RA Flashcards
What are the three most important pro-inflammatory cytokines identified in RA?
IL-1, IL-6, and TNF-alpha
What is infliximab?
A chimeric monoclonal antibody with high affinity and specificity for TNF-alpha
What mad infliximab a problematic treatment?
The antigen binding site was murine, which makes the antibody antigenic
Which anti-TNF antibodies have fully human protein sequences?
Adalimumab and golimumab
What medication is often paired with biologics for RA?
Methotrexate
What is etanercept?
A fusion protein with two copies of the soluble TNF receptor that binds and inactivates TNF-alpha
What are biosimilars?
Drugs with the same protein sequences as the original drug that are made and can greatly reduce costs of biologic therapies
What is the mechanism of tocilizumab and sarilumab?
Monoclonal antibodies against the IL-6 receptor that prevent cytokines from binding to receptors
What do CTLA4:Igs do?
These drugs (ex. abatacept) bind CD80/86 (on APCs) and displace CD28 (on T-lymphocytes), which interrupts T-lymphocyte and APC signaling
What does rituximab do?
It is an anti-CD20 antibody that leads to B-lymphocyte depletion
What do small molecule JAK-inhibitors do?
They target JAK signaling kinases that transport surface signaling to the nucleus
What are three therapeutic goals for treatment with disease modifying anti-rheumatic drugs?
- reduce symptoms - maintain or improve function - prevent further joint damage
What are three mechanics by which biologic response modifiers can block inter-cellular signaling?
- antibodies to cytokines - antibodies to cytokine receptors - recombinant receptor antagonists
List three cytokines inhibited by approved therapies for RA?
TNF-alpha, IL-1, and IL-6
What are key differences between biologic therapies and targeted small molecule therapies?
Biologics: - inter-cellular - parenteral administration Small molecules: - intra-cellular - oral administration
What is the shared epitope hypothesis?
A hypothesis for the genetic risk of RA that states that the most potent genetic risk for RA is conveyed by certain major histocompatibility complex alleles
What is the shared epitope in RA?
A conserved amino acid sequence on the HLA that is over-represented in patients with RA (QKRAA)
Where does the RA shared epitope map to?
Third hypervariable region of DR beta chains at amino acids 70-74 (HLA DR4 and DR1)
What does the presence of the shared epitope suggest?
It is associated with increased susceptibility and severity of RA
What is the theory behind susceptibility alleles in RA?
Susceptibility alleles bind efficiently to arithrogenic peptides. Peptidylarginine deaminases convert arginine to an uncharged citrulline, which allows it to be loaded into the MHC and present to autoreactive T cells
What is the relationship of cigarette smoking to RA?
Smoking increases risk of developing anti-CCP autoantibody positive RA in patients with the shared epitope. It causes inflammation that activates innate immunity in the airway, leading to peptide citrullination, which causes immune hyperreactivity.
What is the structure of a normal synovial membrane?
- 2 layers in intima:
- type A: intimal lining layer that is bone marrow derived with macrophage-like synoviocytes
- type B: fibroblast-like synoviocytes synthesize ECM proteins including collagen, fibronectin, hyaluronic acid
- Sublining layer below intima: loose connective tissue with numerous blood vessels, lymphatics, nerves, fibrous connective tissue
What is a pannus?
Inflammatory synovial membrane
What changes occur in the inflammatory synovial membrane of RA?
- Synovial membrane hyperplasia
- Cellular infiltration into synovium (T and B lymphocytes, plasma cells, dendritic cells, NK cells, macrophages)
- Neoangiogenesis
What is the function of the pannus in RA?
The thickened membrane forms projections that protrude into the joint cavity and destroys periarticular obne and cartilage. The inflammatory cytokines and proteases also cause joint destruction.
RA typically has a(n) _________ onset of _________ ____arthritis.
RA typically has an insidious onset of symmetrical polyarthritis.
What amount of morning stiffness is associated with RA?
> 1 hour of stiffness
What constitutional symptoms are associated with RA?
low grade fevers, fatigue, malaise, myalgias, decreased appetite, weight loss
What are the joint examination findings in RA?
- symmetrical swelling and tenderness of joints
- palpable swelling and “synovial bogginess,” enlargement due to swelling rather than bony hypertrophy
- decreased range of motion and malalignment
- synovial fluid WBC > 2000
What is the joint distribution of early RA?
Wrists, MCPs, PIPs, MTPs (toes), interphalangeal joints of thumbs
What is the jointdistribution of late RA?
Larger joints: ankles, knees, elbows, and shoulders
What two joints are almost always spared in RA?
Distal interphalangeal joints, thoracocolumbar spine.
What are two classic symptoms of RA?
1) worse in the morning
2) pain in the balls of feet upon first ambulating in the morning
What are three classic (but late) signs of RA?
1) swan neck deformity: flexion at DIP and hyperextension of PIP
2) boutonniere deformity: flexion at PIP and hyperextension of DIP
3) ulnar deviation at MCPs
What are extra-articular manifestations of RA?
- secondary sjogren’s syndrome (dry eyes and mouth)
- rheumatoid nodules on pressure areas
- pleuropulmonary problems
- cardiovascular events
- anemia
- Felty’s syndrome
- ophthamologic findings
What autoantibodies are found in RA?
- rheumatoid factor (autoantibodies with specificity for the Fc fragmet of IgG)
- Anti-cyclic citrullinated peptide (anti-CCP) antibodies
What are rheumatoid factor antibodies?
Autoantibodies with specificity for the Fc fragments of IgG
What are high titer positive rheumatoid factor values suggestive of in RA?
Poor prognosis, more aggressive erosive disease, poorer long-term function, extra-articular disease
What are non-RA causes of positive RF?
aging, chronic infection, viral disease, parasitic disease, chronic inflammatory disease, hypergammaglobulinemia
What are anti-CCP antibodies?
They are auto-antibodies directed against citrullinated residues of proteins
What is associated with high titer positive anti-CCP in RA?
poor prognosis, more aggressive disease, functional disability, extra-articular disease
What are the erythrocyte sedimentation rate and c-reactive protein findings associated with RA?
They are elevated inactive disease and decline with disease treatment
What are the x-ray findings of RA?
Juxta-articular bone erosions, diffuse symmetrical joint space narrowing, periarticular osteopenia (less specific), degenerative changes
What are the general goals of RA therapy?
- reduce or eliminate joint pain/swelling
- prevent joint damage
- minimize disability/maintain function
- early diagnosis/treatment
- accurate assessment of disease activity
What is the gold standard, first-line treatment for moderate to severe RA?
Methotrexate
What does methotrexate do?
A variety of mechanisms including inhibition of B and T cell functions, inhibition of IL-1 beta, and inhibition of purine metabolism
What are the side effects of methotrexate?
Nausea, stomatitis, fatigue, alopecia, elevated liver enzymes, increased infection. Contraindicated in renal disease.
What is the mechanism of leflunomide?
Inhibits an enzime in pyrimidine synthesis (orotic acid dehydrogenase)
What are the side effects of leflunomide?
Nausea, elevated liver enzymes, teratogenicity, long half-life
What is the mechanism of hydroxychloroquine?
Antimalarial that interferes with presentation of auto-antigenic peptides
What are the side effects of hydroxychloroquine?
Retinal toxicity
What is the mechanism of sulfasalazine?
It is an antibiotic combined with an anti-inflammatory agent that suppresses lymphocyte and leukocyte functions
Which RA mediciations have been shown to reduce radiographic progression?
Methotrexate, leflunomide, and sulfasalazine
What do tumor necrosis factor antagonists do?
They are antagonists for TNF, which is a proinflammatory cytokien that regulates the production of other proinflammatory cytokines in RA
What are teh side effects of TNF antagonists?
Injection site reactions, infusion reactions, opportunistic infections (especially reactivation of latent TB), increased risk of lymphoproliferative disorders. Can also cause drug induced lupus.
What is the mechanism of abatacept?
It is a CTLA-4 immunoglobulin that binds to CD80/86 on the surface of antigen preventing cells preventing binding to CD28 on T cells, which prevents T-cell activation.
What does rituximab do?
Chimeric anti-CD20 monoclonal antibody that depletes B cells with CD20 on their surface.
What are the side effects of rituximab?
infusion reaction, chronic hypogammaglobulinemia, and infection
What do IL-6 inhibitors do?
They are humanized anti-human IL-6 receptor antibodies that bind to soluble and membrane bound IL-6 and inhibit IL-6 signal transduction.
What are side effects of IL-6 inhibitors?
Mycobacterial infections, liver function test abnormalities, neutropenia, thrombocytopenia, hyperlipidemia, and GI perforations
What do JAK inhibitors do?
They decrease signaling by several cytokine and growth factor receptors.
What are the side effects of JAK inhibitors?
Infections such as herpes zoster, liver function test abnormalities, neutropenia, hyperlipidemia, GI perforators, venous thromboembolism.
Compare hand and wrist joint distribution of RA vs. OA
RA: all MCPs, PIP, IP of the thumbs, all carpal bones
OA: PIP, DIP, IP thumb, 1st MCP, 1st carpal metacarpal joint very commonly involved
All of the following lab abnormalities might be seen in RA except:
a) normochromic normocytic anemia
b) positive anti-CCP antibodies
c) microcytic anemia
d) positive anti-dsDNA
e) positive antinuclear antibody (ANA)
f) positive rheumatoid factor
g) neutropenia
h) thrombocytopenia
d) anti-dsDNA
this is more associated with SLE