BIOLOGIC

DMARD’S
FOR Rheumatoid Arthritis
(bDMARDs)
What are they? (Part 1)
■ As opposed to the normal DMARD’s (e.g. methotrexate), biological DMARD’s (e.g.
anti-TNF) modify the actual biological response to the disease (specific inflammatory
mediators) (e.g. monoclonal Antibodies that inactivate specific cytokines).
■ Unlikely to enable remittance but significantly slow disease progression.
■ Really good in combination with methotrexate.
– Improved disease controls, lower Disease Activity Score and Increased function
than with methotrexate or biologic alone
■ E.g. Anti-TNF + methotrexate has significant anti-erosive effect

■ Cost a lot (those three that are on the top 10 of dollars spent)
What are they? (Part 2)

■ Burgeoning field
■ Parenteral injection (IV or subcutaneous)
■ Mostly used if disease modifying DMARD’s are inadequate.
■ Uncertain about metabolism and excretion pathways and associated interactions.
■ Central Adverse Effects are due to non-specific block (e.g. immunosuppression)
– Not combined that much themselves as it would be too immunosuppressive (e.g.
very high infection risk)
Anti-TNF
■ Humanised Monoclonal Antibodies (1) or Circulating Receptor Fusion Proteins (2)
– (1) Infliximab, Adalimumab, Golimumab and Certolizumab
– (2) Etanercept
■ TNF in RA
■ Increased endothelial activation/vascular permeability  increased inflammatory cell
entry to tissue
■ Also increased Type B synovial cell production of metalloproteinases and collagenases (therefore
inhibition decreases pain and fever in acute inflammation)
■ Increases prolifferation and cytokine production of macrophages, T-Cells and B-Cells
■ Contributes to osteoclastogenesis (bone errosion) and granuloma formation
■ Adverse effects:
– Risk TB reactivation due to granuloma inhibition
– Lymphoma, CHF, Multiple Sclerosis, SLE, T3 hypersensitivity reactions
 Anti-IL1R
■ Humanised Monoclonal Antibodies
■ Anakinra (Should not be used with anti-TNF or Anti-T Cell) [made in E.Coli]
■ IL-1 in RA
– IL-1 is a key mediator (therefore its good to block it binding its receptors)
■ Major mediator of bone resorption and cartillage destruction
■ Lesser mediator of general inflammatory process/swelling
■ Adverse Effects
– Same issues with infections and latent TB reactivation
– Increase cholesterol, headaches, potential cancer risk
 Anti-B Cell
■ Humanised Monoclonal Antibodies
■ Rituximab and tocilizumab
■ Rituximab binds CD20 on the B cell surface triggering cell death
– Decrase self-reactive B-Cell antibody production
■ Used when Anti-TNF therapies are inadequate.
■ Adverse Effects:
– T3 hypersensitivity reaction, MI, AKI, infection susceptibility, Progressive
Multifocal Leukoencephalopathy (viral reactivation)
Anti-T Cell
■ T Cell Co-Stimulation Blockers
■ Abatacept (should not be used with any other biologics)
■ Abatacept is a fusion protein made from IgG Fc regions and CTLA-4 which binds to
CD80 and CD86 molecules on Antigen Presenting Cells and blocks its action
– CD80 and CD86 on APC’s usually bind CD28 on the T Cell surface to provide a
costimulatory signal for T Cell prolifferation.
– T Cells that don’t receive co-stimulation will become anergic (useless and no
function) or apoptosed.
■ Adverse Effects
– Found to be secreted in breast milk of mice and be teratogenic (therefore not good
for pregnancy)
– Infection susceptibility and reactivation of TB
– Increase cancer spread, URTI’s, hypertension, fatigue, rashes, nausea, ulcers
Anti-IL6R

■ Humanised Monoclonal Antibodies

■ Tocilizumab (again if DMARDs and anti-TNF don’t work)
– Binds both soluble and membrane bound IL-6R’s
■ Soluble is the major one in disease progression

■ IL-6 in RA
– Increase CRP, fever, B-cells, T-cells, synovial fibroblasts and osteoclast
prolifferation/differentiation/function.
■ Adverse Effects
– URTi’s, Hypertension, headache, nasopharyngitis, elevated ALT, elevated cholesterol,
gastritis, anaphylaxis