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MDTI > Rheumatology > Flashcards

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
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2
Q

What is the unique feature of synovial lining?

A

No basement membrane

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3
Q

What are the components of synovial interstitium?

A

collagen fibrils and proteoglycans with abundant fenestrated microvessels

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4
Q

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

A

Septic arthritis

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5
Q

How do bacteria spread in septic arthritis?

A
  • typically hematogenous spread
  • also direct puncture/surgical procedures/animal bites
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6
Q

Why is the joint susceptible to septic infection?

A
  1. abundant vascular supply
  2. lack of limiting basement membrane
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7
Q

What are the main categories of septic arthritis causing bacteria?

A

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

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8
Q

What are 4 key risk factors of bacterial arthritis?

A
  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
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9
Q

Virulence factors

A

mechanisms which infectious organsms have evolved to enhance immune evasion

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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.
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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
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12
Q

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

A

Pili

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13
Q

How does N. gonorrhea avoid complement and phagocytosis?

A

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

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14
Q

3 ways septic arthritis leads to joint damage

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

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16
Q

How does joint exudate lead to ischemia in septic arthritis?

A

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

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17
Q

Septic arthritis-clinical features

A
  • fevers/chills
  • malaise
  • monoarticular
  • inflammation
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18
Q

Gonococcal arthritis-clinical features

A
  • sexually active
  • inflammatory arthritis of multiple joints
  • fevers/chills
  • vesiculopustular rash
  • polyarthralgia
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19
Q

Classification of joint effusions

A
  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)
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20
Q

Stages of Lyme disease

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

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23
Q

Molecular mimicry hypothesis for Lyme resistance

A

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

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24
Q

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

A

Molecular mimicry phenomenon

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25
Q

Observations that support molecular mimicry hypothesis

A
  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
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26
Q

Which Borrelia protein is the target of Lyme arthritis autoantibodies?

A

OspA surface protein

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27
Q

Which human autoantigen has sequence homology with the Borrelia antibody target

A

LF1alpha - adhesion molecule on inflamed tissues

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28
Q

Primary issue with molecular mimicry hypothesis re: antibiotic resistant Lyme arthritis

A
  • LF1-alpha is a weak agonist to OspA reactive tcells
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29
Q

What kinds of patients with antibiotic resistant Lyme arthritis have a strong immune response to OspA and LFA-1alpha?

A

DR4+

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30
Q

Tx of antibiotic resitant Lyme arthritis

A

immunosuppressants

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31
Q

Viral arthritis-clinical features

A
  • viral symptoms
  • acute onset
  • symmetric polyarticular small joint
  • rash
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32
Q

Example of immune complex mediated viral arthritis

A

Hepatitis B

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33
Q

Example of antigenic persistence related viral arthritis

A

Parvovirus B19

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34
Q

How does HepB produce arthritis?

A

HepB SA + antibodies form complexes that deposit in synovium –> complement activation, neutrophils –> inflammatory arthritis

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35
Q

Most common viral arthritis in the US

A

Parvovirus B19

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36
Q

What molecule communicates with Parvovirus B19 to allow its entry to the synovium?

A

glyocsphingolipid Gb4 on synovium

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37
Q

Antigen persistence

A

various pieces of infectious agent can cause ongoing immune response even in absence of whole organism

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38
Q

Spondylitis

A
  • multisystem inflammatory arthritides involving the spine, synovium, and enthesis
  • associated with HLAB27
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39
Q

Which HLA is associated with spondyloarthropathies?

A

HLA-B27

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40
Q

Spondyloarthropathies-Clinical features

A
  • sacroilitis
  • dactylitis
  • enthesitis
  • asymmetric polyarticular peripheral arthritis
  • uveitis
  • gut inflammation
  • psoriasis
  • new bone formation
  • Tx: TNF alpha inhibitor, Ibuprofen, PT
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41
Q

What are three defining features of spondyloarthropathies?

A
  1. enthesitis
  2. simultaneous bone catabolism/anabolism
  3. HLA-B27
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42
Q

What process precedes synovitis in SpA?

A

Enthesitis

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43
Q

Cytokines that stimulate RANKL

A

TNFalpha, IL1, 6 –> RANKL –> osteoclast activation

and–> Dkk-1 and sclerostin –> osteoblast inhibition

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44
Q

Three important pathways in pathologic bone formation

A

BMP, Wnt, and PGE

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45
Q

The pathogenic function of HLAB27 is related to antigen presentation to what kinds of cells?

A

CD8+

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46
Q

Relationship between HLAB27 and bacteria

A

HLAB27 rats need colonic bacteria to get SpA

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47
Q

Three theories explaining role of HLA-B27 in SpA

A
  1. arthritogenic peptide
  2. homodimerization
  3. misfolding and unfolded protein response
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48
Q

Cytokine linchpin in unfolded protein response related to SpA and HLA-B27

A

IL 23 –> IFNbeta, IL 17,22,1,6,TNFalpha –> osteproliferation, inflammation, ethesitis

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49
Q
A
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50
Q

SLE

A

systemic autoimmune condition with antibodies to components of cell nucleus + protean clinical manifestions

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51
Q

SLE-key clinical features

A
  • malar rash
  • discoid rash
  • photosensitivity
  • oral ulcers
  • arthritis
  • ANA –> antiDNA or anti-smith or APLA
  • renal casts
  • serositis
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52
Q
A
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53
Q

Environmental contributors to Lupus

A
  • silica dust
  • UV light
  • viruses
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54
Q

When do SLE autoantibodies appear?

A

long before clinical manifestations

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55
Q

ANA

A

antinuclear antibody –> binds to antigens found in nucleus –> immunofluoresence, ELISA (via Hep-2 cells)

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56
Q

Autoantibodies specific for lupus

A

Anti-dsDNA, Anti-Smith

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57
Q

Pathogenic modalities of SLE

A
  1. immune complex
  2. apoptosis –> nuclear antigens
  3. inf-alpha stimulation of immune system
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58
Q

What molecule has been found in association with apoptosis defects in SLE?

A

BLyS –> B lymphocyte stimulator –> Belimumab (Anti-BLyS Ab)

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59
Q

Newest lupus drug

A

Belimumab (anti-BLyS)

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60
Q

Which autoantibodies mediate neonatal lupus?

A

Anti-Ro/La (SSA/SSB) –> passive transfer from maternal system

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61
Q

Neonatal lupus-clinical features

A
  • complete congenital heart block
  • rash
  • hematological
  • hepatobiliary
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62
Q

Clinical measure for immune complexes

A

C3 and C4 levels –> if low, lots of disease activity

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63
Q

Lupus nephritis

A

immune complex mediated sequelae of lupus

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64
Q

Which TLRs activate innate immune system and generate IFN in lupus?

A

TLR 7 and 9 –> recognize immune complexes

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65
Q

Which cytokine is thought to be most important in mediating scleroderma?

A

TGFbeta

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66
Q

Triad of conditions defining scleroderma

A
  1. fibrosis
  2. vascular dysfunction
  3. immune dysregulation
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67
Q

Scleroderma classifications

A
  1. diffuse (above knees/elbows)
    limited
  2. overlap
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68
Q

Scleroderma-clinical features

A
  • sclerodactyly
  • calcinosis
  • raynaud’s
  • esophageal dysmotility
  • teleangiectasia
  • fibrosis
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69
Q

Diffuse cutaneous scleroderma-clinical features

A
  • rapid progression
  • early visceral organ involvmeent
  • absence of anticentromere antibodies
  • poor prognosis
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70
Q

Limited cutaneous scleroderma-clinical features

A
  1. early raynauds
  2. slow progression
  3. anti-centromere antibody

CREST

  • calcinosis
  • rayndauds
  • esophageal dysmotility
  • sclerodactyly
  • telangiectasia
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71
Q

Anti-centromere antibodies are found in what kind of scleroderma?

A

limited

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72
Q

Which autoantibodies are associated with scleroderma?

A
  • anti-Scl-70 in AA//HLA-DQ7
  • anti-centromere in caucasians
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73
Q

Which virus is associated with scleroderma?

A

CMV

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74
Q

Genes associated with scleroderma

A
  • COL1A2 (type 1 collagen)
  • Fibrillin-1
  • TGF-beta 1
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75
Q

Which ANA is associated with rapidly progressive scleroderma?

A

Anti-RNApIII

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76
Q

How does TGF-beta mediate SSc/Scleroderma

A
  • sensitizes fibroblasts to stay persistently activated
  • decreases function of collagen degrading proteases
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77
Q

SMAD pathway in Scleroderma

A

TGFbeta binding –> SMAD 2/3 phosphorylation -> SMAD4 translocation to nucleus –> collagen gene upregulation

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78
Q

Which SMAD downregulates collagen formation in SSc and which cytokines mediate this inhibition?

A
  • SMAD 7
  • INF-gamma and TNF alpha
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79
Q

Which important SSc related factors are stimulated by TGF-beta?

A
  • CTGF: fibroblast, vascular smooth muscle, endothelium
  • PDGF: skin, lungs, vasculature
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80
Q

Initiating event in scleroderma

A

vascular dysfunction

t cells migrate to vessel wall –> cytokines/growth factors –> fibrosis and transdifferentiation of fibroblasts to myocytes –> tissue hypoxia –> ischemia

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81
Q

Major organ consequences of SSc

A
  • scleroderma renal crisis –> renovascular damage from fibrosis
  • pulmonary hypertension –> fibrosis and hypertrophy
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82
Q

Key histological feature of cutaneous SSc

A

thickened dermis with increased collagen bundles

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83
Q

Vasculitis

A

group of immune mediated disorders causing inflammation and damage to vessel walls leading to tissue ischemia and organ failure

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84
Q

Classificiation of vasculitis

A

small/medium/large vessels

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85
Q

Dx of vasculitis

A
  1. Biopsy
  2. Angiogram
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86
Q

Vasculitis-morphology

A
  • leukocyte vessel wall infiltrate (inflammation)
  • vessel wall damage
  • immune complex deposition (in immune-complex mediated small vessel vasculitis)
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87
Q

Medium vessel vasculitis- Polyarteritis nodosum (PAN)-clinical features

A
  • abdominal pain
  • neuropathy
  • fever
  • weight loss
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88
Q

Dx of classical PAN by angiogram requires

A

areas of

  • constriction
  • dilation
  • aneurysm
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89
Q

PAN-morphology

A
  • transmural inflammatory cell infiltrate
  • intimal proliferation (destroying elastic laminae)
  • fibrinoid necrosis

resulting in vessel occlusion

*

90
Q

Which organs are spared by PAN?

A

glomeruli and lungs

91
Q

Renal consequences of PAN

A

renovascular hypertension

reduced blood supply –> renin –> salt/water retention –> hypertension

92
Q

Virus associated with PAN

A

Hep B

93
Q

Where in arteries does PAN tend to manifest?

A

bifurcation sites –> increased sheer stress results in buildup of endothelial adhesion molecules and proinflammatory tf (e.g. NFkB)

94
Q

What pathologic features are absent in PAN?

A

immune complexes and autoantibodies (incl. ANCA)

95
Q

ANCA

A
  • anti-neutrophil cytoplasmic antibodies
  • associated with small vessel vaculitides
  • recognize neutrophil lysosomes
96
Q

c-ANCA vs. p-ANCA

A
  • cytoplasmic: least common, most specific, PR-3
  • perinuclear: most common, least specific, MPO
97
Q

test to confirm c-ANCA

A

anti-PR3 ELISA

98
Q

test to confirm p-ANCA

A

anti-MPO ELISA

99
Q

Organ tropism of ANCA Associated Vasculitides (AAV)

A

microcirculation –> lungs and kidneys

100
Q

Pathology of cresentic glomerulonephritis

A

injury to glomerular capillary wall –> plasma protein/fibrinogen leakage –> macrophages/Tcells –> IL1, TNFalpha –> fibroblast proliferation, collagen deposition, crescent formation –> glomerular nephritis

101
Q

Anasarca

A

whole body edema (due to renal involvement, here b/c of AAV)

102
Q

Role of ANCAs in AAV

A

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
Q

Environmental consequences on ANCA production

A

can trigger anti-PR3 in patients with subacute bacterial endocarditis or amoebiasis –> will disappear with antibiotics

104
Q

What bacterial antigen makes AAV worse?

A

LPS

105
Q

Small Vessel Vasculitis- Immune Complex-clinical features

A
  • skin rash - palpable purpura
  • tropism for dermal vessels
  • low complement
  • circulating complexes
  • benign
106
Q

In what conditions do we find circulating immune complexes?

A
  • connective tissue disorders (lupus)
  • infections (hepatitis)
  • malignancy (hairy cell leukemia)
  • hypersensitivity drug reactions
107
Q

Under what condition do ICs precipitate?

A

Excess Ag

108
Q

Immune Complex SSV-morphology

A

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
Q

Which venules are most susceptible to immune mediated injury due to hypoxia and stasis in SSV?

A

postcapillary venules –> leukocyte adherence best in small vessels with stasis

110
Q
A
111
Q

Why does IC SSV cause palpable purpura?

A

thrombosis –> C3a/5a/histamine –> widens EC jxns –> leakage –> palpable purpura

112
Q

Acute Gouty Arthritis-clinical features

A
  • severe monoarthritis (one joint)
  • 1st mtp joint, ankles, knees
  • acute + gradual resolution
  • middle aged males
  • hyperuricemia and urate crystal shedding in synovial
113
Q

Dx of Acute Gouty Arthritis

A

hyperuricemia (>6.8mg/dL) + MSU crystal dposition

114
Q

What dietary elements are associated with gout?

A

beer, meats, fructose

115
Q

PRPP synthase and gout

A

increased PRPP (x linked) results in more purine synthesis –> hyperuricemia

116
Q

HGPRT and gout

A
  • deficiency (x linked) –> less salvage –> hyperuricemia
117
Q

Xanthine Oxidase and gout

A

target of inhibitors allopurinol and febuxostat

118
Q

Uricase and gout

A

not in humans –> Pegloticase porcine uricase can treat hyperuricemia

119
Q

URAT-1

A
  • reabsorbs filtered urate in proximal tubules
  • stimulators
    • pyrazinamide
    • nicotinate
    • organics: lactate/b-hydroxybutyrate,acetoacetate
  • inhibitors
    • probenecid
120
Q

URAT-1 inhibitor

A

probenecid

121
Q

URAT-1 stimulators

A
  • pyrazinamide
  • nicotinate
  • organics: lactate/b-hydroxybutyrate,acetoacetate
122
Q

Primary Hyperuricemia

A
  1. HGPRT deficiency (x linked)
  2. PRPP synthetase superactivity (x linked rare)
123
Q

Diseases featuring HGPRT deficiency and primary hyperuricemia

A

Lesch-Nyhan (total def w/neuropathy)

Kelle-Seegmiller (partial def w/o neuropathy)

124
Q

Secondary Hyperuricemia

A
  1. excessive dietary intake
  2. neoplasm
  3. accelerated ATP degradation (acute illness)
125
Q

Urate underexcretion

A
  • Renal insufficiency
  • Drugs
    1. URAT stimulators-pyrazinamide, nicotinate, organic acids
    2. diuretics
    3. cyclosporine-decreased GFR
    4. low-dose salicylate
126
Q

Alcohol and hyperuricemia

A
  1. accelerated hepatic ATP breakdown –>overproduction
  2. increased lactic acid –> URAT1 stimulation
  3. dehydration –> underexcretion
  4. high guanosine content
127
Q

Chronic Tophaceous Gout-clinical features

A

inability to eliminate urate as rapidly as produced –> Tophi deposits in olecrenon, ear, forearm, fingers

128
Q

Chronic Tophaceous Gout-morphology

A

granulomas of mononuclear and multinucleated macrophages surrounding debris + MSU crystals + connective tissue

129
Q

Renal failure/Kidney Stones

A
  • uric acid deposition in renal tubules –> acute renal failure
  • uric acid deposition in collecting ducts/ureters–> stones
130
Q

Pathogenesis of Acute Gout

A

MSU crystal phagocytosis –> NLRP3 inflammasome activation –> IL1beta –> induce inflammatory cytokines –> neutrophil influx

131
Q

End pathological event in acute gout

A

neutrophil influx

132
Q

Tx of acute gout

A
  • NSAIDS
  • colchicine
  • glucocorticoids
  • ACTH
133
Q

Tx of chronic gout

A
  • probnecid
  • allopurinol, febuxostat
  • pegloticase
134
Q

Osteoarthritis

A

progressive degenerative changes in shape, composition, and mechanical properties of weight bearing joint tissues, especially articular cartilage

135
Q

Most common cause of arthritis

A

Osteoarthritis

136
Q

Cartilage in joints is composed of

A
  1. matrix (80% water)
  2. chondrocytes
  3. type II collagen
  4. proteoglycan
137
Q

_______ provides tensile strength in joints.

A

Type II collagen

138
Q

_______ resist compression in joints.

A

negatively charged proteoglycans

139
Q

Force in joints is dissipated by ________.

A

water efflux from cartilage matrix

140
Q

Rate and nature of OA progression

A

slow “wear and tear” over time with low-grade chronic inflammation

141
Q
A
142
Q

Cytokines involved in low-grade chronic inflammation in OA and consequence.

A

TNFalpha, IL1b, IL6 –> recruit matrix metalloproteases –> inflammation, tissue damage, suppressed repair

143
Q
A
144
Q

Matrix metalloproteases are regulated by _______.

A

TIMP: tissue inhibitor of metalloproteases

145
Q

Osteoarthritis-clinical features

A
  • joint pain
    • decreased range of motion
    • crepitus
    • tenderness
    • ostephytes
  • worse with use
  • gelling/stiffness
  • variable presentation (worse in women)
146
Q

Bony outgrowths in OA and types

A

Osteophytes:

  1. bouchard’s node (“body of finger”) = pip
  2. heberden’s node (“head of finger”) = dip
147
Q

Cartilage compression results in

A
  • force absorption
  • fluid pressure increase
  • change in osmolarity
  • trigger of mechanoreceptors (stretch-activated)
  • cell signaling
    • normal load = maintenance
    • abnormal load = decreased proteoglycan synthesis
148
Q

Abnormal load on cartilage results in

A

decreased proteoglycan synthesis

149
Q

Osteoarthritis-morphology

A
  • 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
Q

Osteoarthritis-late morphology

A

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
Q

In ______ osteoarthritis, formation outpaces resorption of bone.

A

late

152
Q

Angiogenesis in OA

A
  • dependent on VEGF
  • increase fluid flow
  • increase inflammatory mediators
153
Q

Subchondral sclerosis is a feature of _________.

A

late osteoarthritis

154
Q

In OA, synovial features include

A
  • fibrosis
  • infiltrates
  • hyperplasia
  • cartilage fragments
  • macrophage/lymphocyte infiltrate
  • angiogenesis
  • decreased mw of hyaluronic acid
  • fewer lubricants
155
Q

Links between obesity and OA

A
  • chemical: leptin –> stimulates inflammation in chondrocytes
  • mechanical: weight, load pattern
156
Q

______ is a cardinal feature of OA.

A

cartilage loss

157
Q

Does synovium become thinner in OA?

A

No. Only subchondral bone in early OA and cartilage throughout.

158
Q

Rheumatoid Arthritis

A

polyarticular small joint inflammatory arthritis of the synovium with systemic symptoms –>synovitis unexplained by other diseases

159
Q

What happens to synovium in RA?

A
  • 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
Q

In contrast to osteoarthritis, bony destruction in RA is a ____ process.

A

active

161
Q

RA Pathogenesis

A
  • production of metalloproteases
  • migration of inflammatory cells
  • erosion of bone and collagen
162
Q

Disease of weight bearing joints is

A

osteoarthritis

163
Q

Disease of small joint synovia

A

rheumatoid arthritis

164
Q

Disease of cartilage

A

osteoarthritis

165
Q

Disease of synovium and enthesis

A

spondylitis

166
Q

Implications of “Shared Epitope” hypothesis in RA

A

epitopes in HLA-DR are shared by alleles associated with RA –> autoimmune implications

167
Q

Smoking and RA

A
  • increases risk of ACPA+ RA
168
Q

Which antibodies are associated with smoking and periodontis in RA?

A

anti-cyclic citrullinated peptide (CCP) antibodies

  • targeted against citrulline residues in Type II collagen
  • marker of severe disease
169
Q

Periodontis is associated with

A

RA via anti-CCP antibodies

170
Q

Citrullination hypothesis in RA

A

increased citrullination –> binding with MHC II –> antigen presentation –> antibody development –> immune complex –> inflammation

171
Q

Where in the synovium of many patients do immune cells gather?

A

lymph-node like structures withn autoimmune environment

172
Q

Cytokines produced by macrophages

A

TNF alpha, IFN gamma, IL1, IL6

173
Q

Cytokines produced by dendritic cells

A

TNF alpha, IL1, IL6

174
Q

Autoantibodies associated with RA

A
  • rheumatoid factor -
  • anti-ccp
175
Q

Rheumatoid Factor (RF)

A
  • 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
Q

Cytokines produced by B cells

A

TNFalpha, IL6, IFN gamma, Lymphotoxin

177
Q

Main cytokine in RA

A

TNFalpha

178
Q

How do cytokines upregulate bone and collagen destruction in RA?

A

Cytokines –> collagenase, RANKL

  • cartilage destruction can be inside/out or outside/in
179
Q

Where is RANKL found?

A

stromal cells, osteoblasts, T cells, synovial fibroblasts –> activate RANK on osteoclasts

180
Q

Osteoprotegrin (OPG)

A

RANK antagonist: binds RANKL

181
Q

Systemic sequelae of RA

A
  • atherosclerosis
  • infections
  • neoplasias
  • secondary sjogrens
  • pulmonary disease
182
Q

Increased mortality in RA patients associated with

A

cardiovascular events due to atherosclerosis

183
Q

Classes of drugs used in tx of RA

A
  • NSAIDs
  • Corticosteroids
  • Disease modifying anti rheumatic drugs (DMARDs)
  • Biologics
184
Q

Early treatment of RA

A
  • NSAIDs, aggressive DMARDs (MTX)
  1. window of opportunity to prevent damage
  2. increasing tolerability of DMARDs
185
Q

DMARDs

A
  • methotrexate, leflunomide
  • sulfasalazine, hydroxychloroquine
  • minocycline, cyclosporine
186
Q

First line treatment for RA and MOA

A

Methotrexate

  • inhibits DHFR (inhibit lymphocytes)
  • increases adenosine (reduces inflammation)
  • reduce TNFalpha and IL1
  • SE: abdominal pain, mouth sores, myelosuppresison, teratogenic in utero
187
Q

Alternative first line treatment for RA and MOA

A

Leflunomide

  • inhibits orotic acid dehydrogenase –> pyrimidine synthesis
  • alters cell growth and inflammation
  • SE: weight loss, abdonminal pain, diarrhea, teratogenic
188
Q

-ximabs

A

chimeric mabs

189
Q

-zumabs

A

humanized mabs

190
Q

-umabs

A

fully human mabs

191
Q

-cepts

A

receptor fusion proteins

192
Q

anti-TNF alpha drugs

A
  • 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
Q

anti-IL6 drugs

A

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
Q

Anti-IL1 drugs

A

Anakinra

  • block IL-1 receptor –> reduce immune response
  • lower response rates
  • not common in RA
  • SE: infection, pregnancy
195
Q

Abatacept MOA

A
  • like belatacept: anti CD80/86
  • SE: infection, anaphylaxis, pregnancy, infusion rxn, neoplasms
196
Q

Rituximab MOA

A
  • 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
Q

RA treatment plan

A
  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
Q

Sjogren’s

A

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
Q

Sjogren’s-clinical features

A
  • mucosal dryness
  • musculoskeletal pain
  • fatigue/malaise
  • swollen glands
200
Q

Types of Sjogren’s

A
  1. sicca symptoms develop in healthy person
  2. sicca symptoms in person w/connective tissue disease (e.g. RA)
201
Q

Clinical stages of Sjogren’s

A
  1. 1st stage: sicca, m/s pain
  2. 2nd stage: internal organs, vasculitis
  3. 3rd stage: NHL of salivary glands
202
Q

Sjogren’s Pathogenesis-early

A

injury to exocrine glandular epithelia –> apoptosis –> exposure of autoantigens

203
Q

Sjogren’s Pathogenesis-late

A

infiltration of glands with lymphocytes/inflammatory cells –> cytokines –> autoantibody production –> destruction –> loss of function

204
Q

What kind of cells produce watery saliva and what enzyme does this contain?

A
  • serous acinar cells
  • alpha amylase
205
Q

What kind of cells produce thick saliva and what is the key component?

A
  • mucous acinar cells
  • mucin –> lubrication of food
206
Q

Where do inflammatory cells localize to in early Sjogren’s lymphoepithelial lesions?

A

periacinar and periductal (focal lymphocytic sialadenitis) distribution of

  • CD4>CD8
  • B cells
  • APCs
  • plasma cells
207
Q

Late stage Sjogren’s-morphology

A
  • 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
Q

What chemokine is overexpressed in Sjogren’s and what is its function?

A

CXCL12 –> attracts t cells and dendritic cells

209
Q

What aberrant chemokine is expressed in Sjogren’s and what is its function?

A

CXCL13 –> attract B cells

210
Q

What aberrant molecules are expressed by SGECs in Sjogren’s?

A
  • BAX –> more apoptosis of SGECs
  • MHC
  • costimulatory factors
  • adhesion molecules
211
Q

What aberrant molecules do lymphocytes express in Sjogren’s?

A

BCLX1 –> reduced apoptosis of lymphocytes

212
Q

Which viruses are sialotropic –> cause salivary gland disease?

A

HIV, Hep C –> activation of type 1 INF system

213
Q

Role of Type 1 Interferon system in Sjogren’s

A
  • 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
Q

Main explanation for dryness in Sjogren’s

A

parenchymal loss due to loss of salivary epithelia

215
Q

Alternative mechanism of drness in Sjogren’s

A

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
Q

3 immune mechanisms for dryness in Sjogren’s

A
  1. apoptosis
  2. blocking antibodies (M3R)
  3. AcH breakdown
217
Q

Factors contributing to MALT in late Sjogren’s

A

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
Q

What is the common final oncogenic event in BAFF mediated lymphomagenesis in Sjogren’s?

A

A20 mutations –> abnormal NFkB expression –> uncontrolled B cell proliferation and survival

219
Q

Cytokine that sparks progression to lymphomagenesis in Sjogren’s

A

BAFF/BLyS

220
Q

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

A
  • germinal
  • somatic
221
Q

NALP3 Inflammasome in gout

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

MDTI (10 decks)

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