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)
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
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
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
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
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
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
8
Q
What are risk factors for RA?
A
- multifactorial
i. genetic
ii. epigenetic
iii. hormonal
iv. stochastic (random) environmental triggers
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
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
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)
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)
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
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)
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)
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
What is the swan neck deformity?
- exetended PiP
| - flexed DiP
26
How do we differentiate RA from Osteoarthritis (OA)?
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
What is a useful discriminator of RA vs OA?
- 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
What are extra-articular manifestions of RA?
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
What antibodies are typically present in RA? Can these be used to diagnose RA?
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
What is sensitivity and specificity of testing?
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
What is the diagnostic utility of autoantibodies in RA?
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
When testing for antibodies, what are two subsets of RA? What is this a predictor of?
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
How is RA disease activity assessed?
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
What is teh DAS28-ESR calculator?
- tender joint count
- swollen joint count
- marker of inflammation: ESA, CRP
- patient global health
35
What are DAS28 cutoff criteria?
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
Take home messages of RA?
- 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
