Biologic Therapies For Rheumatic Diseases

Question 1

Which rheumatic diseases have proven biologic treatments?

Answer 1

RA, SNSA, JIA, SLE, vasculitis (ANCA+)

Question 2

When is the rate of progression for RA most rapid?

Answer 2

In the first year

Radio graphic changes can be seen in 93% of RA patients in less than 2 years

Question 3

First line of therapy for RA

Answer 3

Methotrexate- immunosuppressive and antiproliferative agent

Must administer folate with it* because it blocks its production

Question 4

Cytokines signaling pathways involved in inflammatory arthritis

Answer 4

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

Question 5

Anti-inflammatory responses mediated by:

Answer 5

IL-10, TGFbeta, IL-4

Question 6

Tissue remodeling agents relevant in RA

Answer 6

Bone and cartilage destruction- IL-1, TNF, OPG/RANKL
Angiogenesis/growth factors- TNF, VEGF, TGFbeta

*TNF important for pannus formation as welll

Question 7

Different mechanisms of Inhibition of cytokines in biologic therapies

Answer 7

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

Question 8

TNF inhibitors

Answer 8

Infliximab- chimeric mab
Etanercept- mostly human mab
Adalimumab- human mab
Certolizumab and golimumab

Question 9

Etanercept- class, construct, half-life, binding target, administration

Answer 9

sTNFR
Recombinant
4 days
binds TNF/LTalpha
SC administration, 2x weekly

Question 10

Infliximab- class, construct, half-life, binding target, administration

Answer 10

TNF MAb
Chimeric MAb 
8-10 days
TNF
IV with MTX very 4-8 weeks

Question 11

Adalimumab

Answer 11

TNF MAb
Human MAb
10-20 days
Binds TNF
SC every other week

Question 12

Certolizumab and Golimumab

Answer 12

TNF MAb
Humanized MAb to Fab/human MAb
14 days half life
binds TNF
SC every 2 weeks/every 4 weeks

Question 13

Major AE in anti-TNF: adalimumab

Answer 13

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

Question 14

Tuberculosis and TNF

Answer 14

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

Question 15

Early disease and TNF inhibitors

Answer 15

Sustained benefits over time even when TNF inhibitors are withdrawn- perhaps disrupting some early mechanism of RA that allows it to progress

Question 16

Other proven indications for anti-TNF Rx other than RA

Answer 16

JIA
Psoriatic arthritis
Ankylosing spondylitis
Reactive arthritis
Arthritis of IBD
Psoriasis
Inflammatory bowel disease

Question 17

Second generation biologics Rx for RA

Answer 17

Abatacept: CTLA4-Ig
Tocilizumab: anti-IL6
Rituximab: anti-CD20

Question 18

CTLA4Ig (abatacept) inhibits

Answer 18

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

Question 19

Function of IL-6

Answer 19

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

Question 20

Tocilizumab

Answer 20

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

Question 21

Role of B cells in RA

Answer 21

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

Question 22

Targeting B cells in RA

Answer 22

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

Question 23

Rituximab moa

Answer 23

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

Question 24

Effects of Baff (BLyS)

Answer 24

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

Question 25

Belimumab

Answer 25

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