Pathophysiology Flashcards
osteoarthritis
older
NO inflammation
DEGENERATIVE: erosion of articular cartilage, osteophytes, subchondral sclerosis, alterations of the synovial membrane (can thicken) and joint capsule, eburnation (progressive thickening), Herberden nodes (increased activity at pericondrium), loose bodies/ joint mice (fragments of cartilage), cyst formation
Dx: clinical, xray, normal labs
Sx: pain gets worse with use/during the day, morning stiffness
increases mortality
risk factors for osteoarthritis
- age
- joint location
- obesity
- genetics
- joint malalignment
- trauma
- gender: female
- neuromuscular dysfunction
- metabolic disorders
morphologic changes in osteoarthritis: early vs. late
early: articular cartilage surface irregularity, superficial clefts, altered proteoglycan distribution
late: deepened clefts, increase surface irregularities, articular cartilage ulceration, exposed underlying bone, chondrocytes from clusters to self-repair, osteophytes
MMP
matrix metalloproteinases that degrade proteoglycans and collagen
OSTEOARTHRITIS
Most commonly affected joints in osteoarthritis
ASYMMETRIC: more LOWER
hands (DIPS and PIPS), hips, knees, spine, feet
Pseudogout associations
- hemochromatosis
- hyperPTH
- hypothyroidism
- hypophosphatasia
- hypomagnesemia
- neuropathic joints
- trauma
- age, heredity
First line nonopioid analgesic therapy for osteoarthritis
acetaminophen
max safe dose: 4g/day
types of intra-articular therapy for osteoarthritis
- steroids
2. hyaluronate injections
intra-articular steroids
2nd line Tx
up to every 3 mo (knee most often)
Tx: osteoarthritis pain
AE with frequent injections: infection, worsening DM, or CHF
hyaluronate injections
Tx: osteoarthritis symptom relief (improves function)
expensive
no long-term benefit
limited to KNEE
Surgical Tx for osteoarthritis
3rd line Tx
- arthroscopy (may reveal unsuspected focal abnormalities, results in tidal lavage, expensive, complications)
- osteotomy (delay need for total joint replacement)
- total joint replacement (when pain severe and function significantly limited)
anti-CCP (cyclic citrullinated peptide)
most sensitive and specific for RA (can be found in unaffected relatives)
produced by synovial tissue B cells
activate complement pathways, IgE ACPAs cause basophil/ mast cell degranulation
prognosis: more aggressive, accelerated atherosclerosis, risk for ischemic heart disease
HLA-B27
seronegative spondylarthropathies
MHC class I molecule that presents antigens to CD8 T cells
in psoriasis or IBD: indicates likely to develop axial (spinal) arthropathy
ANA
Ab against nucleus
most sensitive SLE: no ANA, no lupus
also: RA, scleroderma, Hashimoto’s, IPF
anti-dsDNA
high specificity for SLE
associated with: NEPHRITIS
anti-RNApol3Ab
HTN renal crisis in diffuse systemic sclerosis
anti-centromere
limited cutaneous sclerosis
anti-Jo1
Ab against histdyl-tRNA synthetase
inflammatory myopathy
associated with: arthritis in myopathies
anti-Mi-2
dermatomyositis
rheumatoid arthritis (RA)
30s-50s female
INFLAMMATORY, SYSTEMIC
SYMMETRIC arthritis
increases mortality
genetic (additive/multiplicative) and environmental
elevated: ESR, CRP
Ab: anti-CCP, RF
Sx: fatigue, anorexia, weight loss, weakness, general aching and stiffness, low fever
joint: morning stiffness at least 30 min, swelling, warmth, erythema
synovial fluid: exudative yellow fluid, WBC elevated, reduced viscosity
onset: one or scattered joints, often large peripheral joints (knee)
immune complexes, lysosomes, ILs, FBGF, mononuclear cells infiltrating synovial membrane (acute: PMN)
HLA-DR4
30% RA risk
binds and presents antigen to T cell
DR4 shared epitope and T cell receptor interact
selection of auto reactive T cells in thymus
PTPN22
5% RA risk
TNFAIP3
5% RA risk
STAT4
5% RA risk
IL2RB
5% RA risk
shared epitope hypothesis
RA is most strongly associated with shared epitope alleles of HLA-DRB1
HLA-DRB1
shared epitopes: RA
rheumatoid factor (RF)
IgM Ab directed against Fc portion IgG
RA: more likely to have extra-articular manifestations
Sjogren’s, MCTD, mixed cryglobulinemia
also (but not as prevalent): SLE, polymyositis, dermatomyositis
other: young, old, chronic infection, CA (B-cell), biliary cirrhosis
examples of antigens in RA
joint: type II collagen
systemic: glucose phosphate isomerase
role of T cells in RA
low levels of T cell cytokines in RA synovium
Th1: IFN-y
Th17: IL-17
suppressed Treg possible
T cells in synovial inflammation can be antigen-independent (direct cell contact with macrophages)
role of macrophages and fibroblasts cytokines in RA
abundant in RA synovium
cytokines: TNFa, IL-6, IL-15, IL-18, GM-CSF, IL-33
recruit inflammatory cells (neutrophils)
anti-inflammatory IL-1Ra and IL-10 are produced but not enough to suppress other inflammatory ones
What joints are involved in RA?
SYMMETRICAL: more UPPER extremity
wrist, MCP, PIP
other: knees, hips, ankles, elbows, shoulders
spares spine (except first 3 joints)
spinal cord compression
C1 slips forward on C2
Sx: sensory loss to catastrophic neurologic compromise to sudden death
risk with RA if cervical spine is affected
What deformities occur in RA?
wrist: volar SUBLUXATION, RADIAL rotation
MCP: ULNAR DEVIATION
PIP, DIP: SWAN NECK, BOUTONNIERE
muscle atrophy, weakened supporting structures (ligaments, joint capsules), fibrosis and tightening of tissues (lumbricals of hand)
flexion contractures in larger peripheral joints (knee, hip, elbow)
extra-articular RA manifestations
- skin: rheumatoid nodules
- vasculitis: PALPABLE PURPURA or skin ulcers
- keratoconjunctivitis and xerostomia (lymphocytes)
- episcleritis and scleritis
- respiratory: interstitial fibrosis, pulmonary nodules (coin lesion), pleuritis with pleural effusion
- cardiac: pericarditis, nodules on valves
- neurologic: cervical myelopathy, compressive peripheral neuropathy (carpal tunnel, ulnar tunnel), peripheral neuropathy
- lymphadenopathy, splenomegaly
Where are rheumatoid nodules found?
- extensor surfaces of skin
- pleura
- meninges
- ears
lungs, heart, tendons
Felty’s syndrome
triad
- splenomegaly
- RA
- leukopenia, thrombocytopenia
Sjogren’s syndrome
middle age female
Sx: keratoconjunctivitis sicca, xerostomia, parotid gland swelling, arthritis, fatigue
other glands: skin and vaginal dryness, nose, pharynx, larynx, tracheobronchial tree (hoarse, pneumonia)
Dx: anti-Ro/SS-A, anti-La/SS-B, labial salivary gland biopsy
complication: NON-HODGKIN’s LYMPHOMA
ANA, LOW C3 and C4, RF
some: leukopenia, thrombocytopenia, cryoglobulinemia, monoclonal gammopathy
Other organs involved in Sjogren’s
- renal: TYPE I RENAL TUBULAR ACIDOSIS, tubular interstitial nephritis, glomerulonephritis, nephrogenic diabetic insipidus
- GI: ESOPHAGEAL DYSFUNCTION, atrophic gastritis, biliary cirrhosis, hepatitis
- CNS/PNS: NEUROMYELITIS OPTICA, optic neuropathy, hemiparesis, movement disorder, cerebellar syndrome, spinal cord syndrome, progressive myelopathy, motor or sensory or autonomic neuropathy
- vasculitis: purpura, Raynaud’s
- NONHODGKIN’S LYMPHOMA, MALT
- PULMONARY: ILD
Schirmer’s test
filter paper to document tear flow
Dx: Sjogren’s
keratoconjunctivitis sicca
keratitis caused by decreased lacrimal secretion
Sx: dry eye, foreign body sensation, burning, photosensitivity
Dx: rose Bengal dye
rose Bengal dye
highlights epithelial lesion in eye
xerostomia
severe dry mouth
Sx: multiple dental caries, fissuring and ulceration of lips, tongue, buccal membranes, difficulty chewing/swallowing, gland enlargement (parotid or submandibular)
secondary Sjogren’s
complication of another autoimmune connective tissue disease
RA, SLE
What does a salivary gland look like grossly in someone with Sjogren’s?
enlarged, white
sometimes cysts
systemic lupus erythematosus (SLE)
african american
multi-system inflammatory disorder with flare and remission
Ab: ANA, anti-DNA, anti-Sm
genes: HLA-DR2/3, complement deficiency
need environmental exposure and genetic susceptibility
complement, immune complexes
Tx: corticosteroids, cyclophosphamide, methotrexate, mycophenolate mofetil, azathioprine, hydroxychloroquine, belimumab
discoid lupus erythematosus (DLE)
confined to skin
drug-induced lupus erythematosus (DILE)
Sx: polyarthritis, fever, rash
less severe: NO nephritis (exception anti-TNFa drugs)
resolves with drug removal
Ab: anti-histone
neonatal lupus erythematosus
newborns of mothers with SLE due to transfer of auto-Ab
Sx: skin rash (transient), HEART BLOCK (permanent), leukopenia
predictors of flare in SLE
- new evidence of complement consumption
- rising anti-dsNDA
- increased ESR
- new lymphopenia
SLE severity
- characteristics
- associations
- abrupt onset, increase renal, near, hematologic, serial involvement, rapid damage (irreversible organ injury)
- race (non-white), younger onset, MALE, low socioeconomic status
Factors contributing to increased mortality in SLE
- early age onset, length of duration
- high severity at Dx
- non-white
- male
- low socioeconomic status
- poor adherence
- inadequate patient support system
- limited patient education
leading causes of mortality in SLE
heart disease, malignancy, infection
ACR criteria for classification of SLE
need 4/11
- malar rash
- discoid rash
- oral ulcers
- arthritis (non-erosive)
- serositis
- glomerulonephritis
- hematologic disorder
- ANA
- anti-dsDNA, anti-Smith, antiphospholipid
- neurologic
- photosensitivity
anti-Smith
specific for SLE
anti-RNP
SLE
associated with: arthritis, myositis, lung disease
anti-Ro/SS-A
Sjogren’s
other: SLE
associated with: dry eyes/mouth, subacute cutaneous lupus (SCLE), neonatal lupus, photosensitivity
anti-La/SS-B
Sjogren’s
other: SLE
associated with: dry eyes/mouth, subacute cutaneous lupus (SCLE), neonatal lupus, photosensitivity
antiphospholipid antibodies (aPLs)
B2-glycoprotein I, anticardiolipin
SLE, RA, increase age
associated with: clotting
determine through: IgG or IgM in serum or coagulation assay (lupus anticoagulant test)
SLE Sx: musculoskeletal
arthralgia
arthritis: symmetric/asymmetric, can be deforming, non-erosive
myalgia, myositis, weakness
SLE Sx: serositis
- pleura: pleuritic chest pain, pleural effusion
- pericardium: chest pain, pericardial effusion
- peritoneal cavity: abdominal pain, fluid accumulation
SLE Sx: renal
ANTI-DNA antibodies
significant morbidity and mortality
any renal structure can be affected: glomerulus, tubules, interstitium, vasculature
immune complexes: in situ and in circulation
other: aggregates of Ig, complement, and MAC
SLE Sx: hematologic
all cell lines RBC: hemolytic anemia, anemia of chronic disease WBC: leukopenia, lymphopenia Platelet: thrombocytopenia lymphadenopathy
SLE Sx: neuropsychiatric
psychiatric: depression, psychosis, cognitive abnormalities
brain: seizure, stroke, movement disorder
spinal cord: transverse myelitis, MS-like disease, peripheral neuropathy
SLE Sx: GI
less common
abdominal pain: serositis, vasculitis, bowel perforation, peritonitis
liver disease: autoimmune hepatitis, liver enzyme elevation
SLE obstetrical problems
fertility normal
small for gestational age, fetal loss (antiphospholipid), neonatal lupus
beware of teratogenic drugs: methotrexate
SLE Sx: cardiovascular
- pericarditis
- myocarditis
- endocarditis (valves: Libman-Sacks)
- coronary artery disease (lupus, medications, inflammation)
- peripheral vascular disease (vasculitis, Raynaud’s phenomenon)
drugs that cause lupus
hydralazine procainamide isoniazid hydantoins chloropromazine methyldopa penicillamine minocycline anti-TNF IFNa other: dietary, smoking, Vit. D deficiency
antiphospholipid syndrome
most common: stroke (arterial)
other: DVT, miscarriages after 10 weeks
Dx: clinical event plus persistently positive aPLs (12 weeks apart)
class I lupus nephritis
normal histology
class II lupus nephritis
mesangial proliferation
class III lupus nephritis
focal proliferative GN (
class IV lupus nephritis
diffuse proliferative ( > 50% of glomeruli)
class V lupus nephritis
membranous pattern
class VI lupus nephritis
advanced sclerosing glomerulopathy
systemic sclerosis
AA, female
Sx: Raynaud’s, microvasculature, renal, GI, pulmonary
major mortality and morbidity: PAH, ILD
pathogenesis of systemic sclerosis
fibroblasts: fibrosis
endothelial cells: obliteration of small arteries
B cells: Ab production
T cells: cellular infiltration, cytokines, GF dysregulation
monocytes: transdifferentiation to fibroblasts when exposed to IFNy
SS Sx: microvasculature/vasculature
increased endothelial cell apoptosis, up regulation MHC class II and ICAM-1 platelets aggregate: microthrombi, digital artery occlusion intimal proliferation (thickening) with narrowing of lumen, adventitial fibrosis, telangiectasis of vasa vasorum
Raynaud’s phenomenon
episodic attacks of vasoconstriction in blood vessels in extremities due to cold/stress
pale: lack of blood flow
blue: vessels dilate to keep blood in tissue
red: flow returns, reactive hyperemia
primary or associated with: SSc, lupus, RA, polymyositis, MCTD (reconsider if not present), etc.
nailfold capillary pattern
indicates the development of a secondary CT disease (ex: SSc) in a Raynaud’s patient
types of scleroderma
localized scleroderma (small area): morphea, linear scleroderma systemic scleroderma: limited, diffuse, sine
limited scleroderma
face, distal extremities
Ab: anti-centromere
Sx: severe digital ischemia, calcinosis
PAH more likely than in diffuse
diffuse scleroderma
all skin
Ab: anti-topoisomerase 1 (Scl70)
anti-centromere
LIMITED SCLERODERMA
clinical: severe digital ischemia, PAH, sicca syndrome, calcinosis
anti-topoisomerase1 (Scl70)
DIFFUSE SCLERODERMA
clinical: pulmonary fibrosis, cardiac involvement
PM/Scl
antigens
overlap of LIMITED/DIFFUSE Scleroderma
clinical: myositis, pulmonary fibrosis, acro-osteolysis
anti-U1-RNP
MCTD
overlap of limited/diffuse scleroderma
clinical: SLE, inflammatory arthritis, pulmonary fibrosis
lack of: severe renal or CNS involvement
scleroderma renal crisis (SRC)
life-threatening
risk factors: corticosteroids, anti-RNA polymerase III Ab
Tx: angiotensin converting enzyme inhibitors
other associations: new anemia or cardiac events, anti polymerase I Ab, NSAIDS, cyclosporine
anti-RNA polymerase III
SCLERODERMA RENAL CRISIS
SSc Sx: GI
gut dysmotility universal
upper: more common
lower: poor prognosis
SSc Sx: pulmonary
pleurisy, pleural effusion, pleural scarring, aspiration pneumonia, malignancy, ILD, PAH
localized scleroderma
children
nonsystematic skin disease
plaque morphea
localized scleroderma
isolated circular patch of thickened skin
generalized morphea
localized scleroderma
multiple lesions involving extensive areas of skin and can occasionally coalesce, mimicking systemic sclerosis
keloid morphea
localized scleroderma
nodular form resembling keloids
bullous morphea
localized scleroderma
subepithelial bullae
linear scleroderma
localized scleroderma
linear streak that crosses dermatomes and is associated with atrophy of muscle
en coupe de sabre
linear scleroderma underlying bone and rarely the brain
mixed connective tissue disease (MCTD)
sequential overlap of lupus, scleroderma, inflammatory myositis over mo. to yrs
Ab: U1-RNP
Sx: Raynaud’s in ALL, membranous glomerulonephritis, pulmonary HTN
What is the most common cause of death in MCTD?
pulmonary HTN
need echo to screen for abnormal P2
ankylosing spondylitis (AS)
adolescence - 35 yrs, male TNFa excess insidious onset Sx: chronic low back pain, back stiffness (limited RoM), ascends spine, worse in morning and improve, sacroiliac tenderness, loss of lumbar lordosis and thoracic/cervical kyphosis abnormal SCHOBER's test (
enteropathic arthritis
inflammatory bowel disease-associated arthropathy: Crohn’s, ulcerative colitis, Whipple’s disease
peripheral: parallels GI
axial: does not parallel GI (B27 associated)
Tx: NSAIDS (can cause IBD flare)
Reactive arthritis (Reiter’s syndrome)
inflammatory arthritis after INFECTION
triad: ARTHRITIS, URETHRITIS (sterile, mucopurulent discharge), CONJUNCTIVITIS, oral ulcers, circinate balanitis (penis ulcer), onycholysis, keratoderma blennorrhagica
GI: Salmonella, Campylobacter, Yersinia, Shigella, C. difficile
GU/resp: chlamydia
common in: HIV/AIDS (more severe and resistant to Tx)
lab: ESR, CRP, culture is usually neg.
OBSERVE: lasts months
recurrence common
psoriatic arthritis
progressive disease CD8 cells synovium: increase vascularity, neutrophils, CD3 T cell (correlate with Tx response) elevated ESR: poor prognosis Tx: TNF inhibitors (infliximab) severe: think HIV other Sx: conjunctivitis, iritis
juvenile chronic arthritis
?
Juvenile-onset ankylosing spondylitis
?
list of spondyloarthropathies
- ankylosing spondylitis
- enteropathic arthritis
- reactive arthritis
- psoriatic arthritis
- undifferentiated spondylarthropathies
- juvenile chronic arthritis and juvenile-onset ankylosing spondylitis
common features of spondylarthropathies
- RF NEGATIVE
- HLA-B27
- AXIAL skeleton
- large joint asymmetric oligoarthritis: LOWER extremities
- familial
- enthesitis, dactylitis
x ray findings on ankylosing spondylitis
spinal osteopenia, bony ankylosis, vertebral fractures, atlantoaxial/ atlantoocipital subluxation, upward subluxation of axis
What is more likely to occur if a patient has peripheral joint involvement in ankylosing spondylitis?
aortic regurgitation, heart block
Tx for ankylosing spondylitis
NSAIDs
then as time progresses: sulfasalazine, local corticosteroids, TNF blockers, surger
always: analgesics, exercise, PT
immunopathology of psoriatic arthritis
elevated immunoglobulins
T cells: HLA-DR, receptors for IL-2 and adhesion molecules, secrete IL-6
fibroblasts: IL-1B, IL-6, PDGF
synovium: TNFa, IL-1, IL-6, IL-8, IL-18
serum: IL-10, IL-13, IFNa, VEGF, FBGF, IL-18
IL-18
PsA
stimulates angiogenesis
upregulates chemokines on synovial fibroblasts
increases mononuclear cell recruitment
Patterns of PsA
- polyarticular pattern: > 4 joints, RA-like
- oligoarticular: 4 joints or less, asymmetric
- DIP involvement pattern
- arthritis Mutilans (severe)
- axial development (B27+: sacroiliitis and spondylitis)
Tx of enteropathic arthritis: ulcerative colitis vs. Crohn’s
NSAIDS
UC: sulfasalazine
CD: adalimumab
both: glucosteroids, azathioprine, methotrexate, infliximab
arthritis of celiac disease
GLUTEN
T cell: HLA-DQ2/8
Sx: fatigue, headache, arthralgias (axial or peripheral)
associated with development: T1DM, anemia, osteoporosis, neuropathies, joint symptoms
Dx: small bowel biopsy, IgA anti tissue transglutaninase and IgA antiedomysial Ab
Tx: eliminate gluten
Diffuse idiopathic skeletal hyperostosis (DISH)
calcification and ossification most common on the right side of the spine (NOT inflammatory)
MELTED CANDLE WAX
left side in people with: dextrocardia, situs inversus
descending thoracic aorta prevents manifestationf of DISH on one side of the spine
