Rheumatology Flashcards
1
Q
2 types of synovial lining cells
A
- A: resemble macrophages with lots of organelles
- B: resemble fibroblastas with lots of ER
2
Q
What is the unique feature of synovial lining?
A
No basement membrane
3
Q
What are the components of synovial interstitium?
A
collagen fibrils and proteoglycans with abundant fenestrated microvessels
4
Q
What is the most rapidly destructive form of bone and joint disease?
A
Septic arthritis
5
Q
How do bacteria spread in septic arthritis?
A
- typically hematogenous spread
- also direct puncture/surgical procedures/animal bites
6
Q
Why is the joint susceptible to septic infection?
A
- abundant vascular supply
- lack of limiting basement membrane
7
Q
What are the main categories of septic arthritis causing bacteria?
A
Gonoccal (N. gonorrhea) vs. Nongonococcal (S. aureus)
8
Q
What are 4 key risk factors of bacterial arthritis?
A
- age (80+)
- bacteremia
- pre-existing joint disease/damage (osteo/rheumatoid arthritis)
- chronic systemic disease (diabetes)
- immunosuppression (steroids)
- trauma
- prosthetic joint
- drug use
9
Q
Virulence factors
A
mechanisms which infectious organsms have evolved to enhance immune evasion
10
Q
What do MSCRAMMs bind and what do they do?
A
- microbial surface components recognizing adhesive matrix molecules*
- bind host matrix proteins like collagen, elastin, etc.
11
Q
In what organism is the agr relevant and what does it do?
A
accessory gene regulator
- regulate S. aureus surface proteins and exotoxins
- upregulates proteins early in infection to promote attachment and upregulates exotoxins later in infection
12
Q
How does N. gonorrhea (G+cocci) attach to cell surfaces?
A
Pili
13
Q
How does N. gonorrhea avoid complement and phagocytosis?
A
Protein IA binds to factor H –> inactivates complement 3b
14
Q
3 ways septic arthritis leads to joint damage
A
- direct bacterial effect/toxins
- host immune response to LPS/cytokines –> autodigestion of cartilage by metalloproteases
- mechanical effects from joint effusion pressure
15
Q
Cytokines implicated in immune-mediated damage in septic arthritis
A
IL1beta and IL6 –> recruit neutrophils and macrophages –> produce TNFalpha, IL1,6,8 –> production of proteases and free radicals
16
Q
How does joint exudate lead to ischemia in septic arthritis?
A
purulent exudate increases intra-articular pressure –> ischemia in avascular cartilage
17
Q
Septic arthritis-clinical features
A
- fevers/chills
- malaise
- monoarticular
- inflammation
18
Q
Gonococcal arthritis-clinical features
A
- sexually active
- inflammatory arthritis of multiple joints
- fevers/chills
- vesiculopustular rash
- polyarthralgia
19
Q
Classification of joint effusions
A
- normal- clear, viscous (<200 leukocytes/mm3)
- noninflammatory- clear/yellow, viscous (200-2000)
- inflammatory-cloudy/yellow, thin (2000-100,000)
- septic-purulent, thin (>50,000)
20
Q
Stages of Lyme disease
A
- early localized-rash, erythema migrans, viral symptoms
- early disseminated-cardiac, neurologic
- late disease-neurologic, inflammatory arthritis
21
Q
Borrelia arthritis-late disease-clinical features
A
- inflammatory arthritis
- monoarticular knee
- spirochetes invade synovium –> accumulation of neutrophils, complexes, complement, cytokines
- fluid count < 50,000 leukocytes/mm3
- Tx: antibiotics
22
Q
Why is joint damage slow-onset with lyme disease?
A
Borrelia does not produce its own proteases so must wait for immune response to generate damage
23
Q
Molecular mimicry hypothesis for Lyme resistance
A
T cell epitope mimicry between spirochete and host protein –> borrelia mediated autoimmunity
24
Q
Phenomenon of autoreactive t cell possing TCR for foreign peptide that also recognizes self-peptide
A
Molecular mimicry phenomenon
25
Observations that support molecular mimicry hypothesis
1. certain MHC II types predisposed to Lyme arthritis --\> **HLA DRB1\*0401/0101**
2. presence of ab to borrelia out surface protein in pts with lyme arthritis
3. id of autoantigen with sequence homology
26
Which Borrelia protein is the target of Lyme arthritis autoantibodies?
OspA surface protein
27
Which human autoantigen has sequence homology with the Borrelia antibody target
LF1alpha - adhesion molecule on inflamed tissues
28
Primary issue with molecular mimicry hypothesis re: antibiotic resistant Lyme arthritis
* LF1-alpha is a weak agonist to OspA reactive tcells
29
What kinds of patients with antibiotic resistant Lyme arthritis have a strong immune response to OspA and LFA-1alpha?
DR4+
30
Tx of antibiotic resitant Lyme arthritis
immunosuppressants
31
Viral arthritis-clinical features
* viral symptoms
* acute onset
* **symmetric polyarticular small joint**
* rash
32
Example of immune complex mediated viral arthritis
Hepatitis B
33
Example of antigenic persistence related viral arthritis
Parvovirus B19
34
How does HepB produce arthritis?
HepB SA + antibodies form complexes that deposit in synovium --\> complement activation, neutrophils --\> inflammatory arthritis
35
Most common viral arthritis in the US
Parvovirus B19
36
What molecule communicates with Parvovirus B19 to allow its entry to the synovium?
glyocsphingolipid Gb4 on synovium
37
Antigen persistence
various pieces of infectious agent can cause ongoing immune response even in absence of whole organism
38
Spondylitis
* multisystem inflammatory arthritides involving the **spine, synovium, and enthesis**
* associated with HLAB27
39
Which HLA is associated with spondyloarthropathies?
HLA-B27
40
Spondyloarthropathies-Clinical features
* sacroilitis
* **dactylitis**
* **enthesitis**
* asymmetric polyarticular peripheral arthritis
* **uveitis**
* gut inflammation
* **psoriasis**
* new bone formation
* Tx: TNF alpha inhibitor, Ibuprofen, PT
41
What are three defining features of spondyloarthropathies?
1. enthesitis
2. simultaneous bone catabolism/anabolism
3. HLA-B27
42
What process precedes synovitis in SpA?
Enthesitis
43
Cytokines that stimulate RANKL
TNFalpha, IL1, 6 --\> RANKL --\> osteoclast activation
and--\> Dkk-1 and sclerostin --\> osteoblast inhibition
44
Three important pathways in pathologic bone formation
BMP, Wnt, and PGE
45
The pathogenic function of HLAB27 is related to antigen presentation to what kinds of cells?
CD8+
46
Relationship between HLAB27 and bacteria
HLAB27 rats need colonic bacteria to get SpA
47
Three theories explaining role of HLA-B27 in SpA
1. arthritogenic peptide
2. homodimerization
3. misfolding and unfolded protein response
48
Cytokine linchpin in unfolded protein response related to SpA and HLA-B27
**IL 23** --\> IFNbeta, IL 17,22,1,6,TNFalpha --\> osteproliferation, inflammation, ethesitis
49
50
SLE
systemic autoimmune condition with antibodies to components of cell nucleus + protean clinical manifestions
51
SLE-key clinical features
* malar rash
* discoid rash
* photosensitivity
* oral ulcers
* arthritis
* ANA --\> antiDNA or anti-smith or APLA
* renal casts
* serositis
52
53
Environmental contributors to Lupus
* silica dust
* UV light
* viruses
54
When do SLE autoantibodies appear?
long before clinical manifestations
55
ANA
antinuclear antibody --\> binds to antigens found in nucleus --\> immunofluoresence, ELISA (via Hep-2 cells)
56
Autoantibodies specific for lupus
Anti-dsDNA, Anti-Smith
57
Pathogenic modalities of SLE
1. immune complex
2. apoptosis --\> nuclear antigens
3. inf-alpha stimulation of immune system
58
What molecule has been found in association with apoptosis defects in SLE?
BLyS --\> B lymphocyte stimulator --\> Belimumab (Anti-BLyS Ab)
59
Newest lupus drug
Belimumab (anti-BLyS)
60
Which autoantibodies mediate neonatal lupus?
Anti-Ro/La (SSA/SSB) --\> passive transfer from maternal system
61
Neonatal lupus-clinical features
* complete congenital heart block
* rash
* hematological
* hepatobiliary
62
Clinical measure for immune complexes
C3 and C4 levels --\> if low, lots of disease activity
63
Lupus nephritis
immune complex mediated sequelae of lupus
64
Which TLRs activate innate immune system and generate IFN in lupus?
TLR 7 and 9 --\> recognize immune complexes
65
Which cytokine is thought to be most important in mediating scleroderma?
TGFbeta
66
Triad of conditions defining scleroderma
1. fibrosis
2. vascular dysfunction
3. immune dysregulation
67
Scleroderma classifications
1. diffuse (above knees/elbows)
limited
2. overlap
68
Scleroderma-clinical features
* sclerodactyly
* calcinosis
* raynaud's
* esophageal dysmotility
* teleangiectasia
* fibrosis
69
Diffuse cutaneous scleroderma-clinical features
* rapid progression
* early visceral organ involvmeent
* absence of anticentromere antibodies
* poor prognosis
70
Limited cutaneous scleroderma-clinical features
1. early raynauds
2. slow progression
3. anti-centromere antibody
CREST
* calcinosis
* rayndauds
* esophageal dysmotility
* sclerodactyly
* telangiectasia
71
Anti-centromere antibodies are found in what kind of scleroderma?
limited
72
Which autoantibodies are associated with scleroderma?
* anti-Scl-70 in AA//HLA-DQ7
* anti-centromere in caucasians
73
Which virus is associated with scleroderma?
CMV
74
Genes associated with scleroderma
* COL1A2 (type 1 collagen)
* Fibrillin-1
* TGF-beta 1
75
Which ANA is associated with rapidly progressive scleroderma?
Anti-RNApIII
76
How does TGF-beta mediate SSc/Scleroderma
* sensitizes fibroblasts to stay persistently activated
* decreases function of collagen degrading proteases
77
SMAD pathway in Scleroderma
TGFbeta binding --\> SMAD 2/3 phosphorylation -\> SMAD4 translocation to nucleus --\> collagen gene upregulation
78
Which SMAD downregulates collagen formation in SSc and which cytokines mediate this inhibition?
* SMAD 7
* INF-gamma and TNF alpha
79
Which important SSc related factors are stimulated by TGF-beta?
* **CTGF**: fibroblast, vascular smooth muscle, endothelium
* **PDGF**: skin, lungs, vasculature
80
Initiating event in scleroderma
vascular dysfunction
t cells migrate to vessel wall --\> cytokines/growth factors --\> fibrosis and transdifferentiation of fibroblasts to myocytes --\> tissue hypoxia --\> ischemia
81
Major organ consequences of SSc
* scleroderma renal crisis --\> renovascular damage from fibrosis
* pulmonary hypertension --\> fibrosis and hypertrophy
82
Key histological feature of cutaneous SSc
thickened dermis with increased collagen bundles
83
Vasculitis
group of immune mediated disorders causing inflammation and damage to vessel walls leading to tissue ischemia and organ failure
84
Classificiation of vasculitis
small/medium/large vessels
85
Dx of vasculitis
1. Biopsy
2. Angiogram
86
Vasculitis-morphology
* leukocyte vessel wall infiltrate (inflammation)
* vessel wall damage
* immune complex deposition (in immune-complex mediated small vessel vasculitis)
87
Medium vessel vasculitis- Polyarteritis nodosum (PAN)-clinical features
* abdominal pain
* neuropathy
* fever
* weight loss
88
Dx of classical PAN by angiogram requires
areas of
* constriction
* dilation
* aneurysm
89
PAN-morphology
* transmural inflammatory cell infiltrate
* intimal proliferation (destroying elastic laminae)
* fibrinoid necrosis
resulting in vessel occlusion
*
90
Which organs are spared by PAN?
glomeruli and lungs
91
Renal consequences of PAN
renovascular hypertension
reduced blood supply --\> renin --\> salt/water retention --\> hypertension
92
Virus associated with PAN
Hep B
93
Where in arteries does PAN tend to manifest?
bifurcation sites --\> increased sheer stress results in buildup of endothelial adhesion molecules and proinflammatory tf (e.g. NFkB)
94
What pathologic features are absent in PAN?
immune complexes and autoantibodies (incl. ANCA)
95
ANCA
* anti-neutrophil cytoplasmic antibodies
* associated with small vessel vaculitides
* recognize neutrophil lysosomes
96
c-ANCA vs. p-ANCA
* cytoplasmic: least common, most specific, PR-3
* perinuclear: most common, least specific, MPO
97
test to confirm c-ANCA
anti-PR3 ELISA
98
test to confirm p-ANCA
anti-MPO ELISA
99
Organ tropism of ANCA Associated Vasculitides (AAV)
microcirculation --\> lungs and kidneys
100
Pathology of cresentic glomerulonephritis
injury to glomerular capillary wall --\> plasma protein/fibrinogen leakage --\> macrophages/Tcells --\> IL1, TNFalpha --\> fibroblast proliferation, collagen deposition, crescent formation --\> glomerular nephritis
101
Anasarca
whole body edema (due to renal involvement, here b/c of AAV)
102
Role of ANCAs in AAV
cytokines prime neutrophils to express ANCA antigens --\> bind to Fab and Fc ANCA--\> neutrophil activation --\> endothelial cell damage in capillaries via lytic enzymes, ROS
103
Environmental consequences on ANCA production
can trigger anti-PR3 in patients with subacute bacterial endocarditis or amoebiasis --\> will disappear with antibiotics
104
What bacterial antigen makes AAV worse?
LPS
105
Small Vessel Vasculitis- Immune Complex-clinical features
* skin rash - palpable purpura
* tropism for dermal vessels
* low complement
* circulating complexes
* benign
106
In what conditions do we find circulating immune complexes?
* connective tissue disorders (lupus)
* infections (hepatitis)
* malignancy (hairy cell leukemia)
* hypersensitivity drug reactions
107
Under what condition do ICs precipitate?
Excess Ag
108
Immune Complex SSV-morphology
leukocytoclastic vasculitis
IC deposit --\> complement C3a/5a attract neutrophils and basophils --\> lysosomal enzyme damage of vessel wall
* neutrophilic infiltration of small vessels
* neutrophil fragmentation (leukocytoclasis)
* nuclear debris (karyorrhexis)
[](http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&docid=GrqTS9SNs0jvNM&tbnid=uabaQu5wQD7MqM:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.epathologies.com%2Fpcoll%2Fderm%2Fp_ref%2Fvsclt1_mkee.htm&ei=lhMTUZOnGoHl0gGR-oCgBw&bvm=bv.42080656,d.dmQ&psig=AFQjCNH7mOoa4pBumw5iX7eeKXTRl6LehQ&ust=1360291091208331)
109
Which venules are most susceptible to immune mediated injury due to hypoxia and stasis in SSV?
postcapillary venules --\> leukocyte adherence best in small vessels with stasis
110
111
Why does IC SSV cause palpable purpura?
thrombosis --\> C3a/5a/histamine --\> widens EC jxns --\> leakage --\> palpable purpura
112
Acute Gouty Arthritis-clinical features
* severe monoarthritis (one joint)
* 1st mtp joint, ankles, knees
* acute + gradual resolution
* middle aged males
* hyperuricemia and urate crystal shedding in synovial
113
Dx of Acute Gouty Arthritis
hyperuricemia (\>6.8mg/dL) + MSU crystal dposition
114
What dietary elements are associated with gout?
beer, meats, fructose
115
PRPP synthase and gout
increased PRPP (x linked) results in more purine synthesis --\> hyperuricemia
116
HGPRT and gout
* deficiency (x linked) --\> less salvage --\> hyperuricemia
117
Xanthine Oxidase and gout
target of inhibitors **allopurinol and febuxostat**
118
Uricase and gout
not in humans --\> **Pegloticase** porcine uricase can treat hyperuricemia
119
URAT-1
* reabsorbs filtered urate in proximal tubules
* stimulators
* pyrazinamide
* nicotinate
* organics: lactate/b-hydroxybutyrate,acetoacetate
* inhibitors
* probenecid
120
URAT-1 inhibitor
probenecid
121
URAT-1 stimulators
* pyrazinamide
* nicotinate
* organics: lactate/b-hydroxybutyrate,acetoacetate
122
Primary Hyperuricemia
1. HGPRT deficiency (x linked)
2. PRPP synthetase superactivity (x linked rare)
123
Diseases featuring HGPRT deficiency and primary hyperuricemia
Lesch-Nyhan (total def w/neuropathy)
Kelle-Seegmiller (partial def w/o neuropathy)
124
Secondary Hyperuricemia
1. excessive dietary intake
2. neoplasm
3. accelerated ATP degradation (acute illness)
125
Urate underexcretion
* Renal insufficiency
* Drugs
1. URAT stimulators-pyrazinamide, nicotinate, organic acids
2. diuretics
3. cyclosporine-decreased GFR
4. low-dose salicylate
126
Alcohol and hyperuricemia
1. accelerated hepatic ATP breakdown --\>overproduction
2. increased lactic acid --\> URAT1 stimulation
3. dehydration --\> underexcretion
4. high guanosine content
127
Chronic Tophaceous Gout-clinical features
inability to eliminate urate as rapidly as produced --\> Tophi deposits in olecrenon, ear, forearm, fingers
128
Chronic Tophaceous Gout-morphology
granulomas of **mononuclear and multinucleated macrophages** surrounding debris + **MSU crystals** + **connective tissue**
129
Renal failure/Kidney Stones
* uric acid deposition in renal tubules --\> acute renal failure
* uric acid deposition in collecting ducts/ureters--\> stones
130
Pathogenesis of Acute Gout
MSU crystal phagocytosis --\> NLRP3 inflammasome activation --\> IL1beta --\> induce inflammatory cytokines --\> neutrophil influx
131
End pathological event in acute gout
neutrophil influx
132
Tx of acute gout
* NSAIDS
* colchicine
* glucocorticoids
* ACTH
133
Tx of chronic gout
* probnecid
* allopurinol, febuxostat
* pegloticase
134
Osteoarthritis
progressive degenerative changes in shape, composition, and mechanical properties of weight bearing joint tissues, especially articular **cartilage**
135
Most common cause of arthritis
Osteoarthritis
136
Cartilage in joints is composed of
1. matrix (80% water)
2. chondrocytes
3. type II collagen
4. proteoglycan
137
\_\_\_\_\_\_\_ provides tensile strength in joints.
Type II collagen
138
\_\_\_\_\_\_\_ resist compression in joints.
negatively charged proteoglycans
139
Force in joints is dissipated by \_\_\_\_\_\_\_\_.
water efflux from cartilage matrix
140
Rate and nature of OA progression
slow "wear and tear" over time with low-grade chronic inflammation
141
142
Cytokines involved in low-grade chronic inflammation in OA and consequence.
TNFalpha, IL1b, IL6 --\> recruit matrix metalloproteases --\> inflammation, tissue damage, suppressed repair
143
144
Matrix metalloproteases are regulated by \_\_\_\_\_\_\_.
TIMP: tissue inhibitor of metalloproteases
145
Osteoarthritis-clinical features
* joint pain
* decreased range of motion
* crepitus
* tenderness
* ostephytes
* worse with use
* gelling/stiffness
* variable presentation (worse in women)
146
Bony outgrowths in OA and types
Osteophytes:
1. bouchard's node ("body of finger") = pip
2. heberden's node ("head of finger") = dip
147
Cartilage compression results in
* force absorption
* fluid pressure increase
* change in osmolarity
* trigger of mechanoreceptors (stretch-activated)
* cell signaling
* normal load = maintenance
* abnormal load = decreased proteoglycan synthesis
148
Abnormal load on cartilage results in
decreased proteoglycan synthesis
149
Osteoarthritis-morphology
* fibrilliation (fibers)
* subchondral eburnation (loss)
* matrix fragments triggers
* clustering of chondrocytes "clones" --\> "confused proliferation of chondrocytes"
* replacement of type II with type I collagen --\>fibrocartilage
150
Osteoarthritis-late morphology
matrix:
* repeated microtrauma (fibrillation/clefts)
* abnormal matrix composition
* calcified cartilage growth
* increase in water
* subchondral bone thickening --\> less dense
chondrocytes
* decrease in number
* senescence
151
In ______ osteoarthritis, formation outpaces resorption of bone.
late
152
Angiogenesis in OA
* dependent on VEGF
* increase fluid flow
* increase inflammatory mediators
153
Subchondral sclerosis is a feature of \_\_\_\_\_\_\_\_\_.
late osteoarthritis
154
In OA, synovial features include
* fibrosis
* infiltrates
* hyperplasia
* cartilage fragments
* macrophage/lymphocyte infiltrate
* angiogenesis
* decreased mw of hyaluronic acid
* fewer lubricants
155
Links between obesity and OA
* chemical: leptin --\> stimulates inflammation in chondrocytes
* mechanical: weight, load pattern
156
\_\_\_\_\_\_ is a cardinal feature of OA.
cartilage loss
157
Does synovium become thinner in OA?
No. Only subchondral bone in early OA and cartilage throughout.
158
Rheumatoid Arthritis
polyarticular small joint inflammatory arthritis of the **synovium** with systemic symptoms --\>synovitis unexplained by other diseases
159
What happens to synovium in RA?
* early: synovium thickens by hypertrophy and hyperplasia --\> distension of joint capsule due to inflammatory fluid/cells
* advanced: inflammation causes bony destruction and cartilage damage--\> "pannus"/wet bread appearance
160
In contrast to osteoarthritis, bony destruction in RA is a ____ process.
active
161
RA Pathogenesis
* production of metalloproteases
* migration of inflammatory cells
* erosion of bone and collagen
162
Disease of weight bearing joints is
osteoarthritis
163
Disease of small joint synovia
rheumatoid arthritis
164
Disease of cartilage
osteoarthritis
165
Disease of synovium and enthesis
spondylitis
166
Implications of "Shared Epitope" hypothesis in RA
epitopes in HLA-DR are shared by alleles associated with RA --\> autoimmune implications
167
Smoking and RA
* increases risk of ACPA+ RA
168
Which antibodies are associated with smoking and periodontis in RA?
anti-cyclic citrullinated peptide (CCP) antibodies
* targeted against citrulline residues in Type II collagen
* marker of severe disease
169
Periodontis is associated with
RA via anti-CCP antibodies
170
Citrullination hypothesis in RA
increased citrullination --\> binding with MHC II --\> antigen presentation --\> antibody development --\> immune complex --\> inflammation
171
Where in the synovium of many patients do immune cells gather?
lymph-node like structures withn autoimmune environment
172
Cytokines produced by macrophages
TNF alpha, IFN gamma, IL1, IL6
173
Cytokines produced by dendritic cells
TNF alpha, IL1, IL6
174
Autoantibodies associated with RA
* rheumatoid factor -
* anti-ccp
175
Rheumatoid Factor (RF)
* IgM antibody that binds to Fc portion of IgG --\> immune complexes --\> B cell presentation of any antigen bound by IgG --\> widespread inflammation
\*also complement fixation and cytokine mediated inflammation
176
Cytokines produced by B cells
**TNFalpha**, IL6, IFN gamma, Lymphotoxin
177
Main cytokine in RA
TNFalpha
178
How do cytokines upregulate bone and collagen destruction in RA?
Cytokines --\> collagenase, RANKL
* cartilage destruction can be inside/out or outside/in
179
Where is RANKL found?
stromal cells, osteoblasts, T cells, synovial fibroblasts --\> activate RANK on osteoclasts
180
Osteoprotegrin (OPG)
RANK antagonist: binds RANKL
181
Systemic sequelae of RA
* atherosclerosis
* infections
* neoplasias
* secondary sjogrens
* pulmonary disease
182
Increased mortality in RA patients associated with
cardiovascular events due to atherosclerosis
183
Classes of drugs used in tx of RA
* NSAIDs
* Corticosteroids
* Disease modifying anti rheumatic drugs (DMARDs)
* Biologics
184
Early treatment of RA
* NSAIDs, aggressive DMARDs (MTX)
1. window of opportunity to prevent damage
2. increasing tolerability of DMARDs
185
DMARDs
* methotrexate, leflunomide
* sulfasalazine, hydroxychloroquine
* minocycline, cyclosporine
186
First line treatment for RA and MOA
Methotrexate
* inhibits DHFR (inhibit lymphocytes)
* increases adenosine (reduces inflammation)
* reduce TNFalpha and IL1
* SE: abdominal pain, mouth sores, myelosuppresison, teratogenic in utero
187
Alternative first line treatment for RA and MOA
Leflunomide
* inhibits orotic acid dehydrogenase --\> pyrimidine synthesis
* alters cell growth and inflammation
* SE: weight loss, abdonminal pain, diarrhea, teratogenic
188
-ximabs
chimeric mabs
189
-zumabs
humanized mabs
190
-umabs
fully human mabs
191
-cepts
receptor fusion proteins
192
anti-TNF alpha drugs
* binds soluble TNF and cell bound TNF (antibody or receptor clone on human Fc + Pegol) --\> reduce inflammation, reduce infiltration
* self-injection/infusion
* SE: injection site rxn, infection, anti-pregnancy, MS-like, tolerance, neoplasms
* e.g. etanercept, glimumamb, inflixumab
193
anti-IL6 drugs
Tocilizumab
* block IL6 cytokine receptor --\> maturation of T/B cells, osteoclasts, macrophages
* reduces immune response
* used after TNFalpha inhibitor
* SE: liver, pregnancy, infusion, infections
194
Anti-IL1 drugs
Anakinra
* block IL-1 receptor --\> reduce immune response
* lower response rates
* not common in RA
* SE: infection, pregnancy
195
Abatacept MOA
* like belatacept: anti CD80/86
* SE: infection, anaphylaxis, pregnancy, infusion rxn, neoplasms
196
Rituximab MOA
* bind CD20 on B cells --\> destruction --\> depletion of B cells
* antibody dependent cell cytoxicity (ADCC)
* complement dependent cytotoxicity (CDC)
* apoptosis
* used after failure of TNFalpha
*
197
RA treatment plan
1. Methotrexate
2. Wait and see
3. Add-in TNFalpha inhibitor like Etanercept
4. if failure, then Anti-IL6 like Tocilizumab
5. if failure, then Abatacept
6. if failure, then Rituximab
198
Sjogren's
chronic, autoimmune inflammatory disorder with **lymphocytic infiltration of exocrine glands** resulting in **reduced glandular/salivary/lacrimal secretion** (sicca) in associatein with **anti-SSA/SSB**
199
Sjogren's-clinical features
* mucosal dryness
* musculoskeletal pain
* fatigue/malaise
* swollen glands
200
Types of Sjogren's
1. sicca symptoms develop in healthy person
2. sicca symptoms in person w/connective tissue disease (e.g. RA)
201
Clinical stages of Sjogren's
1. 1st stage: sicca, m/s pain
2. 2nd stage: internal organs, vasculitis
3. 3rd stage: NHL of salivary glands
202
Sjogren's Pathogenesis-early
injury to exocrine glandular epithelia --\> apoptosis --\> exposure of autoantigens
203
Sjogren's Pathogenesis-late
infiltration of glands with lymphocytes/inflammatory cells --\> cytokines --\> autoantibody production --\> destruction --\> loss of function
204
What kind of cells produce watery saliva and what enzyme does this contain?
* serous acinar cells
* alpha amylase
205
What kind of cells produce thick saliva and what is the key component?
* mucous acinar cells
* mucin --\> lubrication of food
206
Where do inflammatory cells localize to in early Sjogren's lymphoepithelial lesions?
periacinar and periductal (focal lymphocytic sialadenitis) distribution of
* CD4\>CD8
* B cells
* APCs
* plasma cells
207
Late stage Sjogren's-morphology
* fibrosis
* fat deposit
* dilated ducts
* chemokine CXCL12 overexpression --\> attracts lymphocytes and dendritic cells
* CXCL13 expression --\>attracts B cells
* SGECs act more like APCs --\> express MHC, adhesion molecules, costimulatory
208
What chemokine is overexpressed in Sjogren's and what is its function?
CXCL12 --\> attracts t cells and dendritic cells
209
What aberrant chemokine is expressed in Sjogren's and what is its function?
CXCL13 --\> attract B cells
210
What aberrant molecules are expressed by SGECs in Sjogren's?
* BAX --\> more apoptosis of SGECs
* MHC
* costimulatory factors
* adhesion molecules
211
What aberrant molecules do lymphocytes express in Sjogren's?
BCLX1 --\> reduced apoptosis of lymphocytes
212
Which viruses are sialotropic --\> cause salivary gland disease?
HIV, Hep C --\> activation of type 1 INF system
213
Role of Type 1 Interferon system in Sjogren's
* persistence of plasmacytoid dendritic cells (INF1 producing) in salivary glands in ABSENCE of virus
* interferon signature in blood leukocytes
* can be stimulated by viral infection (TLR recognitio nby plamacytoid dendritic cells)
*
214
Main explanation for dryness in Sjogren's
parenchymal loss due to loss of salivary epithelia
215
Alternative mechanism of drness in Sjogren's
anti-M3R antibodies --\> inhibit binding of AcH to M3R receptors on acinar cells --\> no IP3 --\> no Ca release --\> no opening of Ca and K channels --\> no water flow
* associated with Type 1 SS
* could aslo be acceerated degradation of AcH
216
3 immune mechanisms for dryness in Sjogren's
1. apoptosis
2. blocking antibodies (M3R)
3. AcH breakdown
217
Factors contributing to MALT in late Sjogren's
CXCL13 recruits B cells --\> Baff stimulates proliferation, neoplastic formation of ectopic lymphoid structures --\> B cells escape peripheral checkpoints--\>**A20/NFkB final oncogenic event**
* B cell hyperactivity --\> autoantibodies
* increased Ig
* formation of ectopic lymphoid follicles and germinal-like centers
* increased BAFF/BLyS in blood/salivary glands (anti-apoptotic)
* Tx: rituximab
218
What is the common final oncogenic event in BAFF mediated lymphomagenesis in Sjogren's?
A20 mutations --\> abnormal NFkB expression --\> uncontrolled B cell proliferation and survival
219
Cytokine that sparks progression to lymphomagenesis in Sjogren's
BAFF/BLyS
220
2 hit hypothesis for Sjogren's suggests what kinds of mutations necessary for lymphomagenesis?
* germinal
* somatic
221
NALP3 Inflammasome in gout
* uric acid --\>intracellular PRP--\>caspase 1 --\> cleaves and activates IL1beta and IL18 --\> recruits neutrophils and macrophages
