Lecture 12 - rheumatoid arthritis and disease modifying anti-rhematic drugs Flashcards
what is rheumatoid arthritis?
rhematoid arthritis usualy affects the joint symmetrically and may begin in a couple of joints only. it msot frequently attacks the wrists, shoulders, knees, elbows ankles and hands.
what are cellular mechanism involved in joint inflammation and degradation ?
there are increased white blood cells which leads to increased oedema and blood flow, release of cytokines and other mediators, hyper-proliferation of synovial fibroblasts, formation of pannus fibroblasts replacing cartilage, destruction of bone and pain and loss of function.
what is the prognosis of rhematoid arthritis?
70% of patients show evidence of joint damage within 2 years. delays in treatment can result in long term joint damage. the condition is not curable but has chances or remission and the quicker effective treatemtn can halt or slow disease progression.
what types of drug would be useful for the treatment of rheumatoid arthritis?
drugs that Stop production of inflammatory mediators, stop white blood cells from proliferating and inhibit their function, Stop cartilage and bone getting destroyed
(NSAIDs)
glucocorticoids
Disease modifying anti-rheumatic drugs (DMARDs)
Classical DMARDs
biologics
how do we measure arthritis?
By standard criteria- Biochemical (ESR, autoantibodies in blood) and physical markers (Pain, morning stiffness, swollen tender joints)
Designed by different medical bodies across the world
DAS28 in SIGN guidelines- Disease activity score 28 measurements
what are the basic principles across autoimmune diseases
Underlying immune problem
Nature of the inflammation (which cytokines dominate)
Trying to deliver same therapeutic outcomes- reducing inflammation and destructive disease progression
Colitis, MS, IBS etc.
describe DMARDS
a group of drugs which slo down the progression of the disease
such as Methotrexate, Sulfasalazine, Gold salts, hydroxychloroquine
describe sulfalazine
Marketed as Azulfidine, Salazopyrin
It’s a combination of two drugs- sulfapyridine and mesalazine
Used in other conditions for example, ulcerative colitis
Only 10-20% of Sulfasalazine is absorbed
Cleavage in the large Intestine by azoreductases
Sulfapyridine – 90% is absorbed
Mesalazine- 20-30% only absorbed, the rest excreted
what is the mechanism of action of sulfalazine?
Unknown- but large array of cell effects which may link to clinical outcomes
Inhibits chemotaxis and migration of white blood cells (stop cells coming in to joint)
Reduced endothelial cell migration- reduced angiogenesis- reduced excessive blood flow
Inhibit the production of cytokines (IL-1, IL-6 and TNF alpha)
Prevents dendritic cells activating T-cells
Inhibits B cell activity- reduces IgG and RF production
Inhibits osteoclast formation (inhibit bone destruction)
what is the pharmacology of sulfalazine?
No specific cellular mechanism of action
Not a very potent or selective drug (affinity moderate- need to use lots of drug)
Therefore the potential for off-target effects - leads to adverse effects
But it works, is cheap and side-effects manageable
what are clinical management issues of sulfalazine?
Refractory – patients don’t respond to the drug or stop responding to initial treatment. Need another DMARD which may not work either! Combination therapy can be required
what are adverse ffecst of sulfalazine?
Mostly GI; nausea, vomiting, dyspepsia, anorexia, headache, dizziness and rash
Compliance– approximately 30% discontinuation during clinical trial period of 1-2 years- but much greater over longer term.
Enteric coated tablets – some help
Combination therapy may be better for adverse effects (unclear).
2-3% of patients haematological disturbances
Leukopenia- lowering of white blood cell count (not so much neutropenia)
Danger of infection
Megaloblastic anaemia/thrombocytopenia also reported
how is sulfalazine used in disease management?
Early use –within 3 months of diagnosis to limit joint damage and preserve joint function
start with 0.5g daily then increase up to 2-3g daily (continuous)
Relatively early onset of action: 1-2 months
Use with another DMARD- evidence suggests combination therapy is more effective (STEP-up or initial combination therapy)
what are routes of admin for methotrexate ?
oral for less severe RA- subcutaneous/IM for more severe RA
what are clinical outcomes of methotrexate?
40% of patients respond well with good clinical outcomes
As good as any other DMARD in reducing joint damage by standard criteria (DAS28 etc)
Low cost
Weekly treatment - injection/tablets (25mg)
Almost as good as some biologics!
