lecture 25 Flashcards

1
Q

What is arthritis?

A
  • derived from Greek words
  • ‘arthron’ = joint
  • ‘itis’ = inflammation
  • literally means ‘inflamed joint’
  • umbrella term rather than a single disease
  • > 100 different types of arthritis currently identified
  • disability and reduced quality of life (elderly)
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2
Q

What is the prevalence of arthritis in the Australian Population?

A
  • in 2011-12
  • approx, 3.3 million (1 in 6; ~15%) had arthritis
  • prevalence higher in indigenous than non-indigenous
  • 95% of cases due to osteoarthritis
  • less commonly rheumatoid arhtritis, gout
  • in 2012 total cost of arthritis and musculoskeletal conditions
    • $55.1 billion
  • based on current trends, by the year 2050, 7 million australians expected to suffer some form of arthritis
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3
Q

What is a definition of rheumatoid arthritis?

A
  • chronic inflammatory autoimmune disease of unknown aetiology
  • associated with
    • articular manifestations (dominant feature)
    • systemic (or ‘extra-articular’) complications
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4
Q

What does RA lead to in the absence of effective treatment?

A
  • progressive locomotor disability within 10-20 years of diagnosis
  • reduced life expectancy of up to 10 years
  • significant socioeconomic costs - also loss of gainful employment
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5
Q

What is the primary manifestation of RA?

A
  • synovitis
  • primary manifestion is synovial inflammation of ‘synovitis’
  • -> erosion of bone, cartilage, peri-articular structures
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6
Q

What is the epidemiology of RA?

A
  • in adult caucasian populations
  • incidence 8 to 98 cases per 100,000/annum (new cases diagnosed)
  • prevalence 0.5 to 1.0% (number of diagnosed patients over a given point in time)
  • occurs 2-3x more commonly in females than males
  • peak age of onset 40 (range 40 - 70) years
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7
Q

What is the principle of all autoimmune diseases?

A

cocktail of ingredients before someone gets an autoimmune disease:
- genetic susceptibility
plus
- environmental trigger (not always known)

leads to breakdown of immune tolerance (self-reactive antibody or T cells)

consequence of this is autoimmune disease

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8
Q

What are risk factors for RA?

A
  • multifactorial
    i. genetic
    ii. epigenetic
    iii. hormonal
    iv. stochastic (random) environmental triggers
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9
Q

What are genetic risk factors for RA?

A
  • HLA
  • studies of identical twins
    • genetics accounts for 50-60% of disease susceptibility

genetic risk factors

i. human leukocyte antigen (HLA) ~ 12.7%
ii. non-HLA ~4%

  • HLA Class II (most important)
  • DRB1 gene
    • encodes HLA-DR antigen presenting molecule
  • allelic variant
    • DRB1*0401
    • DRB1*404
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10
Q

What is the location and organisation of HLA complex? What allelic variants contribute to RA?

A
  • chromosome 6
  • short arm
  • this area can be divided into three broad regions: class II, class III, class I
  • within the class II region, it is the DRB1 which has been associated with increased risk of RA
  • RA HLA risk alleles: HLA-DRB10401 and DRB10404
  • with this allele risk increased approximately 4 fold
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11
Q

What is the shared epitope hypothesis?

A

HLA-DRB1 alleles (confer RA risk) encode a five amino acid sequence termed a ‘shared epitope’

  • glutamic-leucine-arginine-alanine-alanine (QKRAA)
  • occupies positions 70 to 74 of the HLA-DRβ chain
  • surrounds peptide binding groove (determines antigen-binding specificity and presentation to CD4+ T helper cells)
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12
Q

What is the proposed role of shared epitope?

A

i. efficient binding of arthritogeneic (citrulline) peptides
ii. marker of immunoreactivity
- anti-citrullinated protein antibodies (ACPA) expression
iii. thymic selection of autoimmune T cells (+ve or -ve)
iv. target for T cells
- molecular mimicry - SE and microbes (e.g. epstein-barr virus)
v. polarises T-cell differentiation to T helper type 17 (autoimmunity)

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13
Q

What is the susceptibility associated with shared epitope in RA?

A

Does not necessarily predict progression to RA
- cohort with recent-onset undifferentiated (ACPA+) arthritis, progression to RA occured regardless of HLA-DR genotype

May predict RA severity

  • increased joint damage e.g. increased erosions (two copies)
  • increased prevalaence of extra-articular manifestations
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14
Q

What is microchimerism?

A
  • possible explanation SE not associated with RA in ceratin ethnic and racial groups
  • maternal cells of SE-expressing women persist in their children’s circulation throughout adulthood –> confers increased RA risk
  • termed non-inherited maternal antigens (NIMA)
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15
Q

What are non-HLA genetic risk factors for RA?

A

gene, odds ratio for RA, function

  • PTPN22, ~2 fold, encodes lymphoid tyrosine phosphatase; role in T and B cell signalling, no role in RA risk in asians
  • PADI4, ~2 fold, primarily asian populations
  • TRAF1-C5, b/w 1.2 and 2 fold: encodes TNF-associated factor and complement protein 5c
  • STAT4, b/w 1.2 and 2 fold: encodes a tf that controls genes involved in Th1 cell responses
  • TNFAIP3, b/w 1.2 and 2 fold: encodes TNF-induced protein 3
  • IL2/21, b/w 1.2 and 2 fold: –
  • CCR6, – , encodes chemokine-receptor 6
  • NLRP1, – , encodes inflammasome-related protein (only in Han Chinese)
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16
Q

What is epigenetics?

A
  • modification of a chromsome that leads to altered gene expression, without changing DNA (i.e. nucleotide base) sequences
  • may be heritable
17
Q

What are epigenetic mechanisms in RA?

A
  • histone deacetylase increased in RA
  • DNA methylation - fibroblast-like synoviocytes and T cells
  • microRNAs (miRNA)
18
Q

What are hormonal risk factors of RA?

A

oestrogen exposure

  • B cells (produce autoantibodies) more resistant to apoptosis
  • fibroblast-like synoviocytes (FLS) - increased metalloproteinases
  • macrophage cell line - increased TNF

pregnancy

  • 1st and 2nd trimester: >75% improve (huge progesterone and oestrogen surge)
  • 3rd trimerster: remission (lots of oestrogen circulating)
  • postpartum: 90% flare
19
Q

What is citrullination?

A
  • post-translational conversion of the amino acid arginine to citrulline by peptidyl-arginine deiminase (PADI) enzymes
    • intra- or extra-cellular
    • neoepitopes serve as targets for autoimmunity
    • citrulline binds shared epitope more avidly
    • immune tolerance breakdown –> ACPA

induction of PADI expression and peptide citrullination is not specific to the joint or RA and occurs in many different settings of tissue stress/inflammation

humans have four isoforms of PADI
- PADI2 and PADI4 abundant in inflamed synovium

=NH –> =O

20
Q

What are environmental risk factors of RA?

A
  • RA first described in 1800 (not demonstrated pre-19th century/industrial revolution) - “new world [environmental] pathogen or allergen”
  • smoking (PADI2) (monozygotic twins - 12 of 13 who smoked got it, involved in citrullination process)
  • bronchial stress
    • exposure to silica, traffic pollution (Nurses’ health study)
  • infections (or their products e.g. heat shock protein)
    • porphyromonas gingivalis (peridontal disease, PADI4)
  • epsetin-barr virus, cytomegalovirus, proteus species, excherichia coli
  • Toll-like receptor (TLR) activation
    • increased peptidyl-arginine delminase (PADI) expression
    • directly cause arthritis (e.g. streptococcus via TLR2)
  • Microbiome
    • Two (germ-free) mouse models of RA (K/BxN, IL-1Ra-deficient): bacteria induced arhtritis
    • dietary changes or antibiotics –> equilibrium protective and pathogenic intestinal bacteria altered –> induction innate immune system in genetically predisposed host
21
Q

What are clinical features of RA?

A
  • primary manifestation is synovial inflammation or ‘synovitis’
    • inflammatory pannus of cells
    • particularly fibroblasts and macrophages
    • progressive erosion and damage of articular and periarticular structures
22
Q

What are articular (joint) manifestations?

A

when presenting to physcian:

  • morning stiffness - ≥ 1 hour, ≥ 6 weeks
    • needs to be greater than 6 weeks because some viral diseases mimic rheumatoid
  • pain
  • swelling

distribution

i. symmetrical: i.e. involvement of one hand should be identical to the other side
ii. most commonly affected joints
- upper limbs
- - metacarpophalangeal (MCP)
- - proximal interphalangeal (PiP)
- - wrist
- lower limbs
- - metatarsophalangeal (MTP)

  • Boutonniere deformity
  • subluxed fingers
  • swan neck deformity
  • ulnar deviation
23
Q

What is the Boutonniere deformity?

A
  • flexion of the PiP joint

- extension of the DiP joint

24
Q

What happens with uncontrolled MCP swelling?

A
  • subluxed finger

- slip downwards because of inflammation

25
Q

What is the swan neck deformity?

A
  • exetended PiP

- flexed DiP

26
Q

How do we differentiate RA from Osteoarthritis (OA)?

A

RA vs OA

Age at onset
- childhood and adults, peak incidence in 50s
vs
- increases with age

Predisposing factors
- susceptibility epitopes (HLA-DR4, HLA-DR1), PTPN22, PADI4 polymorphisms, and others
- smoking
vs
- trauma
- congenital abnormalities (e.g. shallow acetabulum)

Early symptoms
- morning stiffness
vs
- pain increases through the day and with use

Joints involved
- metacarpophalangeal joints, wrsits, proximal interphalangeal joints most often; distal interphalangeal joints almost never
vs
- Distal interphalangeal joints (Herberden’s nodes)
- Weight bearing joints (hips, knees)

Physical findings
- soft tissue swelling, warmth
vs
- bony osteophytes, minimal soft tissue swelling early

Radiologic findings
- periarticular osteophenia, marginal erosions
vs
- subcondrial sclerosis, ostephytes

Laboratory findings
- increased C-reactive protein, rheumatoid factor, anticitrullinated protein antibody, anaemia, leukocytosis
vs
- normal

27
Q

What is a useful discriminator of RA vs OA?

A
  • distribution (pattern) of joint involvement

RA

  • very symmetrical
  • classic involvement of the wrists
  • PiP joint involvement
  • MCP
  • soft tissue swelling

OA

  • can affect the spine
  • can be symmetrical but frequently asymmetrical
  • DiP joint involvement
  • base of thumb
  • bony swelling
28
Q

What are extra-articular manifestions of RA?

A

RA can involve almost any organ system you can think of
With the advent of treatment most patients don’t suffer extra-articular manifestations anymore
marker of severity
shortens both quality and quantity of a patients life

Nodules

  • subcutaneous
  • pulmonary
  • cardiac
  • firm rubbery lumps

Pulmonary

  • pieuritis/pleural effusion
  • fribrosing alveolitis

Ocular

  • scleritis
  • episcleritis
  • keratoconjuctivitis sicca (KCS)
  • very bad if left untreated

Vasculitis

  • systemic
  • cutaneous
  • mononeuritis multiplex

Neurological

  • nerve entrapment
  • cervical myelopathy

Cardiovascular

  • ischaemic heart disease (IHD)
  • pericarditis/pericardial effusion
  • conduction defects
  • stroke

Cutaneous

  • palmar erythema
  • ulceration
  • pyoderma gangrenosum
  • neutrophillic dermatoses

Haematologic

  • anaemia
  • feity’s syndrome
  • amyloidosis

Malignancy

  • lymphoma/lymphoproliferative disease
  • large granular lymphocyte syndrome
  • lung cancer
  • skin cancer
29
Q

What antibodies are typically present in RA? Can these be used to diagnose RA?

A

Rheumatoid factor (RF)

  • high-affinity autoantibody against the Fc portion (epitopes) of immunoglobulin IgG
  • prior to RA onset: increase IgM or IgA isotype

Anti-citrullinated protein antibodies (ACPA)

  • antibodies against citrullinated ‘self-proteins’
  • detected via anti-cyclic citrullinated peptide (CCP) assay
    • alpha-enolase, keratin, fibrinogen, fibronectin, type II collagen, vimentin
  • prior to RA onset: increased titre, avidity, epitope spreading, isotype changes

Autoantibodies can develop years before the onset of RA symptoms

  • ACPA seen up to 14 years before
  • RF about 10.5 years before disease symptom onset
30
Q

What is sensitivity and specificity of testing?

A

Test positive:

  • if disease present: A, true positive, (sensitivity)
  • disease absent: B, false positive

Test negative

  • disease present: C, false negative
  • disease absent: D, true negative, specificity
sensitivity = A/(A+C) [SNNout]
specificity = D/(B+D) [SPPin]

positive likelihood ratio = sensitivity / (1 - specificity)
negative likelihood ratio = (1 - sensitivity)/specificity

31
Q

What is the diagnostic utility of autoantibodies in RA?

A

Sensitivity, % (95% CI)

  • IgM RF: 70 (66-73)
    • i.e. not 100% at picking up everyone who’s got the condition
  • ACPA: 67 (64-70)
    • still not 100%

Specificity, % (95% CI)

  • IgM RF: 79 (74-83)
    • a lot of other conditions that can give you a falsely elevated RF without getting RA
  • ACPA: 95 (94-96)
    • specificity, not a lot of diseases outside of RA that will causes presence of ACPA

Positive likelihood ratio (95% CI)

  • IgM RF: 3.3 (2.7-3.9)
  • ACPA: 14.5 (11.6-18.0)

Negative likelihood ratio

  • IgM RF: 0.39 (0.35 - 0.42)
  • ACPA: 0.35 (0.32-0.38)
32
Q

When testing for antibodies, what are two subsets of RA? What is this a predictor of?

A

i. seropositive
- RF or ACPA positive

ii. seronegative
- RF or ACPA negative

  • prognositic information: seropositivity is a predictor of:
  • radiographic progression
  • extra-articular manifestations
  • functional impairment
33
Q

How is RA disease activity assessed?

A

Joint counts *
- tender and/or swollen

Global assessment *
- physician and patient

Pain score *
- visual analogue score

Morning stiffness *
- >60 minutes

Laboratory *

  • erythrocyte sendimentation rate (ESR)
  • C-reactive protein (CRP)

Disability

Fatigue

Radiological damage *

  • erosive changes on serial radiographs
  • on average x-rays every 1 - 2 years
  • is it getting worse?
  • if so escalate treatment
34
Q

What is teh DAS28-ESR calculator?

A
  • tender joint count
  • swollen joint count
  • marker of inflammation: ESA, CRP
  • patient global health
35
Q

What are DAS28 cutoff criteria?

A

Disease activity in 28 joints using C-reactive protein (CRP) or Erythrocyte sedimentation rate (ESR) - DAS28-CRP, or DAS28-ESR

  • DAS28 < 2.6: remission
  • DAS28 ≥ 2.6 and ≤ 3.2: low disease activity
  • DAS28 > 3.2 and ≤ 5.1: moderate disease activity
  • DAS28 > 5.1: high disease activity

objective way of monitoring/scoring patients progress/control
remission is goal for all patients with RA

even with clinical remission: subclinical inflammation remains possible (imaging studies)

36
Q

Take home messages of RA?

A
  • autoantibodies utility
    • diagnostic, classify, prognositc
  • assessing disease activity
    • composite indices (DAS28-CRP/-ESR)
  • differentiating OA from RA
    • distribution (pattern) of joint involvement
  • arthritis: not a single entity, burden of disease