Rheumatoid Arthritis

MODA- Pharmacology of Inflammation

Autoimmune disease
T cells undergo positive + negative
selection  prevents immune
response to self antigen
 failure of self tolerance:
autoimmune diseases often
more prevalent in females
Rheumatoid Arthritis
• Joint damage due to activated Th1
cells macrophages stimulated +
release IL1 + TNFa metalloproteinases
released by osteoclasts + fibroblasts
bone + cartilage destruction
• Exacerbated by infiltrated leukocytes
e.g. neutrophils  release proteases +
ROS
• Hyperplasia of synovium pannus
formation as synoviocytes proliferate +
invade joint  release inflammatory
cytokines + proteases
Treatment
• NSAIDs used to reduce pain + inflammation  don't alter underlying
disease
• Naproxen used due to lower cardiovascular risk
• COX 2 selective NSAIDs e.g. etorixcoxib used: reduced risk of GI bleeding
• Corticosteroids – oral prednisolone  symptom relief + suppress
disease activity  decreased IL-1 + TNFa transcription  only treat
disease flare ups
Conventional DMARDs (disease modifying
anti-rheumatic drugs)
• Methotrexate – main treatment for RA
• Folic acid antagonist, inhibits DHFR + competes with folic acid
transport into cells reduced tetrohydrofolate production for
purine + thymidylate synthesis  anti proliferative, reducing immune
response
Conventional DMARDs (disease modifying
anti-rheumatic drugs)
• Sulfasalazine – taken orally
• Broken down by colonic bacteria, producing sulfapyridine + 5-
aminosalacylic acid that scavenges neutrophil derived ROS
Conventional DMARDs (disease modifying
anti-rheumatic drugs)
• Hydroxychloroquine – treats RA for patients refractory to other
DMARDs (safest in pregnancy)
• Lipophilic weak base accumulates in cytoplasmic acidic vesicles 
reduces antigen presentation by macrophages + ROS generation in
neutrophils
Conventional DMARDs (disease modifying
anti-rheumatic drugs)
• Leflunomide
• Inhibits dihydroorotate dehydrogenase needed for pyrimidine
synthesis  inhibits DNA + RNA synthesis  acts on rapidly diving
cells e.g. T + B cells
Conventional DMARDs (disease modifying
anti-rheumatic drugs)

• Side effects:
• Bone marrow suppression
• Hepatotoxicity
• GI disturbance
Biological DMARDs
• Used when conventional DMARDs fail  given with methotrexate by
injection risk of opportunistic infection due to suppressed immune
system
1. Anti-TNFa
2. Anti IL-6
3. Anti-B cell
4. Anti-T cell
5. Anti IL-1
Biological DMARDs
• Anti-TNFa
• Etanercept  fusion protein of TNFa receptor + Fc portion of IgG1  mops
up TNFa in RA
• Infliximab + adalimumab  monoclonal anti-TNFa antibodies that sequester
TNFa
Side effects: allergic reactions, bone marrow suppression + susceptibility to
infections
Biological DMARDs
• Anti IL-6
• Tocilizumab  mAb targets IL-6 receptor, inhibiting IL-6(pro inflammatory
cytokine + drives CRP production)  used if patient has high CRP levels
Biological DMARDs
• Anti-B cell
• Rituximab  mAb targeting
CD20 expressed by B cells 
causes B cell destruction
• Iincreases risk of infection +
progressive leukoencephalopathy
caused by reactivation of JC virus
Biological DMARDs
• Anti-T cell
• Abatacept  synthetic fusion protein of cytotoxic T-lymphocyte protein
4(CTLA-4) + Fc fragment of human IgG1 binds to CD80/CD86 on T cells 
prevents APC activating T cell
Biological DMARDs
• Anti IL-1
• Anakinra recombinant IL-1 receptor
antagonist  blocks IL-1 from binding to
IL-1R(higher affinity than IL-1)