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Flashcards in Rheumatology Deck (221):
1


2 types of synovial lining cells

  • A: resemble macrophages with lots of organelles
  • B: resemble fibroblastas with lots of ER

2


What is the unique feature of synovial lining?


No basement membrane

3

What are the components of synovial interstitium?


collagen fibrils and proteoglycans with abundant fenestrated microvessels

4

What is the most rapidly destructive form of bone and joint disease?


Septic arthritis

5


How do bacteria spread in septic arthritis?

  • typically hematogenous spread
  • also direct puncture/surgical procedures/animal bites

6


Why is the joint susceptible to septic infection?

 

  1. abundant vascular supply
  2. lack of limiting basement membrane

7

What are the main categories of septic arthritis causing bacteria?


Gonoccal (N. gonorrhea) vs. Nongonococcal (S. aureus)

8


What are 4 key risk factors of bacterial arthritis?

 

  1. age (80+)
  2. bacteremia
  3. pre-existing joint disease/damage (osteo/rheumatoid arthritis)
  4. chronic systemic disease (diabetes)
  5. immunosuppression (steroids)
  6. trauma
  7. prosthetic joint
  8. drug use

9


Virulence factors


mechanisms which infectious organsms have evolved to enhance immune evasion

10

What do MSCRAMMs bind and what do they do?

microbial surface components recognizing adhesive matrix molecules

  • bind host matrix proteins like collagen, elastin, etc.

11


In what organism is the agr relevant and what does it do?

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

How does N. gonorrhea (G+cocci) attach to cell surfaces?

Pili

13

How does N. gonorrhea avoid complement and phagocytosis?


Protein IA binds to factor H --> inactivates complement 3b

14


3 ways septic arthritis leads to joint damage

 

  1. direct bacterial effect/toxins
  2. host immune response to LPS/cytokines --> autodigestion of cartilage by metalloproteases
  3. mechanical effects from joint effusion pressure

15

Cytokines implicated in immune-mediated damage in septic arthritis

IL1beta and IL6 --> recruit neutrophils and macrophages --> produce TNFalpha, IL1,6,8 --> production of proteases and free radicals

16

How does joint exudate lead to ischemia in septic arthritis?

purulent exudate increases intra-articular pressure --> ischemia in avascular cartilage

17

Septic arthritis-clinical features

 

  • fevers/chills
  • malaise
  • monoarticular
  • inflammation

18

Gonococcal arthritis-clinical features

  • sexually active
  • inflammatory arthritis of multiple joints
  • fevers/chills
  • vesiculopustular rash
  • polyarthralgia

19


Classification of joint effusions

  1. normal- clear, viscous (<200 leukocytes/mm3)
  2. noninflammatory- clear/yellow, viscous (200-2000)
  3. inflammatory-cloudy/yellow, thin (2000-100,000)
  4. septic-purulent, thin (>50,000)

20


Stages of Lyme disease

  1. early localized-rash, erythema migrans, viral symptoms
  2. early disseminated-cardiac, neurologic
  3. late disease-neurologic, inflammatory arthritis

21


Borrelia arthritis-late disease-clinical features

  • inflammatory arthritis
    • monoarticular knee
  • spirochetes invade synovium --> accumulation of neutrophils, complexes, complement, cytokines
  • fluid count < 50,000 leukocytes/mm3
  • Tx: antibiotics

22


Why is joint damage slow-onset with lyme disease?

Borrelia does not produce its own proteases so must wait for immune response to generate damage

23


Molecular mimicry hypothesis for Lyme resistance

T cell epitope mimicry between spirochete and host protein --> borrelia mediated autoimmunity

24


Phenomenon of autoreactive t cell possing TCR for foreign peptide that also recognizes self-peptide


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)

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)
  •  

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Main explanation for dryness in Sjogren's

parenchymal loss due to loss of salivary epithelia

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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

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3 immune mechanisms for dryness in Sjogren's

  1. apoptosis
  2. blocking antibodies (M3R)
  3. AcH breakdown

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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

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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

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Cytokine that sparks progression to lymphomagenesis in Sjogren's

BAFF/BLyS

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2 hit hypothesis for Sjogren's suggests what kinds of mutations necessary for lymphomagenesis?

  • germinal
  • somatic

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NALP3 Inflammasome in gout

 

  • uric acid -->intracellular PRP-->caspase 1 --> cleaves and activates IL1beta and IL18 --> recruits neutrophils and macrophages