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- decreased ROM, joint instability, bony enlargement, crepitus, variable swelling, minimal morning stiffness but gets worse during the day
- Osteoarthritis
- Imaging of osteoarthritis --> (5)
- Joint space narrowing, marginal osteophytes, subchondral cysts, bony sclerosis, malalignment
- OA labs
-
none:
CXR cartelige loss or joint fluid indicators - OA risk factors (7)
-
Risk Factors:
age, female, fat, heredity (dwarfism), trauma, neuromuscular prob (in lower extremities; diabetes), metabolic (upper extremities ; psudogout) - OA prognosis
- progressive cartelidge loss
- OA pathophysiology
- stress--> chg chondrocyte metabolism in stress --> shift away from Col II (hyaline) = proteoglycan degredation, subchondral bone prolif (osteophytes) due to TGF beta
- OA distribution
- spine, DIP, PIP, carpometacarpal, Hip, knee, big toe,
- Secondary OA causes
-
1) previous trauma
2) Neuromuscular ds (DM)
3) Metabolic Ds (pseudogout) - Diabetic Neuropathy in OA
-
MTP 1-5
destrictuve chg =FAR in XS of primary OA
midfoot involvment - OA and Pseudogout (CPPD)--causes (5)
-
hemochromatosis
hyperParathyroidism (hypothyroidism)
HypoPhosphatemia, hypomagnesemia
neuropathic joints
trauma
aging and heredity -
Drugs for OA:
six major drug types -
1) non-opiod analgesics
2) topical anesthetics
3) intraarticular agents
4) opioid analgesics
5) NSAIDS
6) unconventional therapies -
Acetominophin:
efficacy
toxicity -
FX: pain relief w low tox (vs NSAIDS)
Tox: beware multiple source of actominophin over the counter! -
NSAID:
dose
FX
fancy
SideFX (5) -
dose: lower dose may be effective
FX: do not retard disease progression
fancy: gastroprotection
SideFX: GI, renal, worse CHF, edema, antiplatelet -
COX2i:
FX
side FX (2)
risk pop
cost -
FX: pain relief equiv to old NSAIDS
side: lower GI tox, no FX on platelet
risk: old and multimed user
cost: similar to NSAID + H pump-i -
Tramadol:
mech
benefit
regimen
sidefx -
mech: effects opioid and seratonin fx
benefit: non ulcerogenic
recimen: added to NSAID/acetominaphin
sideFX: N/V, low seizure thresh, rash, constipation, dizziness, drowsiness - OA: topical Agents (2)
-
1. Capasin (avoid eyes, use 2wks b4 works)
2. Liniment = methyl salicates - OA: invasive (4)
-
1. IntraArticular Tx
2. IntraArticular Steroids
(good relief, /3mo, risk infection/worse-dm/chf)
3. Joint lavage (good fx)
4. Hyaluronate injections
(relief &improv func but $$$, no long-term benefit, and ltd to knees) - OA: Opioid Analgesics (3)
-
1. Codeine/Oxycodone
(anticipate constipation)
2. Propoxyphene
3. Morphine&Fentanyl Patch - OA: unconventional tx (2)
-
1. Polysufated Glycans
(ad w chondroitin sulfate)
2. Tetracyclines
(protease/cytokine inhibitors) - OA: surgical tx (3)
-
1. Arthroscopy
2. Osteotomy
3. Total joint replacement - Bone Structure
-
ECM: osteoid (type I col) and minearal crystals
architecture: cortical & trabecular bone - Bone Cells
- Osteoblasts, Osteoclasts
-
Osteoblasts:
from
produce
yield
growth activates -
from: ct progenitors
produce: ECM proteins
yield: mineralization
activated by: TCFbeta, IGF-1 -
Osteoclast:
from
loc
produce
activated by -
from: hemipoetic precursors
LOc: contact bone at ruffled border
produce: acid environ
act by: IL-1/6, TNF, and gonadal steroid - Bone remodeling (4 steps)
-
1) ostoeclastic activity (7-10 days)
2) O-Blast bone reformation (3 mo)
3)mech loading is an important stimulus
4)immobilization --> incr absorb and block formation -
Clinical Synd with:
decreased but normal bone mass - Osteoporosis
- Risk factor of osteoporosis: (7)
-
1. polymorphism of the Vit-D Receptor
2. Fam Hx
3. Thin body habitus
4. white/asian
5. cigarettes
6.low glucocortocoids
7. increases with age -
Func of Glucocortocoid on bones:
direct action
result -
inhibits:
GI calcum absorbtion
osteoblast activity
bone matrix formation
result: hypogonadism -
Sx of:
1. Early osteoporosis
2. Osteoporosis (2)
3. end stage osteoporosis -
1. a-sx
2.
2a) decreased skeletal integrity --> fractures
2b) veribral compression fractures
3. dorsal kyphosis -
Bone Markers for Osteoporosis :
for oblast (2)
for o clast (2) -
OBlast: 1) alkaline phosphatase 2) osteocalcin
O-Clast: 1) pyridinoline crosslinks, 2) telopeptide - Differential Diagnosis for osteoporosis:
-
1 hyperparathyroidism
2 cushings syndrome
3 hyperthyroidsm
4 osteomalacia
5 multiple myeloma
6 hypogonadism - Ts for osteoporosis:
-
preventative:
1. fall prevention
2. devices and PT
Suppliment
1. Ca suppliment
2. Vit D suppliment
3. gonadal steroid if req (hypogonadism)
Dx:
1. Raloxifine
2. Bisphospates
3. Calcitonin
4. PTH - Best measure of bone density
-
Bone Densiometry
criteria are 2.5 std deviations below normal young person -
Gonadal Steroid Replacement
what act to do
long term fx (2) -
major well established fx to decreased osteoclast
long term tx: increased bone mass, and decreased fracture risk -
Raloxifine:
what
mech
fx (2)
not fx
side fx (2) -
what: selective estrogen receptor modulator (SERM)
mech: mimics estrogen action on bone
FX: 1) increased bone density and decreased fracure risk
what not FX: breast or endometrium (not increase cancer risk)
side FX: 1) hot flast, 2) risk of thromboembolic ds - Bisphosphonates
-
1. Alendronate
2. Risedronate
3. Ibandronate -
Alendronate, Risedronate, Ibandronate
type of dx:
mech:
dose form:
fx (2):
side fx: (2) -
class: bisphosphate
mech: bind hydroxyapetite crystals and stabilize matrix or may inhib c-strol metabolism in osteoclast
dose form: oral
fx: 1) increase bone mass & 2) decreased fracture risk
side fx: 1. (rare) severe erosive esophagitis 2. osteonecrosis of mandible -
Calcitonin:
does form
FX (2)
sideFX: (2) -
dose form: nasal form
FX: 1) decreased bone loss (not restore bone) 2) pain control for fracture
sideFX: 1) ocasional N/V 2) flushing -
PTH:
dose form
act
FX (2)
side fX -
dose: subQ inject daily
act: activate osetblastic activity
FX: 1) increase bone density and 2) decrease fracture risk
sideFX: low risk of hypocalcemia - Prevention of Osteoporosis for patients on glucocorticoids:
-
1. adequate Ca2+ and Vit D
2. Gonadal / steroid replacement if req
3. bisphosphonates -
clinical syndromes (2):
resulting from inadequate bone mineralization -
What is:
Osteomalacia
Rickets - Causes of Osteomalacia/Rickets (3)
-
1. decreased Vit D:
(inadequate intake, malabsorb, liver ds, renal failure, hereditary)
2. decreased Phosphate
(renal tube ds, tumor assoc osteomalacia, x-linked hypophosphatemia, phosphate binders)
3. inhibit mineralization:
(aluminum, fluoride) - Osteomalacia pathogenesis
-
1. decreased vit D --> decreased Ca2+ absorb in GI
2. decreased Ca in serum --> 2ary hypoparathyroidism
3. icreasede PTH -> [Ca]serum--> phosphoturia/hypophosphatemia/ (increasedbone resorbtion)
4. decreased [phosphate]serum-->inadequate bone mineralizaiton and osteopenia
and if severe then --> hypocalcemia - Bone pain and decreased density, pseudo fractures
-
Sx:
Osteomalacia
Rickets - low blood phosphate, high alk phos, high pth, low bone density and late hypocalcemia
-
Labs of :
Osteomalacia and rickets - Children with bowing of the legs,, rachitic rosary, short stature
- rickets
-
To Ds Osteomalacia or rickets:
3 tests -
1) 25-hydroxyvitament D level
2) PTH level and alk phosphatase
3) bone biopsy -
How further evaluate rickets/osteomalacia:
5 way -
1) diet and sunlight
2) renal func
3) fecal fat
4) Anti-IgA endomysial and tissue transaminase Ab
5) small bowel biopsy - Tx of Osteomalacia & rickets
-
1) Vit D def --> get Vit D
2) renal failure --> get 1,25 calciferol - Pathophysiology of Pagets Ds
-
increased bone turnover :
increased resorbtion and compersitory increased fromation
--> abnormal bones -
Many are asx:
bone pain/deformity, fractures, arthritis, nerve compression, osteogenic sarcoma - Pagets Ds
- How Ds Pagets Ds?
-
Dx:
1. increased alk phos levels
2. char radiograph
3. bone scan --> extent of ds - Tx of pagets
-
Tx:
tx the sx-->
bisphosphate and calcitonin - 20-60 yr old with morning stiffness and hand/wt-bearing/spine/wrist/elbow/ankle pain, soft tissue swelling, Thrombocytosis and hypoalbuminemia, increased SED rate
- RA
- older with pain increasing thru day, hand/wtbearing/spine pain wiht minimal swelling and normal labs
- OA
-
What are common and rare diseases for:
TMJ -
common: RA, Juvie arthritis
Rare: Gout -
What are common and rare diseases for:
Larynx -
common: RA
Rare: other diseases -
What are common and rare diseases for:
Elbow, wrist, MCP -
common: synoviitis
Rare: OA -
What are common and rare diseases for:
DIP -
common: OA or psoriatic arthritis
Rare: RA -
What are common and rare diseases for:
Hips -
common: OA, RA
Rare: Gout -
What are common and rare ds for:
Cervical Spine -
common: RA, OA, juvie arth, psoriasis, spondyloarthropathies
Rare: Gout -
What are common and rare ds for:
Thoracolumbar spine -
common: OA, Spondylarthropathies ( ankylosing spondylitis, psoriatic arthritis, reiters synd, IBS)
Rare: Gout, RA - morning stiffness, arthritis of >2joints, hand arthritis, symmetrical arthritis, rh nodules, abrom serum Rh, typical chg or pa x-ray of hand wrist
- RA
-
Causes of RA:
3 families each with many -
1. Systemic rh disease ( SLE, Scleroderma, polymyolitis, vasculitis)
2. Spondylarthropathies (ankylosing spondylitis, reiters)
3. Other: ( gout, pseudogout, Rh fever, juvie RA, psoriatic RA) - early vs late sx in RA
-
early: a-sx and non uniform
late: symmetric and uniform - Histo of RA
- synoviocyte transformation --> synoviocyte interact with macrophage, cartelidge and bone
- mechanisms of RA (3 things)
- T-cell, cytokines, monocyte are the mech of path
- humoral effects of RA (3 humors)
- RF, immune complex complement)
- Bacterial trigger of RA (4)
-
gram + cocci
mycobacteria
proteus
e-coli - Viral trigger (6)
-
epstein barr
parvovirus
retrovirus
CMV
Reubella
Herpes 6 - Genetics of RA
-
evidence: twinstudies --> multi gene
HLADR-4 --> 80% of RA - what is most predictive of RA course
- RF titres
-
RF:
produced in
act on -
ori: most prominant in synovial tissue
act: enhanse formation of path Ic (B cell w surface Rf can trap Ag in Ic and present to primed t -cell) - RF found in what ds (Rh = 6; non-Rh = 6)
-
Rh:
1. RA 2. Sjorgrens 3. SLE 4. Progressive systemic sclerosis 5. polymyositis / dermatomyositis 6. cryoglobulinemia
Non Rheumatic: 1) Bact endocarditis, 2) TB, 3) the syph, 4) hepatitis, 5) leprosy, 6) schisto - RF not found in what ds (2 major type)
-
Rh = 1) OA, 2) gout, 3) ank spondy 4)supperative/psoriatic/EntHep Arthritis
non Rh= Chronic Hepatitis -
Anti-CCP Ab
gen when
loc
risk to get it -
anticitrullinated peptide
gen: arg --> ditruline via PADI (peptidyl arg de-iminase)
loc: in inflamed synovium
risk = smoking --> citrulination - Risk factors for RA (4)
-
genetic: MCH class II< multiple other
smoking
Anti CPP
environ: smoking and infection -
RA pathogenesis (2 schools of thought)
what is import for each -
1) Immune process: t cells are import
assoc with an MHC class and an auto antigen (collagen, gp39, MHC or IgG) or a microbial antigen ( parvovirus, peptidoglycan, staph, EBV, HSP, mycobact)
2) Non immune process: t cells arent import
IL-7 is important (secreted by active memory t cwells ) induced by IL6 and TGFbeta
APC --> IL-23 (like IL12)--> IL17 - Cell cell interactions in the synovium (6)
-
1. leukocyte / endothelial
2. t-cell / dendritic cell
3. t-cell / macrophage
4. t-cell / firbroblast
5. macrophage / fibroblast
6. B cell / fibroblast -
Cytokine:
def
proinflamm (2)
antiinflam (3) -
def: intercellular messanger
proinflamm: 1) TNFalpha, 2) IL-1
antiinflamm: 1) IL-1R 2) TNF-R, 3) IL10 -
TNFalpha
5 interactions and what they do! -
1. Macrophage --> increased pro inflam (IL-1 / TNFalpha) --> inflammation
2. Endothelial --> increased adhesions molecules--> increased cell infiltration
endothelial --> increased VEGF --> angiogenesis
3. Hepatocytes--> increased acute phase response --> increased CRP in serum
4. Synoviocytes--> increased MMP --> articular cartelige degredation
5. Osteoclast progenitors--> increased RANKL --> bone erosions - Monocyte cytokine cascade
-
1. --> TNF alpha --> three things:
(a) TNF alpha-->endothelial cell--> increased adhesion --> extravesation
(b) TNFalpha-->active synovial fibroblast-->1. (IL-8 --> increased extravesation) and 2.(MMP/PGE/IL6 --> kills cartelidge)
(c) TNFalpha--> stim macphage
2. --> ODF --> osteoclast
3. -->IL-1 --> stimulates 1.( t cells) and 2.(synovial fibroblast see above) -
gamma IFN
made by
target -
made by: T cell
target: macrophage and fibroblast -
IL-1
made by
target -
made by: synovial mac (and some t cell)
target: t cells, macphage and Oclast -
TNF alpha
made by
target -
made by: synovial (and some t cell)
target: t cell and synovial mac -
IL-6
made by
target -
made by: synovial mac
target: t cell and benatocyte -
IL-8
made by
target -
made by: synovial mac or fibroblast
target: pmn and t cell -
IL-10
made by
target -
made by: synovial mac and t cell
target: synovial mac and t cell -
IL-12
made by
target -
made by: synovial mac
target: t cell -
IL-15
made by
target -
made by: synovial mac
target: t cell -
IL-17
made by
target -
made by: t cell
target: synovial mac -
IL-1 and RA
mech of IL-1
result (3) -
mech: triggers production of other pro inflam cytokin and TNF
result:
1) --> t cell / pmn accumulate in synovium by activating endothelial adhesion molecule
2) activate collagenate / stomelysinm
3) activate oxteoclast differentiation thru (TNF and RANKL) -
RANK : OPG ratio
what is the action of RANK
what is the action of OPG
Ratio of RANK to OPG -
RANK: stimulates joint destruction
OPG: decreases destruction of joints
RANK : OPG = corr with the rate of joint destruction -
IL-15
produced by
func (2) -
produced by: RA synovial mac in vivo
func:
1) activate T cell prolif via bind R that share with IL-2R
2) chemotactic activity for t-cell - Anemia, Thrombocytopenia, Felty's sign, subQ nodules (pallasading granuloma), +/- vasculitis, Interstitial infiltrates, BOOP (broncholitis obliterans organising pneumonia), Caplans synd , sclerosisits (pleural and pericardial effusions), peripheral neuro
- RA
- Felty's sign
-
1. leukocytopenia
2. spenomegaly
3. injections/leg ulcers - Caplans synd
- RA and coal dust
- Sjogren's synd
- dry eye/mouth, lymphocytic infiltrate to salivary and lacrimal glands
- Classes of Drugs for RA
-
NSAIDS
Corticosteroids
DMARDS - NSAIDS -- mech (2)
-
mech:
1) inhibit cox --> decreased prosteoglandins
2) inhibit pmn aggregation and inhibit NFKB which is an inflam Transcrip factor - Cox-1 vs Cox-2
-
Cox-1 = toxicity
Cox-2 = antiinflamatory - NSAIDs= use
-
long: tx for chronic inflam arthritis
short:
analgesic -->
antiinflammatory--> arthriis/ soft tissue / non MSK cond
antipyretic-->
DO NOT USE >1 TOGETHER - Toxicities
-
GI: pain, ulcer, bleeding, diarrhea, constipation
Heme: platelet dysfunction and activate warfarin kinetic
Liver: hepatitis
Kidney: transient azotemia / interstitial nephritis or nephritic synd / hyprkalemia / edema
CNS: tinnitus (esp salicylate) and confusion
Immuno: hypersensitivity
Vascular: MI esp with cox2i - RA and Steroids
-
1. intra-articular injection
2. low dose prednisone and DMARD
3. high dose for vasculitis and severe manifestations