Term
| What are the basic epidemiological characteristics that define RA? |
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Definition
1) Peak onset 40-50, with sharp increase thereafter
2) 2:1 Women:Men
3) Initially in hands, wrists and feet, and later can spread to anything with a synovium |
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Term
| What is the most compelling case for a genetic link to RA |
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Definition
Monozygotic twins have 30-50% concordance when one twin is affected, compared to 17% for the general population
HLA-DRB1 (QKRAA epitope) confer susceptibility |
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Term
| What is the link between pregnancy and RA? |
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Definition
| >75% go into remission during pregnancy (hormonal?), but >90% experience flares weeks/months after delivery. |
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Term
| What is the "hallmark" of RA? |
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Definition
Pannus= hypertrophic synovial villi with dense inflammatory cell infiltrates. Steps in formation include:
Neovascularization, cellular infiltration, inflammation and destruction.
1) Neovascularization (high endothelial expression of adhesion molecules to promote migration of inflammatory cells)
2) Cellular Infiltration- Selectins and integrins determine extravascular destination of inflammatory cells (IL-8 attracts PMNS!)
3) Cellular components-
Type A synoviocytes (macrophages)
Type B synoviocytes (fibroblast-like)
Lymphocytes (CD4+ T cells and B cells)
Plasma cells making rheumatoid factor
4) Release of pro-inflammatory cytokines (TNF-a, IL-1, IL-6) leads to tissue destruction by MMPs and free radicals. |
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Term
| What is the difference b/w type A and type B synoviocytes? |
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Definition
A= macrophage-like
B= fibroblast-like |
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Term
| Explain the basic pathogenesis of RA |
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Definition
| Joint erosions develop at cartilage-bone interface as pannus penetrates articular cartilage and subchondral bone with leading edge of activated type A and B synoviocytes (Osteoclasts at junction are critical for bone loss) |
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Term
| What is the prognostic and diagnostic significance of Rheumatoid Factor? |
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Definition
High titers are found in RA (15% of patients don't), but also in other diseases and normal people
1) Produced by plasma cells (can be induced by EBV and LPS) , RF's are autoantibodies against Fc portion of IgG
** by age 70, 10% of population may have high RF** |
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Term
| What is the prognostic and diagnostic significance of anti-CCP? |
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Definition
autoantibodies against epitopes containing citrulline and HIGHLY specific for RA (>95%) and can be present years before onset.
1) Formed by post-translational deimination of arginyl residues by PADI. Antibodies against these epitopes are called ACPAs)
2) Specificity>Sensitivity
3) Smoking linked to shared epitope and production of ACPA |
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Term
| What are highly prognostic factors of RA progression at 1 year? |
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Definition
1) Morning stiffness
2) Number of swollen joints
3) Hemoglobin
4) ESR
5) RF test |
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Term
| What accounts for over 50% of excess mortality seen in untreated RA? |
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Definition
| premature atherosclerosis |
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Term
| How does one go about diagnosis RA? |
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Definition
1) look at symptoms (joint pain and morning stiffness), fatigue and mechanical joint problems.
**morning stiffness is key as it represents accumulated edema fluid within inflamed tissue= synovitis**
Lower back pain not characteristic, nor "pain all over"
2) Order blood count, basic metabolic panel; RF, anti-CCP and ANA
3) Polymyalgia rheumatic (PMR) with elevated ESR but not RF (treat with prednisone)
ACR/EULAR classification system involves scoring "joint involvement", "serology," "Acute phase reactants," and "Duration of symptoms" |
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Term
| What Articular features are seen in RA? |
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Definition
1) involvement of small joints of hand (squishy, swollen hands)
2) MCP, PIP and DIP (less frequently)
** earliest in 2nd and 3rd MCP, and 3rd PIP**
3) Symmetric, fusiform soft tissue swelling and concentric joint space loss (on X-ray)
4) Forefoot involvement (80-90%), usualy in MTP joints (5th)
5) Erosions (8-40%) |
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Term
| What Extra-articular features are seen in RA? |
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Definition
EVERYWHERE
1) Rheumatoid nodules (palpable purpura in response to drug- found on extensor surfaces with variable consistency)
2) Cardiac- premature CVD accounts for 50% of excess mortality
3) Pulmonary (2nd most common)- pleural disease, interstitial fibrosis, nodular lung disease, bronchiolitis obliterous, arteritis, small airway
4) Vasculitis
5) Eye- Scleritis, episcleritis or both (<1%!). Does nto cause vision loss directly, but cataracts are secondary
6) Sjogren syndrome- ocular, oral, Schirmer/Rose Bengal, Salivary gland biopsy, Scintography for salivary involvement, serum antibodies (LYMPHOMA CAN RESULT)
7) Felty syndrome (RARE)- infections and hepatic abnormalities (leukopenia)
8) Bone- Glucocorticoid-induced osteoporosis (GIOP)
9) Infection
10) Malignancy
11) Hematology- anemia of chronic disease, Iron deficiency anemia, acute phase reactants
12) Neurologic- nerve compression |
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Term
| Why use NSAIDs in RA? What side effects need to be considered? |
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Definition
Inhibit prostaglandin synthesis by inhibiting COX.
Can induce peptic ulcer disease |
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Term
| Why use Steroids in RA? What side effects need to be considered? |
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Definition
| low-dose prednisone is used for flares of swollen joints as a "bridge therapy" until DMARDs are administered |
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Term
| Why use Oral DMARDS in RA? What side effects need to be considered? |
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Definition
Hydroxychloroquine (Antimalarial) - can cause ocular toxicity from retinal deposits (more common in chloroquine)
Sulfassalazine (SSZ)- 1-1.5mg twice daily for anti-inflammatory and immmunomodulatory effects- GI side effects
Methotrexate (MTX) most common- immunomodulatory avoid if renal insufficiency or on dialysis. Can cause mouth ulcers, Nausea and bone marrow suppression
Leflunomide- immunomodulatory that is activated in GI following oral administration to inhibit DHODH and prevent pyrimidine synthesis, preventing lymphocyte turnover- Can have bone marrow toxicity, rash, diarhea |
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Term
| What Biological therapies are available for RA? |
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Definition
1) anti-TNF-a very promising (5 versions)
2) Anikinra (IL-1R antagonist)
3) Ritaximab (anti-CD20 in B cells)
4) Abatacept (co-stimulatory blocker) |
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Term
| What pregnancy considerations are important in RA treatment? |
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Definition
1) Improvement seen in 75% of pregnant women starting in 1st trimester
2) Postpartum active arthritis
** risks of treatment during birth UNCLEAR** |
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Term
| What is most widely excepted idea behind RA pathogenesis? |
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Definition
Antigen in synovial tissue is presented by APC to TCR and numerous cytokines (both activating and inhibiting) are produced leading to 3 effector mechanisms of joint destruction.:
1) Activation of synoviocytes (MMP production)
2) Activation of Vascular adhesion molecules (PMNs, lymphocytes and macrophages into joint)
3) Activation of B cells (producing Ig) |
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Term
| What are the 3 primary predisposing factors for RA? |
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Definition
| CCP (+), HLA-DRB1 and Smoking! |
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Term
| How is the activity of RF different in normal conditions than in RA? |
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Definition
RF are autoantibodies that bind to Fc regions of IgM and allow complement fixation and uptake of immune complexes.
1) In normal immune response, RF enhances the avidity and size of immune complexes, improving complement-mediated clearance.
2) High titer IgM-RF (and IgA RF) are of high diagnostic importance and prognostic value
Out of every 100, 5 or 6 will have a (+) ANA or RF, and 4 of them will be just fine! |
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Term
| What are CCP antibodies and how do they relate to RA? |
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Definition
anti-Citrulinated protein antibodies (ACPA) that are associated with HLA-DR alleles and smoking
- 95% specificity (i.e. 95% of people w/o RA will not have ACPA)
- correlate with erosive disease |
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Term
| What is the mortality associated with RA? |
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Definition
1) if untreated, permanent joint damage
2) 20-30% of people become permanently disabled in first 2 or 3 years of disease
3) Reduced life expectancy by 3-18 years (CVD- biggest issue, infection, respiratory, GI, cancer) |
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Term
| What is the biggest associated cause of mortality associated with RA? |
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Definition
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Term
| What other diseases are on the differential diagnosis for RA? |
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Definition
1) Lupus- young women with ANA and photosensitivity (70% of patients with RA also have (+) ANA
2) AS (but back should be involved here)
3) Osteoarthritis (usually non-inflammatory, but you can see both at the same time) |
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Term
| What is PMR and how does it relate to RA? |
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Definition
Polymyalgia Rheumatica: over age 55 with hip/shoulder stiffness and pain.
Often associated with RA, but not always (could be something more serious that could cause blindness!) |
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Term
| What 4 features are measured for the ACR/Eular diagnostic system for RA? |
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Definition
ACR/EULAR classification system involves scoring
"joint involvement"
"Serology"
"Acute phase reactants"
"Duration of symptoms" |
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Term
| What is an issue with treating patients with RA with steroids? |
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Definition
1) Steroid-induced osteroperosis (stress fractures)
2) Sometimes muscle weakness secondary to joint weakness and lack of excercise |
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Term
| What do you see in a blood sample from RA? |
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Definition
1) Anemia (Il-6 and inflammation-mediated)
2) Leukocyte elevation or depression (MTX lowers)
3) Platelet count elevation
4) Acute phase reactants (ESR, CRP)
5) SSA/SSB (Sjogren's)(not routinely performed)
6) ANA (check for neonatal lupus possibility) |
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Term
| What neurological syndromes are associated with RA? |
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Definition
1) Median nerve compression from carpel tunnel syndrome
2) Cervical spine involvement. |
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Term
| Why is there such a problem with infection in RA? |
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Definition
| Steroids, MTX and anti-TFN ALL increase the risk (all therapies makes it more likely). |
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Term
| Explain a general course of treatment for a 48-year old woman with RA. |
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Definition
1) Start with Prednisone (bridge therapy) and MTX
2) Decrease prednisone and increase MTX
3) Use anti-TNF therapy if disease persists |
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Term
| What drug might you use for mild RA? |
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Definition
| Hydroxychloroquine (MHC-II action) |
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Term
| Which is the best drug for RA and which are some that are less desirable? |
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Definition
1) MTX is preferred (inhibits folic acid-dependent pathways to inhibit cytokines, lymphocyte proliferation).
It is teratogenic though and bad in cases of kidney failure.
2) Sulfsalazone has more side-effects
3) Leflunomide inhibits lymphocyte turnover, but has GI, hematologic and hepatic toxicity as well as being a teratogen. |
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Term
| What drugs can you give for RA during pregnancy? |
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Definition
MTX and Leflunamide are teratogenic.
However, in 75% of cases, RA gets better during pregnancy, and then you can treat with MTX afterwords when symptoms return. |
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