Rheumatoid arthritis Flashcards
What is the MC systemic inflammatory disease
RA
characterized by symmetric joint involvement
What extraarticular sites are involved in RA
Rheumatoid nodules vasculitis eye inflammation neuro dysfunction cardiopulmonary disease LAD splenomegaly
What is the pathogenesis of the inflammatory response in RA
- Antigen presenting cells present antigens to T cells
- T cells stimulate B cells to make antibodies and osteoclasts, which destroy and remove bone
- Immune response stimulates macrophages, which promote inflammation by stimulating T cells and osteoclasts
- Macrophages also stim. fibroblasts (degrade bone matrix, produce inflammatory cytokines)
- Activated T cells and macrophages release factors that increase blood flow&destroy tissue= cellular invasion of synovial joint
What are assessment tools used to measure RA activity and remission
Clinical Disease Activity Index: Remission <2.8; Dz >2.8-10
What are the goals of RA treatment
achieve remission or low disease activity (treat to target)
Reduce inflammation using drugs known to alter disease progression
What deformities are associated with RA
Ulnar deviation
Swan neck deformity
Active synovitis
Nodules
What is the overall treatment plan for rheumatoid arthritis
Drug therapy should be part of comprehensive management; PT, exercise, and rest, assistive devices, +/- orthopedic services
When should you start disease modifying anti-rheumatic drugs
within 3 months of RA diagnosis
What is considered adjunct treatment early in RA Tx
NSAIDs and Corticosteroids
can also use them as needed if Sx are not controlled with DMARDs
What are your options when DMARDs fails
combination therapy w/ 2+ DMARDs
DMARD + biologic agent
-in either case, pt needs closer monitoring for toxicity and therapeutic benefit for duration of Tx
Early, aggressive Tx of RA may prevent
irreversible joint damage and disability
How do you decide which patients get which Tx
Less active disease and good prognostic indicator: Tx with oral monotherapy
High activity dz or poor prognostic factors: combo therapy and biologics
Controlling inflammation w/ therapeutic interventions improves
symptoms
also slows disease course
What are the non-biologic DMARDs
Methotrexate Leflunomide Hydroxychloroquin Sulfasalazine Minocycline Tofacitinib
Less frequently used agents 2/2 reduced efficacy or greater toxicity include
Azathioprine D-penicilamine Gold Cyclosporine Cyclophosphamide
Biologic DMARDs include
Anti-TNF: etanercept, infliximab, adalimumab, certolizumab, golimumab
Non-TNF: Abatacept, Tocilizumab, Rituximab, Anakinra
What type of drugs are the non-TNF drugs
Abatacept: costimulation modulator
Tocilizumab: IL-6 receptor antagonist
Rituximab: peripheral B cell depletion
Anakinra: IL-1 receptor antagonist
Long term data suggests superior outcomes of RA patients on this drug
Methotrexate, that is why it’s first line
Leflunomide has similar long-term efficacy as methotrexate
Examples of combination therapy are
Methotrexate, Sulfasalazine + Prednisone
Infliximab + Methotrexate
If moderate to high dz: Methotrexate + Hydroxychloroquine, Leflunomide, or Sulfasalazine
Recommended triple therapy is
Methotrexate + Sulfasalazine + Hydroxychloroquin
ACR endorses the use of anti-TNF biologics (enteracept, infliximab, etc.) in patients with
early disease of high activity and poor prognostic factors, regardless of whether they have used DMARDs
Algorithm for RA treatment is essentially
Start with MTX (DMARD) +/- prednisone
If it’s bad, do a combo DMARD, or anti-TNF, non-TNF, or Tofacitinib +/- MTX
If a single anti-TNF fails, do non-TNF or anti-TNF +/- MTX
If non-TNF fails, do another non-TNF +/- MTX
What is the MOA of methotrexate
inhibits cytokine production, purine biosynthesis
May stimulate release of adenosine (anti-inflammatory properties)
Folic acid antagonist (give 1-5mg xwk to counteract deficiency)
Methotrexate is contraindicated in
pregnancy chronic liver disease immunodeficiency Pleural or peritoneal effusions leukopenia thrombocytopenia CrCl <40
Toxicities of methotrexate include
N/V/D thrombocytopenia pulmonary fibrosis, pneumonitis elevated liver enzymes Stomatitis (first Sx)
What is the MOA of Leflunomide
inhibit pyrimidine synthesis= decreased lymphocyte proliferation
Modulate inflammation
Leflunomide is contraindicated in
liver disease
pregnancy (teratogenic)
Toxicities of Leflunomide include
GI, hair loss, liver, bone marrow toxicity
What is the MOA of hydroxychloroquine
Lessens antigen-antibody reaction at inflammatory sites
Good for mild RA or as an adjunct w/ DMARD in more severe disease
NOT myelosuppressive!
Toxicities of Hydroxychloroquin are
hepatic and renal toxicities Decreased night or peripheral vision rash, alopecia HA, vertigo N/V/D
What is the MOA of Sulfasalazine
Prodrug; cleaved to Sulfapyridine and 5-aminosalicylic acid in colon
Rapid absorption in GI, onset in 2 months
-Decreased absorption with antibiotics (destroy colonic bacteria) and Iron supplements
-Potentiated warfarin’s effects
ADE of Sulfasalazine are
N/V/D Rash, urticaria leukopenia alopecia stomatitis *elevated liver enzymes *turns skin yellow-orange (normal)
What is the MOA of Minocycline
inhibit metalloproteinases that damage articular cartilage
Good for low disease activity w/o poor prognosis (mildly reduces swollen joints and ESR)
NO effect on erosion progression
What s Tofacitinib
inhibit JAK (tyrosine kinase) which suppresses the immune system by reducing cytokine response
Good for moderate to severe RA who can’t take MTX
Do NOT give live vaccines!
ADE of Tofacitinib are
serious infections
lymphomas
latent TB
elevated lipids and liver enzymes
What are ADE of other disease modifying RA drugs
Gold salts: myelosuppression Azatioprine: leukopenia, hepatotoxicity D-penicillamine: myelosuppression Cyclosporine: nephrotoxicity Cyclophosphamide: gastritis
what is the overall MOA of biologic agents
genetically engineered protein molecules that block the proinflammatory cytokines
TNF: infliximab, enteracept, adalimumab, golimumab, certolizumab
IL-1: anakinra
IL-6: Tocilizumab
deplete B cells: Rituximab
prevent t cell costimulation needed for activation by binding CD80/86: Abatacept
What is the MOA of anti-TNF drugs
Block proinflammatory cytokines of TNF-a
do NOT use in CHF!
ADE od anti-TNF drugs are
MS like illness or MS exacerbation
Increased risk of lymphoproliferative cancer
What is Etanercept
a fusion protein that binds TNF and makes it biologically inactive
Prevents TNF from interacting with receptors that lead to cell activation
What is Infliximab
Chimeric antibody combining mouse and human IgG1
Binds to TNF and prevents interaction with receptors on inflammatory cells
Given WITH methotrexate to prevent formation of antibody response to the foreign protein (mouse)
What are the other anti-TNF biologics
Adalimumab: human IgG1 Ab to TNF
Golimumab: human Ab to TNF-a
Certolizumab: humanized antibody specific for human TNF-a
Golimumab can be used for
RA
Psoriatic arthritis
ankylosing spondylitis
What in Anakinra
IL-1 receptor antagonist
What is Tocilizumab
Attaches to IL-6 receptor and prevents cytokine from interacting with receptors
Monotherapy or with MTX or another DMARD
Do NOT give live vaccines during Tx
ADE of Tocilizumab are
risk of infx elevated plasma lipids and liver enzymes risk of GI perforation CYP450 3A4 inducer (warfarin) TB
What is Rituximab
Binds B cells and nearly completely depletes them
Good for pts who failed MTX of anti-TNF drugs (but continue MTX in combo with Rituximab)
Do NOT give live vaccines during Tx
What can be given with Rituximab to reduce the reaction
methylprednisone
APAP
antihistamines
What is Abatacept
a costimulation modulator for mod-severe RA that 1+ DMARDs don’t work in
Binds CD80/86 in APC, inhibit interaction between APC and T cells, and prevents T cell activation= no inflammation
Do NOT give live vaccines during Tx or 3 months after
ADE of Abatacept are
**HTN HA nasopharyngitis dizziness cough back pain UTI rash
Abatacept results in
reductions in cytokines, T cell proliferation, and other consequences of T cell activation
What can be used for symptomatic relief of RA
NSAIDs or Corticosteroids
Relatively rapid improvement in Sx compared to DMARDs (weeks to months)
but, they do NOT impact disease progression; they are simply symptomatic Tx
Also corticosteroids have a lot of long term ADE
What can be used for symptomatic relief of RA
NSAIDs or Corticosteroids
Relatively rapid improvement in Sx compared to DMARDs (weeks to months)
but, they do NOT impact disease progression; they are simply symptomatic Tx
Also corticosteroids have a lot of long term ADE
What is the MOA of corticosteroids
interfere with antigen presentation to T cells
Inhibit prostaglandin and LT synthesis
inhibit neutrophil and monocyte superoxide radical generation
Impair cell migration and redistribute monocytes, PMN, and lymphocytes= blunt inflammatory/auto-immune responses
Corticosteroids are good for
bridging therapy
pain
bursts or flares
How do you admin corticosteroids
Injection into joint q3 months (no more than 2-3x yr at the same joint)
ADE of corticosteroids are
HPA suppression Cushings Osteoporosis Glaucoma, cataracts gastritis HTN Glucose intolerance skin atrophy increased infx
