Intro to joint disease Flashcards
(56 cards)
1
Q
Define “pauci”
A
Synonym of oligo (2-3 joints involved); commonly used in pediatrics
2
Q
What are the general time frames of joint disease?
A
- acute= days to weeks
- subacute= weeks to 2 months
- chronic > 3 months
3
Q
Contrast the axial and appendicular skeleton
A
- axial
- skull
- mandible
- spine
- pelvis
- appendicular
- arms/legs
- coxa
- clavicle/scapula
4
Q
What are synovial joints?
A
- also known as diarthrodial joints
- allow gliding movement facilitated by lubricated cartilagenous surfaces
- hyaline cartilage on articular surfaces
- synovial cavity
5
Q
Describe hyaline cartilage
A
- functions
- elastic shock absorber
- friction free surface (along with synovial fluid)
- avascular; composed of…
- type II collagen (tensile strength)
- water/proteoglycans (elasticity and decreases friction)
- chondrocytes (maintain cartilaginous matrix)
6
Q
Describe the parts of the synovial cavity
A
-
synovial cells line cavity; cuboidal typically 1-4 layers thick
- produce synovial fluid
- remove debris (phagocytic function)
- regulate movement of solutes, electrolytes and proteins from capillaries to synovial fluid
-
synovial fluid= viscous filtrate of plasma containing hyaluronic acid
- lubricant
- provides nutrients to articular cartilage
7
Q
What laboratory testing is helpful in assessment of arthritis?
A
- Markers of inflammation
- Sed rate (inflammatory cells neutralize negative charge surrounding RBCs, increasing sedimentation)
- CRP (small molecule synthesized in liver that binds dying cells and/or pathogens) -> bacterial infection
- Anemia (in chronic disease)
- Leukocytosis (high WBC count)
- Serology
- Rheumatoid factor (autoantibody that binds Fc region of IgG; good specificity for RA but several things that create “false positives”)
- CCP antibody (>90% specific for RA)
- Anti-nuclear antigen (ANA); many subtypes identify various diseases (autoimmune, inflammatory, etc)
- Synovial (joint) fluid analysis; “string sign”
8
Q
What does a WBC count of the synovial fluid tell you?
A
- <200= normal
- 200-2,000= non-inflammatory
- 2,000-10,000= inflammatory
- >80,000= septic
- 200-2,000 + bloody fluid= hemorrhagic
9
Q
What defines gout? What is its prevalence?
A
- very inflammatory arthritis linked to metabolic disorders resulting in elevation of blood uric acid (hyperuricemia) and pro inflammatory crystals in the joint
- HOWEVER, during acute gout flare, serum uric acid levels can be falsely low
- 4% of US (becoming more prevalent with rise in BMI)
- Slightly more common in men (prevalence increases in women after menopause)
10
Q
What are some causes of hyperuricemia?
A
- Overproduction (10%)
- inherited enzyme defects
- myeloproliferative disorders
- purine rich diet
- alcohol
- Underexcretion (90%)
- renal failure
- metabolic syndrome/obesity
- diuretics
- alcohol
11
Q
What is the clinical presentation of acute gout?
A
- abrupt onset of severe pain
- most commonly monoarticular involving lower extremity **esp big toe
- synovitis with redness, swelling, and extreme tenderness over the joint
- self limited and resolves in 8-10 days (although ideally want to treat symptoms)
12
Q
What triggers an acute attack of gout?
A
**not fully understood:
- probably release of crystals from pre-formed deposits
- changes in temp, fluid status, and purine load (i.e. steak and beer)
- use of thiazide diauretics
- often occur in setting of acute illness
13
Q
What is the chronic clinical presentation of gout?
A
**polyarticular and destructive
- urate encrusts articular surfaces and form deposits that destroy cartilage and bone
- tophi
- large aggregates of urate crystals
- surrounded by lymphocytes, giant cells, and fibroblasts
14
Q
Describe the appearance of synovial crystals in gout
A
**negatively birefrigent
15
Q
What are the therapeutic goals in gout treatment?
A
- increase uric acid excretion
- inhibit inflammatory cells
- inhibit uric acid biosynthesis
- provide symptomatic relief (NSAIDs or steroids)
16
Q
Describe NSAID use in gout
A
- need to use within 24 hours (for gout)
- e.g. indomethacin, naproxen
-
aspirin= NO! (contraindicated in gout)
- low dose salicylic acid decreases uric acid excretion
- NSAIDs contraindicated in diseases of GI, platelet, renal, hypersensitivity
17
Q
Describe corticosteroid use in gout
A
- symptomatic relief in patients that can’t take NSAIDs
- short term use (adverse effects with extended use)
- orally or directly into joint
18
Q
Describe Colchicine
A
- MOA= antimitotic (arrests cell division in G1 by interfering with microtubules, esp in inflammatory cells)
- inhibit neutrophil activation and migration
- metabolized by CYP3A4
- substrate for P-glycoprotein (contraindicated in combination with P-gp inhibitors)
- significant adverse effects (GI) and narrow therapeutic window greatly limits its use
- contraindicated in hepatic/renal disease and in elderly patients
19
Q
When is colchicine used?
A
- acute gout attacks (within hours)
- prophylactically in patients with chronic gout
**Tends not to be first line drug because of adverse effects
20
Q
What non-pharmacological measures can be used to treat gout?
A
- abstain from alcohol
- weight loss
- discontinue medicines that impair uric acid excretion
- aspirin
- thiazide diuretics
21
Q
What 4 drug therapies are used to prevent gout flare and destructive effects on joints/kidneys?
A
- allopurinol
- febuxostat
- probenecid
- pegloticase
22
Q
Describe allopurinol
A
- MOA= inhibits terminal steps in uric acid biosynthesis (blocks xanthine oxidase)
- metabolized to active compound (oxypurinol) with longer plasma half life (18-30 hrs)
- Adverse effects;
- can cause acute gout attack (decreased synthesis mobilizes tissue stores of uric acid; give with colchicine or NSAID)
- serious hypersensitivity reaction possible
- USE: prevent primary hyperurecemia of chronic gout
23
Q
Describe febuxostat
A
- newer drug
- non-purine xanthine oxidase inhibitor (not an analog of allopurinol)
- more potent than allopurinol (and more effective in patients with impaired renal function)
- similar adverse effects (dizziness, diarrhea/nausea, headache), but HIGHER CV side effects
24
Q
Describe pegloticase
A
- recombinant form of urate-oxidase enzyme (uricase; normally absent in humans)
- adverse effects
- infusion site reactions (needs to be given IV)
- gout flare (give with prophylaxis)
- immune response
25
Describe probenecid
* uricosuric agent; monotherapy
* **increases the rate of excretion of uric acid** by competing with the renal tubular acid transporter (OAT/URAT1) so that _less urate is reabsorbed_
* some GI side effects
* ineffective in patients with renal insufficiency, contraindicated with uric acid kidney stones
26
Describe the major drug interactions of gout medications
* **allopurinol/febuxostat** _inhibit azathioprine and mercaptopurine metabolism_ -\> increased toxicity
* **colchicine** is susceptible to inhibition of _CYP3A4 and P-gp transport_
* **probenecid** interferes with renal excretion of drugs that undergo active tubular secretion (esp _weak acids_; penicillin)
27
What is rheumatoid arthritis? What is its prevalence?
* inflammatory symmetric chronic polyarthritis (unsure of exact mechanism; smoking/stress risk factors?)
* immunological disease (both T and B cells)
* genetic predisposition (e.g. HLA-DR4, HLA-DR1)
* ~1% of the world has RA (women\>men)
28
Describe the cellular pathogenesis of rheumatoid arthritis
1. DCs/APCs _phagocytose antigens_ and present them to T cells
2. activated T cells simulate B and T cell production
3. B cells produce plasma cells that form _rheumatoid antibodies_
4. helper T cells activate _macrophages_ and cytotoxic T cells
5. T cells, macrophage, and cytotoxic T cells produce _cytokines_ (TNFalpha, IL1, IL6, others) and _prostaglandins_ that cause joint inflammation, synovial proliferation, and bone/cartilage destruction (by _osteoclasts)_
29
What is the clinical presentation of rheumatoid arthritis?
* gradual onset of joint _pain, swelling, and inflammation_ present for \>6 weeks
* elevated markers of inflammation and abnormal serology
* symmetrical in nature and often involving small joints (MIP/PIP of hand, often spares DIP)
* _morning stiffness_ lasting greater than 1 hour
* _nodules_ can form at sites of trauma
30
What are some extra-articular manifestations of rheumatoid arthritis?
* rheumatoid vasculitis
* interstitial lung disease
* premature coronary artery disease
* secondary sjogren's syndrome (dry eye/mouth)
* felty's syndrome (big spleen, low WBC)
31
Describe the gross pathology of rheumatoid arthritis
\*\*chronic papillary synovitis;
* chronic _inflammation_ of synovium (CD4+ T cells, plasma cells, macrophages, giant cells)
* _synovial hyperplasia_ (results in **papillary** pattern)
* extends over the surface forming a **pannus** which fills the joint space; destroying articular cartilage and bone (via osteoclasts) overtime
* neutrophils and fibrin on joint surfaces in acute phase
32
Describe how rheumatoid arthritis looks on histology
* _lymphoid cells_ condense into follicles
* papillary synovitis (hyperplasia)
* _fibrinoid necrosis_ surrounded by inflammatory cells (epithelioid histiocytes, lymphocytes, plasma cells) seen in nodules
33
What are rheumatoid nodules?
* develop most commonly on skin in areas exposed to pressure (extensor surfaces of forearm/elbow)
* occur in 25% (usually in severe disease)
* non-tender, firm, round/oval
34
Describe NSAID use in rheumatoid arthritis
* large doses for long duration
* no effect on progression, just relieve symptom of pain
* long term GI upset consequences
35
Describe biologic response modifier use in rheumatoid arthritis
* monoclonal antibodies, receptor analogues, chimeric small molecules (bind or mimic molecular targets)
* notes: _cytokines_ are involved in all stages of RA
* better potency and specificity
* helpful that most have _long half lives_
* administered SQ/IM/IV
* possible side effects (all RA drugs);
* endogenous Ab formation against therapeutic Ab (e.g. _injection site reactions_)
* increased risk of serious _infections_
36
Describe the MOA of etanercept
* recombinant fusion protein
* inhibits ability of _soluble TNFalpha_ to bind to its receptor (inhibits its potent proinflammatory and immunoregulatory effects)
\*\*for rheumatoid arthritis
37
Describe the MOA of adalimumab
* human IgG monoclonal antibody
* binds to _soluble and transmembrane forms of TNFalpha_, preventing its binding to receptors
\*\*for rheumatoid arthritis
38
Describe the MOA of tocilizumab
* humanized antibody
* binds _soluble and membrane-bound IL6 receptors_ (inhibits IL6 mediated signaling that activates T/B cells, macrophages and osteoclasts)
\*\*for rheumatoid arthritis IF patient has had inadequate to 1+ TNF antagonists
39
What are some adverse effects of tocilizumab?
* similar to other anti-RA drugs (injection site reaction, increased risk of infection)
* _alterations in lipid profile_
40
Describe the MOA of tofacitinib
* inhibits Janus Kinase (JAK) enzymes invovled in stimulating immunce cell function
\*\*oral administration
\*\*for rheumatoid arthritis IF patient has had inadequate response/intolerance to methotrexate
41
What are some adverse effects of tofacitinib?
* similar to other anti-RA drugs (increased risk of infection)
* _alterations in lipid profile_
42
Describe the MOA of rituximab
* B cell depleting monoclonal anti-CD20 antibody
* inhibits complement dependent cytotoxicity and Ab-depndent cellular toxicity (CDC and ADCC)
\*\*for rheumatoid arthritis IF patient has had inadequate response to 1+ TNF antagonists
43
Describe the MAO of abatacept
* fusion protein
* inhibits the binding of CD28 and prevents the activation of T cells
\*\*for rheumatoid arthritis IF patient has had inadequate response to 1+ TNF antagonists/Disease-modifying antirheumatic drugs (DMARDs)
44
What are non-biologic DMARDs?
* Disease-modifying antirheumatic drugs (DMARDs)
* **methotrexate** (structural folic acid analog; _inhibits folate pathway_ -\> stops DNA/RNA synthesis)
* also, _accumulation of adenosine -\> antiinflammatory_
* leflunomide
* hydroxychloroquine
45
What is the goal of rheumatoid arthritis treatment?
\*\*REMISSION; treat with...
1. symptomatic relief (until methotrexate effects begin; NSAIDs and/or glucocorticoids)
2. non-biologic DMARD (methotrexate)
3. DMARD biologics (e.g. TNFalpha inhibitors)
4. if no remission, _combination therapy_ used
46
Describe osetoarthritis
* progressive, degenerative joint disorder caused by gradual loss of _cartilage_
* worse with activity
* _minutes_ of morning stiffness/after prolonged immobility ("gelling")
* associated with "crunching"
* most common cause of arthritis in adults (many risk factors; women, age, genetics, obesity, diabetes, trauma)
47
How do you diagnose osteoarthritis? How does it compare with rheumatoid arthritis on physical exam?
* diagnosis primarily based on
* joint distribution
* character of pain
* exam findings
* blood tests/xrays not helpful
* synovial fluid aspiration may rule out other types of arthritis (will be non-inflammatory; \<2000 WBC/mm3)
48
What is observed on radiograph in osteoarthritis?
* osteophytes
* joint space narrowing
49
What is the pathogenesis of osteoarthritis?
* imbalance of cytokine and growth factor activity results in matrix loss and degradation (unsure of mechanism)
* early: superficial layers of cartilage are destroyed, leading to _fibrillation and cracking_ of cartilage matrix
* _subchondral cysts_ form as synovial fluid is forced into subchodral space
* absence of articular cartilage (eburnation) and _bone underneath becomes more dense/sclerotic_
* remaining cartilage has a rough "sandpaper" look
50
What are osetophytes? What are they called on the distal and proximal interphalangeal joints?
* bony outgrowths that develop at the margins of articular surfaces
* DIP= Heberden nodes
* PIP= Bouchard nodes
51
What are the common therapies for osteoarthritis?
* weight loss, exercise, physical therapy
* intra-articular therapies (corticosteroids, hyaluronans)
* topical therapies (capsaicin, salicylates, menthol)
* systemic therapies
* acetaminophen
* duloxetine
* NSAIDs
52
Describe capsaicin
* MOA= _TRPV1 receptor agonist_ (a transmembrane receptor ion channel)
* induces _release of substance P_ (mediator of pain impulses from periphery to CNS)
* initially causes local/transient application site pain
* after repeated application, capsaicin depletes the neuron of substance P (and prevents reaccumulation)
\*\*topical over the counter use
53
Describe the MOA of duloxetine
* SNRI; analgesic effect sooner than antidepressant effect and at lower dose
* centrally acting oral analgesic by stimulating the inhibitory decending pain pathways (mediated by 5HT and NE)
54
What are SYSADOAs?
* symptomatic slow acting drugs for OA \*\*dietary supplements (effectiveness of these agents remains to be established)
* **glucosamine sulfate**
* principle substrate in the biosynthesis of proteoglycan, which is essential for maintaining _cartilage integrity_
* **chondroitin sulfate**
* _maintains viscosity_ in joints, stimulates _cartilage repair_ mechanisms and inhibit enzymes that break down cartilage
55
Describe hyaluronic acid (use as a drug)
* exists in the normal synovial fluid, but given via injection for osteoarthritis of the knee;
* inhibits inflammatory mediators
* descreases cartilage degradation
* promotes cartilage matrix synthesis
* not a first line drug; doesn't slow progression, just helps symptoms (esp for patients unable to take NSAIDs)
56
Describe opioid use for osteoarthritis
* NO evidence that opioids improve function more than nonopioid analgesics
* may be useful in patients with severe symptoms not treated in other ways (2nd or 3rd line option)
* need to consider opioid epidemic
