Intro to joint disease Flashcards
Define “pauci”
Synonym of oligo (2-3 joints involved); commonly used in pediatrics
What are the general time frames of joint disease?
- acute= days to weeks
- subacute= weeks to 2 months
- chronic > 3 months
Contrast the axial and appendicular skeleton
- axial
- skull
- mandible
- spine
- pelvis
- appendicular
- arms/legs
- coxa
- clavicle/scapula
What are synovial joints?
- also known as diarthrodial joints
- allow gliding movement facilitated by lubricated cartilagenous surfaces
- hyaline cartilage on articular surfaces
- synovial cavity
Describe hyaline cartilage
- 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)
Describe the parts of the synovial cavity
-
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
What laboratory testing is helpful in assessment of arthritis?
- 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”
What does a WBC count of the synovial fluid tell you?
- <200= normal
- 200-2,000= non-inflammatory
- 2,000-10,000= inflammatory
- >80,000= septic
- 200-2,000 + bloody fluid= hemorrhagic
What defines gout? What is its prevalence?
- 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)
What are some causes of hyperuricemia?
- Overproduction (10%)
- inherited enzyme defects
- myeloproliferative disorders
- purine rich diet
- alcohol
- Underexcretion (90%)
- renal failure
- metabolic syndrome/obesity
- diuretics
- alcohol
What is the clinical presentation of acute gout?
- 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)
What triggers an acute attack of gout?
**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
What is the chronic clinical presentation of gout?
**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
Describe the appearance of synovial crystals in gout
**negatively birefrigent
What are the therapeutic goals in gout treatment?
- increase uric acid excretion
- inhibit inflammatory cells
- inhibit uric acid biosynthesis
- provide symptomatic relief (NSAIDs or steroids)
Describe NSAID use in gout
- 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
Describe corticosteroid use in gout
- symptomatic relief in patients that can’t take NSAIDs
- short term use (adverse effects with extended use)
- orally or directly into joint
Describe Colchicine
- 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
When is colchicine used?
- acute gout attacks (within hours)
- prophylactically in patients with chronic gout
**Tends not to be first line drug because of adverse effects
What non-pharmacological measures can be used to treat gout?
- abstain from alcohol
- weight loss
- discontinue medicines that impair uric acid excretion
- aspirin
- thiazide diuretics
What 4 drug therapies are used to prevent gout flare and destructive effects on joints/kidneys?
- allopurinol
- febuxostat
- probenecid
- pegloticase
Describe allopurinol
- 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
Describe febuxostat
- 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
Describe pegloticase
- 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
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
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)
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)
Describe the cellular pathogenesis of rheumatoid arthritis
- DCs/APCs phagocytose antigens and present them to T cells
- activated T cells simulate B and T cell production
- B cells produce plasma cells that form rheumatoid antibodies
- helper T cells activate macrophages and cytotoxic T cells
- 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)
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
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)
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
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
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
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
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
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
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
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
What are some adverse effects of tocilizumab?
- similar to other anti-RA drugs (injection site reaction, increased risk of infection)
- alterations in lipid profile
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
What are some adverse effects of tofacitinib?
- similar to other anti-RA drugs (increased risk of infection)
- alterations in lipid profile
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
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)
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
What is the goal of rheumatoid arthritis treatment?
**REMISSION; treat with…
- symptomatic relief (until methotrexate effects begin; NSAIDs and/or glucocorticoids)
- non-biologic DMARD (methotrexate)
- DMARD biologics (e.g. TNFalpha inhibitors)
- if no remission, combination therapy used
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)
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)
What is observed on radiograph in osteoarthritis?
- osteophytes
- joint space narrowing
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
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
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
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
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)
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
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)
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
