RA and DMARDS Flashcards
pathophysiology of RA
Chronic, autoimmune inflammatory disease characterized by:
o Joint swelling and tenderness
o Destruction of synovial joints
o Severe disability
o Premature mortality
***combination of genetic and environmental factors
All cause cells to appear where they would not normally be
osteoclasts -break down bone
chondrocyte
synovial fibroblasts
cytokine hits receptor ligand JAK -> and activates STAT -> gets to nucleus and alters DNA in cell
cytokines
leads to inflammation and stimulate synovial fibroblasts
TNF a
IL-1
IL-6
EFFECTS: increased endothelial perm stimulate osteoclasts - break down bone stimuate release of collagenase progressive, irreversible deformities in joint and functional impairment
TNF alpha
o Macrophage creates
o Important mediator of acute inflammation,
o recruits neutrophils and macrophages to site of injury and infection
IL-1
o Macrophages secrete
o Similar to TNF alpha, helps with activation of T cells
IL-6
o Activates T cells
o Stimulated synovial fibroblasts
DMARDS
slow disease progression and preserve structure and function of joints -> Start as soon as possible after diagnosis
o MOA: inhibit cytokines
o Take 1-3mo to work
TWO TYPES: slow disease process
o Biologic
o Nonbiologic
SAFETY considerations are CRITICAL for drug selection !!!!
bridging therapy
oBridging therapies until DMARDs are sufficiently effective and during disease flares
o NSAIDS - Do not affect disease process, DO NOT slow progression of diseased -> Reduce pain and inflammation
o Corticosteroids - Can slow disease, poor safety, Oral or intra-articular
biologic DMARDS
Anti-TNF antibody
non ANTI TNF
large protein like made form monocolonal antibodies
can be used in combo with nonbiologic or instead
Adv: work faster than nonbio (1-3wks), safety profile is better
Disadv: expensive, increase risk of infection, must vaccinate
anti TNF antibody
Adalimumab Certolizumab Etanercept Golimumab Infliximab (IV)
MOA:• Interfere with cytokine function, signal transduction, and/or production
• Inhibit “second signal” required for T-cell activation
• Depletion of B-cells
ADR: • Immunosuppression • Exacerbation of HF (negative inotropic effects) • Increased risk of lymphoma • Injection site reactions • Arthralgia • Rash • Cough
non Anti TNF
- Anakinra
- Rituximab
- Abatacept
- Tocilizumab
- Sarilumab
Anakinra
IL-1 receptor antagonist
ADR: increased risk of severe adverse events
do not combine with other anti TNF biologics
Rituximab
B-cell inhibitor
ADR • Fatal infusion reactions • Sever mucocutaneous reaction • Hep B reactivation • Infections
Abatacept
MOA T cell co-stimulation inhibitor
ADR:
• Immunosuppression
• Respiratory events in COPD
Tocilizumab
MOA: IL-6 receptor antagonist
ADR: • Severe infections • GI perforations • Neutropenia • Thrombocytopenia • Elevated LFTs • Hyperlipidemia
Sarilumab
IL-6 receptor antoagonist
Non biologic DMARDS
monitor - CBC, LFT, SCr every 2-4 weeks
administered orally, inexpensive, slow onset, muliple side effects
methotrexate
leflunomide
sulfalazine
methotrexate
nonbio - first line
MOA Reduced purine biosynthesis → reduced DNA synthesis
• Selective inhibition of cytokine production & replication of B-cells & T-cells
ADR: • Myelosuppression • GI toxicity • Pulmonary toxicity • Hepatic fibrosis • Thrombocytopenia • Mild alopecia
add folic acid supplement
CANNOT use while pregnant /breastfeeding
leflunomide
nonbio - second line, longer 1/2 life (18-19 days)
MOA: Inhibits autoimmune T-cell proliferation & productions of autoantibodies by B-cell
ADR • Alopecia • Hematologic toxicity • Diarrhea • Rash (Steven’s Johnson Syndrome) • Severe hepatotoxicity
cannot use while pregnant/breastfeeding
sulfalazine
non bio (8-12 weeks)
MOA unknown
ADR
• GI toxicity • Lupus-like syndrome • HA/fever/rash • Hepatotoxicity documented sulfa allergy
OK in pregnancy
NO breastfeeding
kinase inhibitors
tofacitinib, batricinib (NOT biologics)
MOA:Inhibits activity of JAK enzymes at cytokine receptors → reduce inflammation
NOT USED with biologics
OK with methotrexate (nonbio)
ADR • Diarrhea • Infections • Reactivation of TB • Risk of malignancy • Gi perforation • Hyperlipidemia • Anemia/neutropenia • Hepatotoxicity • Thrombosis
