Biologic Therapies For Rheumatic Diseases Flashcards
Which rheumatic diseases have proven biologic treatments?
RA, SNSA, JIA, SLE, vasculitis (ANCA+)
When is the rate of progression for RA most rapid?
In the first year
Radio graphic changes can be seen in 93% of RA patients in less than 2 years
First line of therapy for RA
Methotrexate- immunosuppressive and antiproliferative agent
Must administer folate with it* because it blocks its production
Cytokines signaling pathways involved in inflammatory arthritis
Lymphocytes predominate in the synovial membrane- CD4+ activated by antigen, IFN-gamma activates macrophages, which make TNF, IL-1/6 (proinflammatory), and these act on osteoblasts/clasts/chondrocytes to modify their activity/destruction
T cell also enables B cells to mature into plasma cells which secrete RF and autoantibodies
Anti-inflammatory responses mediated by:
IL-10, TGFbeta, IL-4
Tissue remodeling agents relevant in RA
Bone and cartilage destruction- IL-1, TNF, OPG/RANKL
Angiogenesis/growth factors- TNF, VEGF, TGFbeta
*TNF important for pannus formation as welll
Different mechanisms of Inhibition of cytokines in biologic therapies
Monoclonal antibody to bind IL and prevent it getting to receptor and signaling
Soluble receptor without business signal end to bind cytokines without signaling the cell
Antibody to the receptor- prevents binding by cytokines via receptor inactivation instead
Create more endogenous receptor antagonist (anti-inflammatory cytokines) to overwhelm cytokine and prevent activation
TNF inhibitors
Infliximab- chimeric mab
Etanercept- mostly human mab
Adalimumab- human mab
Certolizumab and golimumab
Etanercept- class, construct, half-life, binding target, administration
sTNFR Recombinant 4 days binds TNF/LTalpha SC administration, 2x weekly
Infliximab- class, construct, half-life, binding target, administration
TNF MAb Chimeric MAb 8-10 days TNF IV with MTX very 4-8 weeks
Adalimumab
TNF MAb Human MAb 10-20 days Binds TNF SC every other week
Certolizumab and Golimumab
TNF MAb Humanized MAb to Fab/human MAb 14 days half life binds TNF SC every 2 weeks/every 4 weeks
Major AE in anti-TNF: adalimumab
Serious infection rate is doubled from 0.02 in placebo RA to 0.04 in adalimumab RA patients
Resp tract, pneumonia, UTI, skin diseases, etc
Tuberculosis and TNF
TNF is necessary for granuloma homeostasis in animals
Reactivate pre-existing TB infections in humans with anti-TNF biologics, usually extra-pulmonary
risk factors- diabetes and corticosteroids use
Early disease and TNF inhibitors
Sustained benefits over time even when TNF inhibitors are withdrawn- perhaps disrupting some early mechanism of RA that allows it to progress
Other proven indications for anti-TNF Rx other than RA
JIA Psoriatic arthritis Ankylosing spondylitis Reactive arthritis Arthritis of IBD Psoriasis Inflammatory bowel disease
Second generation biologics Rx for RA
Abatacept: CTLA4-Ig
Tocilizumab: anti-IL6
Rituximab: anti-CD20
CTLA4Ig (abatacept) inhibits
T cell activation via costimulation blockade of the CD80/86 (B7)-CD28 signal 2
Given before T cell activation can prevent its eventual antigen activation
Recombinant fusion protein of a human trans-membrane protein (CTLA4) and human antibody IgG1
Side effects similar to first line anti-TNF agents, except TB reactivation
Headaches, sinusitis, and infusion reactions more frequent with abatacept
Function of IL-6
Acts on liver to increase CRP and other markers for inflammation
Augment B cell and plasma cell antibody production
CD4+ T cell stimulation
TH17 cells- helper that are important for development of auto-immunity and breaking of tolerance
Cytotoxic helper cell, osteoclasts, etc
Naive T cell driven to being helper to auto-immunity by IL-g and TGF-beta
Also block T regulator cells development, which down regulate this and impairs ability to develop autoimminuty
Tocilizumab
Antibody to IL-6 receptor, prevents dimerization/activation by IL-6 to cell.
Decreases production of TH17 and augments production of T regs (collectively promotes avoidance of auto-immunity)
AE’s- transient neutropenia, ALT (alanine aminotransferase in liver) increased in blood, elevates cholesterol (detrimental to those with atherosclerosis), GI perforation, anaphylaxis, thrombocytopenia, enhancement of CYP450 enzymes may affect warfarin, station, cyclosporine, OCP, omeprozole, etc
Usually used as 4th line because of all the toxicities
Role of B cells in RA
B cells evolve into plasma cells, which secrete RF and anti-CCP antibodies, which fix complement to cause damage
Antigen presenter cells and stimulate T cells
Source of pro-inflammatory cytokines: IL-6, TNFalpha, IL-10
Targeting B cells in RA
Target them before they become mature, activated plasma cells, but not at pre-pre stage/pluripotent stem cell phase where you eliminate B cells forever
Ideally, target CD20- receptor is not shed from cell so it can still have a function ON the cell when therapeutic binds, not on stem cells or early pre-B cells, or plasma cells
Binding of CD20 does not down modulate expression of CD20, does not cause internalization of CD20
Rituximab moa
MAb to CD-20 receptor on B cells- Apoptosis induced by inhibition of Bcl-2 expression
Prevents erosions and damage
Increased infection- doubled from placebo RA
Effects of Baff (BLyS)
B lymphocyte stimulator- Baff-receptor important for survival of B cells and maturation into memory and plasma B cells
Role in differentiation of T cells into TH17 cells
Dendritic cell inflammatory molecule production and costimulatory molecule production
Belimumab
Binds to baff before it attaches to receptor and depletes it, disruption of B cells without apoptosis with Rituximab
Doesn’t work in RA*, but approved for lupus
