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Musc > Rheumoid arthritis > Flashcards

Rheumoid arthritis Flashcards

1
Q

Define rehumatoid arthritis

A

Chronic autoimmune disease characterised by pain, stiffness and symmetrical synovitis (inflammation of the synovial membrane) of synovial (diarthrodial) joints

THE SYNOVIUM IS THE SYNOVIAL MEMBRANE
SYNOVITIS IS INFLAMMATION OF THE SYNOVIAL MEMBRANE

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2
Q

T/f rheumatoid arthritis can result in problems with the lumbar spine

A

F… there is no synovium here… the only axial synovial joint is the atlanto-axial joint, the pivot joint for yes and no (but mostly peripheral joints)

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3
Q

Outline chronic arthristis assocciated with rheumatoid arthritis

A

CHRONIC arthritis:

Polyarthritis - swelling of the small joints of the hand and wrists is common

Symmetrical

Early morning stiffness in and around joints

May lead to joint damage and destruction - ‘joint erosions’ on radiographs

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4
Q

What disease outside of joints could be seen in RA

A

Rheumatoid nodules
Others rare e.g. vasculitis, episcleritis

(watch osmosis)

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5
Q

What kind of antibodies does rheumatoid factor involve?

A

IgM autoantibody against IgG

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6
Q

What is the genetic component of RA

A

Disease concordance rates for twins are 15-30% (monzygotic) and 5% (dizygotic) and heritability estimates of up to 60%

Specific HLA-DRB gene variants mapping to amino acids 70-74 of the DRb-chains are strongly associated with rheumatoid arthritis

Region encodes conserved amino acid sequence in the HLA-DR antigen-binding groove which is common to rheumatoid arthritis-associated DR alleles – termed ‘shared epitope’

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7
Q

What is the important environmental component associated with RA

A

Smoking – contributes 25% of population-attributable risk and interacts with shared epitope to increase risk

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8
Q

What are the most commonly affected joints in RA

A 
Metacarpophalangeal joints (MCP)
Proximal interphalangeal joints (PIP)
Wrists 
Knees
Ankles
Metatarsophalangeal joints (MTP)
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9
Q

Examples of the joint damage and destruction present in RA

A

Swan-neck deformity affecting the ring finger – there is hyper-extension at the PIP joint and hyper-flexion at the DIP joint

Boutonnière (‘button-like’) deformity affecting little finger – there is hyper-flexion at the PIP joint

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10
Q

What is the primary site of damage in RA

A

Synovium

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11
Q

What structures does the synovium include (so are involved in RA)

A

The synovial joint

The tenosynovium (surrounding tendons)

The bursa

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12
Q

Outline disease relating to the synovial joint in RA

A

e.g. proximal inter-phalangeal joint synovitis

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13
Q

Outline disease relating to the tenosynovium in RA

A

Extensor tenosynovitis – note swelling is not above either the wrist or MCP joints

(incomplete extension of little and ring finger)

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14
Q

Outline disease relating to the bursa in RA

A

Olecranon bursitis

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15
Q

What is rheumatoid factor

A

IgM antibodies (pentameric) binding to Fc portion of IgG

So IgM anti-IgG antibody

Positive in 70% at disease onset and further 10-15% become positive over the first 2 years of diagnosis

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16
Q

Aside from Rheumatoid factor, which other auto antibody is presnet in RA

A

Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis

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17
Q

How are proteins citrullinated

A

By peptidyl arginine deiminases (PADs)

Convert arginine –> citrulline

This process is enhanced by smoking in the lungs

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18
Q

Why do ACPAs develop in rheumatoid arthritis

A

Inflamed synovium means lots of neutrophils and monocytes. These have high levels of PADs

More citrulliation

Shared epitope of HLA-DRb chain (found in some HLA-DR4 and also other HLA types) preferentially binds non-polar AAs (such as citrulline, but the original arginine is polar, so this wouldn’t be presented) and presents them

Anti citrullinated protein antibodies (ACPA) more likely to develop because of increased presentation of the antigen

Smoking – increases ACPA-positive rheumatoid arthritis risk. ? Smoking enhances citrullination in lungs

19
Q

T/f all patient swith the HLA-DR4 show the ‘shared epitope’, but no other HLA type does

A

F…

shared epitope= shared sequence in amino acids 70-74 of the HLA-DRβ chain

this is why multiple different HLA serotypes were associated with disease (HLA-DR4, -DR1, -DR6, DR10) – all contained the shared epitope and some individuals with HLA-DR4 not at risk – these HLA-DR4 did not contain shared epitope

20
Q

What might cause inflammation and citrullination in RA

A

smoking, changes in microbiota, chronic infections (gingivitis)

might increase citrullination which might then increase shared epitope binding and thus presentation

21
Q

Outline common adn uncommon extra-articular features in RA

A

Common:
Fever, weight loss, FATIGUE (due to cytokines)
Subcutaneous nodules

Uncommon:
vasculitis
Ocular inflammation e.g. episcleritis
Neuropathies
Amyloidosis
Lung disease – nodules, fibrosis, pleuritis
Felty’s syndrome – triad of splenomegaly, leukopenia and rheumatoid arthritis

22
Q

Outlien the radiographic abnormalities seen in RA

A

Radiographic abnormalities

Early
Juxta-articular osteopenia (reduced bone density near joints)

Later
Joint erosions at margins of the joint

Later still
Joint deformity and destruction

23
Q

Outline the pathology seen within the joint in RA (diagram)

A

Bone erosion, pannus, cartilage degradation (joint space narrowing), synovitis

24
Q

Outline the synovium component of a synovial joint

A

SYNOVIUM= SYNOVIAL MEMBRANE NOT SYNOVIAL FLUID

1-3 cell deep lining containing macrophage-like phagocytic cells (type A synoviocyte)
and fibroblast-like cells that produce hyaluronic acid (type B synoviocyte)

Type I collagen

NB: the synovium has type I and the articular cartilate has type II collagen

25
Q

Outline the synovial fluid component of a synovial joint

A

Hyaluronic acid-rich viscous fluid

26
Q

Outline the articular cartilage component of an articular cartilage

A

Type II collagen

Proteoglycan (aggrecan)

27
Q

What is a pannus and why does it form

A

Pannus = The synovium becomes a proliferated mass of tissue in RA

Because:

  1. Neovascularitsation
    2, Lymphangiogenesis
  2. Inflammatory cells (activated T/B cell, plasma cells, mast cells and activated macrophages)

These things are all controlled by cytokines, and there is:

Excess of pro-inflammatory vs anti-inflammatory cytokines (cytokine imbalance) in RA.

28
Q

What is the function of the synovial membrane

A

Functions include the maintenance of synovial fluid, the hyaluronate-rich viscous fluid within joint space

29
Q

What is the cause of the extra-articular symptoms in reumatoid arthritis

A

Mostly due to rheumatoid factor (immune complexes)

30
Q

Why might rheumatoid patients experience malaise or fatigue

A

Due to the cytokines

31
Q

What is an importnat epidemiologyical point in rheumatoid arthritis

A

Afects women to men 3:1… quite common cause of disability in young girls

32
Q

In addition to damage to synvovium, tenosynvoium and the bursa, subcutaneous nodules are also formed (extra-articular disease). What are the sub-cutaneous nodules made of

A

Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue

33
Q

What are the subcutaenous nodules associated with and where are they commonly located (important)

A

ASSOCIATED WITH RHEUMATOID FACTOR, and severe disease

In the ulnar border of the forearm
Hands (PIP)

34
Q

What is the pathogenesis of RA

A

The cytokine tumour necrosis factor-alpha (TNFα) is the dominant pro-inflammatory cytokine in the rheumatoid synovium and its pleotropic actions are detrimental in this setting:

  1. Panus formation (cytokine imbalance involves increased TNFa/IL1 and cause all of neovasc, lymphagio and lymphocyte recruitment)
  2. Osteoclasts stimulates for bone resorption and thus erosion (and the osteopaenia seen in radiographs)
  3. Chondrocytes stimulated to produce MMP (matrix metalloproteinase) causing cartilage degradation. Joint space narrowing

TNFa also causes leukocyte accumulation, endothelial activation, PGE2 production etc.

35
Q

Which cytokines can be blocked in clinical practice

A

TNF-a, IL6 and IL1 (IL1 less effective than IL6/TNFa so not used with NICE))

36
Q

Types of biological therapy

A
  1. Inhibit TNF-a (Ab e.g. infliximab or fusion protein e.g. etanercept)
  2. B cell depletion (rituximab)
  3. Modulation of T cell costimulation (abracept- fusion protein)
  4. Inhibit IL-6 (tocilizumab/sarilumab both ABs against IL6 RECEPTOR)

The difference between rituximab and belimumab is that rituximab sticks to all the CD20 it can find and the immune system then kills the beta cells. Whereas belimumab there is inhibition of the BLyS (b lymphocyte stimulating factor)

37
Q

Why can TNF-a inhibition work

A

Dominant detrimental role of TNFα in rheumatoid arthritis validated by the therapeutic success of TNFα inhibition in this condition

38
Q

How is TNF-a inhibitor administered

A

TNFα inhibition is achieved through parenteral administration (most commonly sub-cutaneous injection) of antibodies or fusion proteins

39
Q

Approach to management for RA

A

Multidisciplinary: physiotherapy, occupational therapy, hydrotherapy, surgery

DMARDs (basically biological therapies especially the TNF-a inhibitor) which are STEROID SPARING

GCs used to control flare of disease or control inflammation of single joint

Biological therapies offer potent and targeted treatment strategies

40
Q

How do DMARDs work?

A

drugs that may induce remission (not cure) and prevent joint damage

achieve this by:
reducing the amount of inflammation in the synovium
slow or prevent structural joint damage e.g. bone erosions

41
Q

What type of antibodies are ritruximab and infliximab?

A
  • mumab is full hoan antibody
  • imab is chimeric (human/mouse… the Fab part is mouse sequence)

Infliximab and rituximab are chimeric (human/mouse) antibodies

42
Q

Downside with biological therapy

A

Side-effects for all include increased infection risk

43
Q

What is associated with TNF-a inhibition

A

susceptibility to mycobacterial infection

e.g. tuberculosis so need to screen all patients for tuberculosis before starting treatment and may use prophylactic antibiotics in those at high risk

44
Q

What is associated with b cell depletion

A

hepatitis B reactivation so need to screen all patients for hepatitis B before treatment

JC virus infection and progressive multifocal leukoencephalopathy (PML) - rare

Musc (12 decks)

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