DNA
• Also it interfere with binding of cGAS to cytoplasmic FNA
• It leads to reduced production of type 1 interferons

Question 5

What is cGAS?

Answer 5

molecule/receptor that recognises nucleic acids in the cytoplasm

Question 6

What are side effects of hydroxychloroquine?

Answer 6

• retinopathy - damage to retina (eye), risk increased by higher dose, longer duration of treatment, reduced renal function, usually occurs after 5-10 years of treatment, it is not related to weight or age, there is no treatment for retinopathy if it occurs treatment with hydroxychloroquine needs to be stopped
• can cause prolponged QTc (arrhythmia) but it is very rare and was seen in COVID patients not SLE patients
• Can cause cardiomyopathy but also is very rare

Question 7

Cyclophosphamide?

Answer 7

• old drug
• alkylating agent - forms strands within the DNA at particular position of one of the guanine molecules which leads to cell death so it is a toxic drug
• side effects include acrolein accumulation in the bladder and can cause inflammation of the bladder. It can also lead to bladder cancer
• It works by stopping lymphocytes from dividing
• it reduces development of renal scarring and risk of relapse
• increased risk of infertility
  (Houssiau 2002)

Question 8

Mycophenolate mofetil (MMF)?

Answer 8

• It inhibits IMPDH.
• It works on type 2 isoform of IMPDH
• it decreases proliferation of lymphocytes, production of Ig and monocyte/lymphocyte recruitment to sites of inflammation (Allison 2005)
• It induces remission same like cyclophosphamide but causes way less side effects

Question 9

IMPDH?

Answer 9

It comes in 2 isoforms:
- type 1 - in most cells
- type 2 - in lymphocytes and proliferating cells

Question 10

Azathiporine (AZA)?

Answer 10

• Metabolised to active compound 6-mercaptopurine
• It is metabolised by TPMT but around 10% of population have mutations which lead to not metabolising the drug effectively and leads to high toxicity
• It can be either metabolised into ^-TGN or 6-MMP. 6-TGN has immunosuppressive effects but 6-MMP can cause liver toxicity
• It reduces T cell migration and survival, reduces iNOS and adhesion molecules (Broen 2020)
• side effect: bone marrow suppression, liver inflammation
• some patients have predisposed to metabolise to 6-MMP so they can be given allopurinol to stop that and metabolise to 6-TGN

Question 11

Calcineurin inhibitors?

Answer 11

• in SLE only cyclosporin A and tacrolimus are used
• They inhibit calcineurin to switch off TCR/MHC cascade which leads to less NFAT phosphorylation and less IL-2 production so less proliferation of T cells
• It inhibits T cells (proliferation, cytokines production), B cells (stimulates class switching and decreased IgG production)
• It has effects on NF-kB signalling
• It is difficult to use because interacts with many drugs and has many metabolites
• side effects: stomach upset, diabetes, high blood pressure, facial hair growth in women, swollen gums and growth, it can also be toxic for kidneys