Musculoskeletal 5 - Rheumatoid Arthritis

Question 1

What is rheumatoid arthritis?

Answer 1

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

Question 2

List the key features of rheumatoid arthritis

Answer 2

Chronic arthritis

• Polyarthritis - swelling of the small joints of the hand and wrists is common, affects 5 or more joints
• Symmetrical
• Early morning stiffness in and around joints (lasting several hours)
• May lead to joint damage and destruction - ‘joint erosions’ on radiographs

Extra-articular disease can occur

• Rheumatoid nodules
• Others rare e.g. vasculitis, episcleritis
• Rheumatoid ‘factor’ may be detected in blood (IgM autoantibody against IgG)

Question 3

Describe epidemiology of rheumatoid arthritis

Answer 3

• 1% population affected
• F:M 3:1
• Heritability estimates of 60%
• Smoking contributes 25% of population attributable risk
• HLA-DRB gene variants associated with rheumatoid arthritis (shared epitope - common amino acid sequence)

Question 4

List the most commonly affected joints in rheumatoid arthritis

Answer 4

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

Question 5

List features of rheumatoid arthritis in the hand

Answer 5

• Callus formation under heads of metatarsals
• Swan neck deformity (hyperextension of PIP and hyper-flexion of DIP)
• Boutonniere deformity (affecting the little finger, fixed flexion at the PIP)
• Ulnar deviation of the fingers
• Commonly synovium is affected causing proximal inter-phalangeal joint synovitis, extensory tenosynovitis and olecranon bursitis
• Damage to extensor tendons so unable to extend fingers

Question 6

What are subcutaneous nodules?

Answer 6

• Central area of fibrinoid necrosis surrounded by histiocytes and peripheral layer of connective tissue
• Occurs in 30% of patients
• Associated with severe disease, extra-articular manifestations and 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
• Forms aggregates of antibodies which generate immune response
• Positive in 70% at disease onset, and 10-15% become positive over the first 2 years of diagnosis

Question 8

List the antibodies that develop in rheumatoid arthritis

Answer 8

• Rheumatoid factor
• Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis
• Anti-cyclic citrullinated peptide antibody ‘anti-CCP antibody’
• Citrullination of peptides is mediated by enzymes termed: Peptidyl arginine deiminases (PADs)
• Smoking triggers citrullination of proteins

Question 9

Describe the relationship between HLA molecules and rheumatology

Answer 9

• Individual susceptible since they carry conserved amino acid sequence in their HLA-DR antigen-binding groove (‘shared epitope’)
• Shared sequence in amino acids 70-74 of the HLA-DRβ chain (class II)
• 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
• This shared epitope preferentially binds non-polar amino acids such as citrulline and citrulline-containing peptide antigens increased during inflammation
• Inflammation and citrullination in rheumatoid arthritis – smoking, changes in microbiota, chronic infections (gingivitis)

Question 10

List examples of extra-articular features of rheumatoid arthritis

Answer 10

Common
- Fever, weight loss
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

Question 11

List the radiographic abnormalities in rheumatoid arthritis

Answer 11

• Early juxta-articular osteopenia (thinning of the bone - bone looks darker around the joint)
• Later joint erosions at margins of the joint
• Later still joint deformity and destruction

Question 12

Describe the pathology of rheumatoid arthritis

Answer 12

• Abnormal synovial membrane (hypertropied)
• Becomes a proliferated mass of tissue (pannus) due to neovascularisation, lymphangiogenesis, inflammatory cells
• Activated B and T cells, plasma cells, mast cells, activated macrophages
• Cytokine tumour necrosis factor-alpha (TNF-a) dominant pro-inflammatory cytokine

Question 13

Describe the healthy synovial membrane

Answer 13

• 1 to 3 cell layer that lines synovial joints
• Contains macrophage-like (type A synoviocyte) and fibroblast-like (type B synoviocyte) cells and type II collagen in the articular cartilage
• Functions include the maintenance of synovial fluid, the hyaluronate-rich viscous fluid within joint space

Question 14

Describe biological therapy of rheumatoid arthritis

Answer 14

• Many other cytokines under investigation but interleukin-6 and interleukin-1 blockade now available in clinic
• In addition to 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
• TNF-alpha inhibition given via parenteral agministration, highly effective (antibodies or fusion proteins)

Question 15

Describe management of rheumatoid arthritis

Answer 15

• Treatment goal is to prevent joint damage
• Multidisciplinary approach e.g. physiotherapy, occupational therapy, hydrotherapy, surgery
• Medication includes:
  drugs that control the disease process are termed disease- modifying anti-rheumatic drugs - ‘DMARDs’
• Glucocorticoid therapy (‘steroids’, ‘prednisolone’) - avoid long-term use because of side-effects. Useful as short-term treatment options in many settings e.g. to control flare of disease or control inflammation of single joint
• Biological therapies offer potent and targeted treatment strategies

Question 16

List the new therapies for rheumatoid arthritis

Answer 16

Janus Kinase inhibitors

• Tofacitinib (Xeljanz)
• Baricitinib (Olumiant)

Question 17

List qualities of disease modifying anti-rheumatic drugs

Answer 17

• Started early in the disease because joint destruction = inflammation x time
• DMARDs offer safer and more effective long-term treatment than ‘steroids’ so DMARDs are often referred to as ‘steroid-sparing agents’ since they enable us to avoid long-term steroid use
• Drugs that may induce remission and prevent joint damage by reducing the amount of inflammation in the synovium, slow or prevent structural joint damage (eg. bone erosions)
• However not a treatment

Question 18

List examples of DMARD therapy drugs

Answer 18

• Methotrexate (first line)
• Sulphasalazine
• Hydroxychloroquine
• Lefunomide
• Janus Kinase inhibitors

Question 19

Why is blood test monitoring required during DMARD therapy?

Answer 19

As the drugs used have significant adverse effects (eg. methotrexate and renal function)

Question 20

List the downsides of biological therapy

Answer 20

• All are expensive treatments
• Side effects include increased infection risk
• TNFα inhibition is associated with increased susceptibility to mycobacterial infection e.g. previously latent 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

Question 21

Describe the synovial membrane in rheumatoid arthritis

Answer 21

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

Question 22

What controls the inflammatory effects on the synovial membrane in rheumatoid arthritis?

Answer 22

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

Question 23

List the drugs used in biological therapy of rheumatoid arthritis

Answer 23

• Tumour necrosis factor inhibition includes antibodies (infliximab) and fusion proteins (etanercept)
• B cell depletion (rituximab against CD20)
• Modulation of T cell co-stimulation (abatacept fusion protein)
• Inhibition of interleukin-6 (tocilizumab and sarilumab)