Rheumatology Flashcards
RA involves ___ joints except for ___
small joints
DIP
*** NO thoracic/lumbar spine involvement
Synovial fluid of osteoarthritis
Low WBC in synovial fluid (Type I fluid, 200-2,000 WBCs), normal viscosity, negative crystals (uric acid, calcium), normal glucose
Symptoms of OA (3)
i. Pain with activity, crepitus, deformity, limited ROM
ii. Pain at END of day
iii. Non-inflammatory pain = worse with use, worse at end of day
X rays of OA
asymmetric joint space loss, osteophytes, less cartilage, bony cysts, bone sclerosis
- Heberden’s (distal interphalangeal joints) and Bouchard’s (proximal phalangeal joints) nodes
1. Hard, nontender, not warm 2. Formation of calcified spurs of articular cartilage
Risk factors of OA
age, obesity, genetics, prior trauma/surgery to joint, family history
Pathology of OA
Imbalance between destruction/production of articular cartilage by chondrocytes - More destruction in late disease
Cartilage is AVASCULAR
4 things made my chondrocytes in cartilage
collagen II, proteoglycans, aggrecan, hyaluronic acid
Synovium contains (3)
i. Cytokines (IL-1, TNF)
ii. Growth factors (TGF-B, BMP)
iii. Enzymes (MMPs)
Degradation of cartilage in OA
five associated factors
catabolic - chondrocytes/synovium release pro-inflammatory cytokines to degrade ECM
i. MMPs (13, 3)
ii. ADAMTS
iii. Cytokines (IL-1, TNF)
iv. NO
v. Prostaglandins
Synthesis of cartilage
5 associated factors
anabolic
i. Collagen II
ii. Aggrecan
iii. Link protein
iv. Inhibitory cytokines (IL-4, IL-10, IL-13)
v. Growth factors (TGF-B, BMP)
Treatment of OA
NSAIDS, topical NSAIDS, hyaluronic acid matrix injections, analgesics (opioid and nonopioid), PT, surgery
RA manifestations (6)
- what joint is spared?
- symmetric or asymmetric?
- what two kinds of classic deformities?
- what kinds of extra-articular manifestations?
- morning or night stiffness?
- Peripheral, systemic, inflammatory synovitis
- Cartilage/bone destruction, and joint deformities
a. Erosions into the joint space - PIPs and MCPs abnormal (proximal) - warm, tender, soft (spongy/boggy)
a. DIPs and thumb joint often spared
b. Cervical spine commonly involved (C1-2)
c. Often symmetric
4.Swan neck and boutonniere deformity
- Fewer extra-articular manifestations
a. Episcleritis (in eye)
b. Pulmonary nodules
6.MORNING stiffness, limited ROM
Serologic findings of RA (5)
- Rheumatoid Factor present in 85%
a. IgM anti IgG (binds Fc portion of IgG) - Elevated ESR or CRP
- Anemia, hypergammaglobulinemia
- Anti-cyclic citrullinated peptide (CCP) antibodies present
- “Seropositive” when CCP and RF both present
a. Prognostically bad when both present
Synovial fluid RA
inflammatory (> 2000 WBC, neutrophils)
-Low complement and glucose levels
XRAY RA (3)
- Soft tissue swelling
- Erosions in marginal distribution
- Symmetric loss of joint space
Risk factors RA
genetics, smoking, infections, environmental factors, microbiome, hormones
Risk alleles: encode enzymes/inflammatory pathways we can block
Risk Alleles in RA (2)
- HLA-DR4
2. HLA-DR-1
HLA-DR4 and HLADR-1
biggest risk alleles
Antigen ingested by APC → digest in endosome → goes through golgi and becomes citrullinated (BAD) → put on MHC II - in hypervariable region (QKRAA sequence motif) of HLA-DR4/1 groove (aka SHARED EPITOPE) → presented to T cell
T cell → RF production, CCP, and autoimmunity
RF B cells
Can secrete RF or have RF receptors on surface
- RF-IgG immune complexes are PATHOGENIC
- RF not ver specific for RA
- Results in classical complement activation
- RF and complement can deposit in joint, sclera, lungs, skin and cause problems
Late stage RA: synovial tissue
cell types present (4)
synovial hyperplasia
1) CD4 T cells
2) Macrophages
3) B cells
4) Th17 cells
5) DCs
NO PMNS
Late stage RA synovial tissue:
macrophages –> ?
B cells –> ?
Th17 cells –> ?
macrophages –> cytokine cascade (IL-1, IL-6, TNFa, MMPs)
B cells –> activated by T cells, RF and anti-CCP abs –> complement
Th17 cells –> IL-17
CD4+ memory T cells –> modulate and amplify local immune response through antigen recognition + IL-6
Pannus
Present in Late stage RA
organized mass of granulation tissue
Consists of: macrophages, T cells, B cells, fibroblasts
Arises due to inflamed synovium and cytokines
→ Bony destruction
Extra-articular disease in RA is mediated by…
complement pathway destruction
-Complement induced vasculitis and Rheumatoid nodule formation
You can get hyperuricemia with…
overproduction
underexcretion
Increased production of urate typically due to super-activity in __________ or deficiency in ___________
superactivity of PRPP (phosphoribosyl-pyrophosphate) synthetase
OR
deficiencies in HGPRT (hypoxanthine-guanine phosphoribosyltransferase)
Increase production of urate defined as urinary excretion of UA > _______
750 mg per 24 hours
Overproduction gout is usually genetic
Lesch-Nyhan
complete deficiency of HGPRT
Decreased excretion of urate defined as urinary excretion of UA less than _______
750 mg per 24 hours
MAJORITY of primary gout patients are UNDER EXCRETORS of uric acid
Uricase
enzyme that oxidizes uric acid to allantoin (highly soluble)
Humans DO NOT have this enzyme
MSU crystals are formed when…
what decreases urate solubility?
supersaturation of uric acid (hyperuricemia)→ gout crystal formation
Decreased urate solubility with: low temp, dehydration, trauma, low pH
MSU crystals cause an inflammatory response. This can involve…(4)
1) inflammatory response PMN dependent
2) TLR 2 and 4 (on PMN)
3) NLRP3 Inflammasome (in PMN) –> IL-1B production
4) activate complement
IL-1 + TNF –>
endothelial activation (allowing PMN infiltration)
MSU crystals bind TLR 2 and 4 on PMNs –> ?
intracellular cascade that causes GENE UPREGULATION
→ critical to inflammatory response
MSU crystals engage _______ –> NLRP3 inflammasome activated in PMN –> release of what cytokine?
caspase-1
IL-1B
MSU crystals can also be coated with IgG. This results in…
→ promotion of phagocytosed into PMN
IgG binding MSU crystals in NONSPECIFIC anti-crystal antibodies
___________ coating of crystals inhibits phagocytosis and cellular response
Apolipoprotein-B
Acute Gouty Arthritis
- abrupt onset
- VERY painful, warm, red swollen joint
-MTP joint of great toe most often involved, also ankles, heels, knees, wrists, fingers, and elbows
[Podagra = painful condition of big toe]
- Spontaneously resolve over 3-10 days
- Predilection for cooler, acral sites (MSU crystals have lower solubility)
ASYMMETRIC
Synovial fluid in gout (3)
MSU crystals present (needle-shaped, negatively birefringent)
Inflammatory - 2,000-100,000 WBCs (neutrophils predominantly)
Elevated ESR (test of inflammation)
Gout vs. pseudogout
Gout = MSU crystal
- Process of supersaturation
- Diet, pH and temperature are all variables - DO NOT matter in pseudogout
- Tissue deposition of monosodium urate (MSU) crystals due to hyperuricemia (MSU supersaturation of extracellular fluids)
Psuedogout = CPPD crystals (calcium crystals)
- MTP rarely involved
- Usually in women and older patients
- due to abnormal pyrophosphate metabolism
Calcium Phosphate Dihydrate Deposition Disease (psuedogout)
Pathology
- CPDD crystals are rhomboid-shaped, blue, positively birefringent - PREFORMED, NOT SOLUBILTY EVENT
- due to abnormal pyrophosphate metabolism
What causes pseudogout?
Due to abnormal pyrophosphate metabolism
1) ANKH gene mutation: membrane transporter of pyrophosphate in chondrocytes → CPPD crystal formation due to excess PPi being pushed out of chondrocytes
2) NTP pyrophosphohydrolase defect that converts NTP –> NMP + Pi –> more Pi extracellularly
Too much extracellular pyrophosphate precipitates with calcium → CPPD
“Shedding Phenomena” (aka strip mining)
preformed CPPD crystals released into synovial fluid
Allopurinol and febuxostat are…
Xanthine Oxidase Inhibitor
Anti-hyperuricemic medications
decrease uric acid production
Risk factors for gout
dietary obesity, genetic factors, HTN, certain meds
Dairy is protective!
Large and medium-vessel vasculitis pathophysiology
infiltration of WBCs through vessel wall, associated with granuloma, disruption of elastic lamina, thickening of intima → obliteration of vessel lumen (same as medium vessel)
Small-vessel vasculitis pathophysiology
typically leukocytoclastic vasculitis
Giant cell arteritis
Large-vessel vasculitis
temporal arteries or vessels originating from aortic arch → Temporal headache, scalp tenderness, visual loss
Takayasu’s arteritis
large-vessel vasculitis
ANCA positive vasculitis
- Granulomatosis with polyangiitis (GPA)
- Eosinophilic granulomatosis with polyangiitis
- Microscopic polyangiitis (MPA)
Granulomatosis with polyangiitis (GPA)
Effects upper respiratory tract, lungs, kidneys
Associated with serum cytoplasmic-ANCA (c-ANCA)
Microscopic polyangiitis (MPA) are positive for serum ____________
Serum perinuclear-ANCA (p-ANCA)
Clinical features of vasculitis
- Skin lesions, palpable purpura
- Fever, anorexia, weight loss, weakness, fatigue
- MSK symptoms: arthralgias, arthritis myalgias, peripheral neuropathy
- Inflammatory infiltration into nerve and nerve blood supply → neuropathy (Mononeuritis multiplex)
- Glomerulonephritis (IC deposition in glomeruli) → protein in urine
Lab findings of vasculitis (8)
- Anemia, thrombocytosis
- Low albumin
- Elevated ESR and CRP
- Polyclonal gammopathy
- Elevated liver enzymes (AST, ALT)
- Low complement (consumed by immune complex formation, classical complement pathway)
- Cryoglobulins
- Detection of serum autoantibodies (RF, ANA, ANCA)
Different immunopathogenic mechanisms that mediate vasculitis (5)
1) Immune Complexes
2) Anti-neutrophil Cytoplasmic Antibodies (ANCA)
3) Anti-endothelial antibodies
4) T cell dependent mediated endothelial cell injury
5) Infection of endothelial cells
Immune complex mechanisms of vasculitis
Deposition of circulating ICs at the vascular endothelium → activation of complement and attraction of PMNs
- Deposition in skin, kidneys, nerves, etc.
- Results in decreased complement levels
- Antigen can be: drugs, bugs, connective tissue disease, malignancy
mechanism of ANCA in vasculitis
ANCA = abs to antigens found in the cytoplasm of neutrophils
Inflammatory cytokines → activated PMNs that express PR3 or MPO on cell surface
ANCA binds neutrophil surface → further neutrophil activation and binding to vascular endothelial cells → vascular damage
-Role in amplifying inflammatory vascular response
Types of ANCA (2)
1) cytoplasmic-ANCA
2) perinuclear-ANCA
c-ANCA
stains what?
associated with what disease?
cytoplasmic staining, binds proteinase 3 (PR3) in primary granules of PMNs
→ Granulomatosis with polyangiitis (GPA)
Effects Lung, kidney, mononeuritis
p-ANCA
stains what?
associated with what disease?
perinuclear staining, binds MPO in primary granule of PMN
→ Microscopic polyangiitis (MPA)
Effects Kidney
Clinical features of Polymyositis and Dermatomyositis (4)
1) Chronic muscle weakness (symmetric proximal muscle weakness, problem standing, climbing stairs, etc.)
* *WEAKNESS MORE THAN PAIN**
2) Inflammation of muscle tissues by chronic inflammatory cells
3) Skin disease
4) Constitutional symptoms
Lab findings of Polymyositis and Dermatomyositis
1) Elevated muscle enzymes (CPK, aldolase, AST, ALT, LDH)
2) Autoantibodies (ANAs, MSA, MAA)
3) Elevated ESR
4) EMG findings (myopathic findings)
5) MRI findings (muscle inflammation, edema, fibrosis, calcinosis)
EMG findings of PM/DM (3)
myopathic findings
1) Decreased amplitude of motor unit APs
2) Spontaneous fibrillations
3) Increased insertional activity
Anti-synthetase Syndrome
- type of antibody?
- presentation
Anti-synthase abs: directed against Anti-histidyl-tRNA synthetase (aminoacyl-tRNA synthetase)
-anti-Jo-1 antibody
PM or DM presenting with **Interstitial lung disease (very SOB, new onset cough)
NOT PATHOLOGIC OR MYOTOXIC ANTIBODIES
Biopsy findings in PM
PM → CD8+ T cells, macrophages
*CTL mediated muscle injury
Biopsy findings in DM
DM → CD4+ T cells, B cells, macrophages, dendritic cells)
Concentrated in perivascular regions of muscle
*Complement mediated vasculopathy
Polymyositis
Distribution?
Inflammatory infiltrate?
Rash?
Endomysial distribution of inflammatory cells surrounding and invading muscle fibers (more generalized inflammation)
CD8+ T cells
No rashes
Dermatomyositis
Distribution?
Inflammatory infiltrate?
Rash?
Perivascular and perifascicular inflammatory infiltrate
CD4+ T cells
Skin RASHES present
Rashes = Gottron’s, Heliotrope, Shawl, Gun Holster
More atrophy of muscles
PM and DM may be triggered by…
Viral infections
- Disease pattern is seasonal
- Elevated IFN
Ankylosing Spondylitis
Onset?
Pain - when, where, what kind, what makes it better?
1) Onset YOUNG (16-40yrs)
2) Axial
3) Morning stiffness
4) improved with exercise
5) Effects Sacroilitis, entheses
Lab findings in Ankylosing Spondylitis
elevated _______
no _____ or ______
Elevated ESR
no RF, no ANA (seronegative)
(NO ANTIBODIES)
Xray findings in Ankylosing Spondylitis (3)
- Spinal fusion (bambooing of spine)
- peripheral arthritis involving large joints
- asymmetric distribution
Ankylosing Spondylitis, reactive arthritis, psoriatic arthritis all associated with what risk allele?
HLA-B27
HLA-B27 people are genetically susceptible to develop disease when exposed to _________ such as ____________
environmental trigger
salmonella, shigella, yersinia, campylobacter, chlamydia* can induce reactive arthritis in 20% of B27+ individuals
HLA-B27 theories (4)
1) Arthritogenic peptide hypothesis
2) Molecular mimicry
3) Free heavy chain hypothesis
4) Unfolded protein hypothesis
Arthritogenic peptide hypothesis
specific microbial peptides bind HLA-B27 → present to CD8+ CTLs*
Molecular Mimicry
autoreactivity to self antigens due to similarity between epitopes on antigen and HLA-B27 molecule
Free heavy chain hypothesis
formation of stable homodimers of HLA-B27 heavy chains* without antigen in a cell
→ activate NK cells* via interaction with Killer Cell Immunoglobulin-like Receptor (KIR)*
Unfolded protein hypothesis
HLA-B27 has propensity to misfold in ER → unfolded protein stress response → inflammatory cytokines* (IL-23) → upregulate Th17*
Seronegative spondyloarthropathies pathology (2)
Synovium has increased ________ (cyotkine)
Enthesis: inflammation of ligament, tendon, and fibrous structures as they insert into bone
Synovium has increased TNFa
No RF or ANA antibodies
Types of spondyloarthropathy (4)
1) Ankylosing Spondyloarthritis
2) Psoriatic arthritis
3) IBD (Crohn’s, UC)
4) Reactive Arthritis (STDs, Cdiff, etc.)
RA vs. Spondylo
1) symmetric or asymmetric?
2) peripheral or axial?
3) big or small joints?
4) antibodies?
5) where does it occur?
6) gender?
RA:
1) symmetric
2) peripheral
3) small joints
4) RF+, CCP+
5) synovitis
6) female 2:1
Spondylo:
1) asymmetric
2) axial
3) BIG joints
4) no abs (seronegative)
5) occurs at entheses
6) male
Systemic Lupus Erythematosus Symptoms and clinical features (6)
- Malar rash
- Discoid rash
- photosensitivity
- arthritis
- 9:1 females (young)
- affects kidneys (Type III immune complex deposition or type II ab against specific cell/tissue
Organ specific immunity
Immune response against single/restricted set of autoantigens within a given organ → autoimmune destruction of only those organs
Systemic Autoimmunity
Immune response against multiple auto-antigens → disease affects multiple organs with immune complexes and direct immune attack
e.g. SLE
Genetics of SLE
Multigenic disease with a major MHC contribution
-HLA-DR3, C4 Null Alleles
Pathophysiology theories of SLE (5)
1) Sex hormones (disease accelerating effect of estrogen, protective effect of androgens)
2) Sun exposure
3) Type II antibody-mediated disease
4) Type III immune complex disease
5) BOTH innate and adaptive immune systems involved
SLE has antibodies to…
nuclear component (ANA) –> markers of disease, causes of tissue damage (LUMPY BUMPY)
-anti-dsDNA antibodies
> 95% of SLE patients have ANA, but ANA is NOT specific to SLE
T cell involvement in pathogenesis of SLE (2)
Recognition of self as foreign –> T AND B cell response
Antibody responses towards autoantigen are antigen driven and require CD4+ T cells
Loss of T cell tolerance for self –> activation of autoreactive B cells
Antiphospholipid antibodies act to increase ___________
clotting
Vasculitis T cell mediated endothelial injury
HLA-DR4 and giant cell arteritis; suggests ANTIGEN-DRIVEN vascular inflammation
The worst symptoms of PM and DM is ________ and it occurs in 60% of patients.
Interstitial lung disease
Reactive arthritis often occurs with a history of __________
infectious diarrhea or urethritis
Reactive arthritis is asymmetric, oligoarticular and _________ arthritis. Can include _________ and _________
Lower extremity
Dactylitis (sausage fingers)
Reiter’s Syndrome (can’t see, can’t pee, can’t climb a tree)
Chance of developing AS:
______ if HLA-B27 +
______ if HLA-B27 + and 1st degree relative with AS
2%
20%
