Rheumatoid arthritis

Question 1

Define rheumatoid arthritis

Answer 1

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

Spinal joints are synovial so the spine isn’t affected

Question 2

What are the key features of rheumatoid arthritis?

Answer 2

• Chronic arthritis
  1) Polyarthritis - swelling of the small joints of the hand and wrists is common
  2) Symmetrical
  3) Early morning stiffness in and around joints
  4) May lead to joint damage and destruction - ‘joint erosions’ on radiographs
• Extra-articular disease can occur
  1) Rheumatoid nodules
  2) Others rare e.g. vasculitis, episcleritis
• Rheumatoid ‘factor’ may be detected in blood
  1) IgM autoantibody against IgG - should really call this rheumatoid ‘antibody’ not ‘factor’

Question 3

Describe the genetic component of rheumatoid arthritis

Answer 3

• 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’

Question 4

What are the commonest affected joints?

Answer 4

• Metacarpophalangeal joints (MCP)
• Proximal interphalangeal joints (PIP)
• Wrists
• Knees
• Ankles
• Metatarsophalangeal joints (MTP)

Question 5

Where is the primary site of pathology in rheumatoid arthritis?

Answer 5

Synovium

• Synovial joints
• Tenosynovium surrounding tendons
• Bursa

Question 6

What are sub-cutaneous nodules in rheumatoid arthritis?

Answer 6

• Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
• Occur in ~30% of patients
• Associated with:
  1) Severe disease
  2) Extra-articular manifestations
  3) Rheumatoid factor

Question 7

What is rheumatoid factor?

Answer 7

• Antibodies that recognize the Fc portion of IgG as their target antigen
• Typically IgM antibodies i.e. IgM anti-IgG antibody !

See slides

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

Question 8

What antibodies are highly specific to RA?

Answer 8

Antibodies to citrullinated peptides - Anti-cyclic citrullinated peptide antibodies.

Citrullination of peptides is mediated by enzymes termed:
Peptidyl arginine deiminases (PADs)

Arginine –> Citrulline

Question 9

Why do antibodies to citrullinated protein antigens develop in RA?

Answer 9

PADs are present in high concentrations in neutrophils and monocytes and consequently there is increased citrullination of autologous peptides in the inflammed synovium
ACPA is strongly associated with smoking and HLA ‘shared epitope’
The shared epitope [amino acids 70-74 of the HLA-DRb-chains associated with rheumatoid arthritis] preferentially binds non-polar amino acids like citrulline but not positively charged amino acids like arginine – so ACPA more likely to develop among individuals with citrulinated autoantigens who have the shared eptiope
Smoking – increases ACPA-positive rheumatoid arthritis risk. ? Smoking enhances citrullination in lungs….

Don’t really need to know.

Question 10

HLA molecules in RA?

Answer 10

Slide 13 - don’t really need to know. Just think immune complexes

Question 11

What are some common extra-articular features of RA?

Answer 11

• Fever, weight loss

- Subcutaneous nodules

Question 12

What are some uncommon extra-articular features of RA?

Answer 12

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

Question 13

Describe the early, later and later still radiographic abnormalities that may be seen in RA?

Answer 13

Early
- Juxta-articular osteopenia

Later
- Joint erosions at margins of the joint

Later still
- Joint deformity and destruction

Question 14

Describe the pathogenesis of RA?

Answer 14

Synovial membrane is abnormal in rheumatoid arthritis:
The synovium becomes a proliferated mass of tissue (pannus) due to:
 - neovascularisation
 - lymphangiogenesis
 - inflammatory cells:
activated B and T cells
plasma cells
mast cells
activated macrophages

Recruitment, activation and effector functions of these cells is controlled by a cytokine network
there is an excess of pro-inflammatory vs. anti-inflammatory cytokines (‘cytokine imbalance’)

Question 15

What is the dominant pro-inflammatory cytokine in rheumatoid synovium?

Answer 15

TNF-alpha - its detrimental role in RA is validated by TNF-alpha inhibition. This was done via paraenteral administration of antibodies or fusion proteins.

Question 16

What are some other biological therapies to treat RA?

Answer 16

IL-6 + 1 - cytokine blockade
We can also deplete B cells in rheumatoid arthritis by parenteral (intravenous) administration of an antibody against a B cell surface antigen, CD20

Question 17

What is the management of RA?

Answer 17

Treatment is prevent joint damage

1) Multidisciplinary approach: physiotherapy, occupational therapy, hydrotherapy, surgery

2) Medication
- DMARDs - ‘steroid sparing’. Disease modifying
- Glucocorticoid therapy (avoid long term use)
- Biological therapies

You don’t really need to know the details.

Question 18

Describe DMARD therapy?

Answer 18

Drugs that may indice remission (not cure) and prevent joint damage. This is achieved by reducing the amount of inflammation in the synovium. It also slows or prevents structural joint damage e.g bone erosions.

Question 19

Give some examples of DMARDs

Answer 19

1) methotrexate – commonly used
2) sulphasalazine – commonly used
3) hydroxychloroquine – commonly used
4) leflunomide – uncommon
5) Janus Kinase inhibitors

all have significant adverse effects and therefore require regular blood test monitoring during therapy

Question 20

What are the different biological therapies?

Answer 20

Inhibition of tumour necrosis factor-alpha (‘anti-TNF’)

• antibodies (infliximab, and others)
• fusion proteins (etanercept)

B cell depletion
- Rituximab – antibody against the B cell antigen, CD20

Modulation of T cell co-stimulation
- Abatacept - fusion protein - extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to modified Fc (hinge, CH2, and CH3 domains) of human immunoglobulin G1

Inhibition of interleukin-6

• Tocilizumab (RoActemra) – antibody against interleukin-6 receptor. November 2012 NICE appraisal TA247
• Sarilumab (Kevzara) – antibody against interleukin-6 receptor. November 2017 NICE appraisal TA485

Question 21

What are the downsides of biological therapy?

Answer 21

TNFα inhibition is associated with increased 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

B cell depletion therapy can be associated with hepatitis B reactivation so need to screen all patients for hepatitis B before treatment

B cell depletion therapy can be associated with JC virus infection and progressive multifocal leukoencephalopathy (PML) - rare