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

Question 2

What are the features of chronic arthritis?

Answer 2

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

Question 3

What are the features of extra-articular disease?

Answer 3

Rheumatoid nodules and other rarer features like vasculitis and episcleritis

Question 4

What is the rheumatoid factor that can be detected in blood?

Answer 4

Rheumatoid ‘factor’ may be detected in blood IgM autoantibody against IgG - should really call this rheumatoid ‘antibody’ not ‘factor’

Question 5

What percentage of the population has rheumatoid arthritis?

Answer 5

1% it is a common cause of significant disability in young adults

Question 6

What is the gender ratio?

Answer 6

F:M=3:1

Question 7

Describe the genetic component of rheumatoid arthritis in twins and family

Answer 7

disease concordance rates for twins are 15-30% (monozytic) and 5% (dizygotic). Heritability estimates 60%

Question 8

What are the specific genes involved with rheumatoid arthritis?

Answer 8

Specific HLA-DRB genes variants mapping to amino acids 70-74 of the BRbeta-chains are strongly associated with rheumatoid arthritis. Ther region encodes conserved amino acid sequence in the HLA-DR antigen-binding groovewhich is common to rheumatoid arthritis-associated DR alleles – termed ‘shared epitope’

Question 9

Describe the environmental component of rheumatoid arthritis

Answer 9

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

Question 10

What are the most comments effected joints in RA?

Answer 10

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

Question 11

What the significance of callous formation under metatarsals?

Answer 11

Callous formation under heads of metatarsals due to joint deformity

Question 12

what are some of the features of joint deformity and destruction

Answer 12

Swan neck deformity Boutonniere deformity

Question 13

What is meant by symmetrical polyarthritis?

Answer 13

Damage and destruction tends to occur symmetrically. E.g. symmetrical involvement of the metacarpo-phalangeal joints and the bilateral ulnar deviation of the fingers

Question 14

What is meant by swan-neck deformity?

Answer 14

there is hyper-extension at the PIP (proximal interphalangeal) joint and hyperflexion and the DIP (distal interphalangeal) joint

Question 15

What is meant by a Boutonniere deformity?

Answer 15

There is hyperflexion at the PIP joint

Question 16

What is the primary site of pathology for RA?

Answer 16

synovium

Question 17

What are some examples of synovium?

Answer 17

• Synovial joints (proximal inter-phalangeal joints)
• Tenosynovium surrounding tendons
• Bursa

Question 18

What is proximal inter-phalangeal joint synovitis?

Answer 18

Question 19

What is extensor tenosynovitis?

Answer 19

Question 20

What are subcutaneous nodules?

Answer 20

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

Question 21

What are sub-cutaneous nodules associated with?

Answer 21

• Severe disease
• Extra-articular manifestations
• Rheumatoid factor

Question 22

Where are subcutanous nodules normally located?

Answer 22

• In the hands- e.g. around the PIP joint
• Rheumatoid nodule- e.g in the ulnar

Question 23

What are rheumatoid factors?

Answer 23

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

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

Question 24

What are antibodies to citrullinated protein antigens?

Answer 24

Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis.

Question 25

What are some of the common extra-articular features?

Answer 25

**Common** * Fever, weight loss * Subcutaneous nodules

Question 26

What are some uncommon extra-articular features?

Answer 26

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

Question 27

What does the synovitis cause?

Answer 27

Bone erosion, pannus (abnormal layer of fibrovascular tissue) and cartilage degradation (joint space narrowing)

Question 28

What can be found inside the synovial joint?

Answer 28

1. Synovium 2. Synovial fluid 3. Articular cartilage

Question 29

What is in the synovium?

Answer 29

it is 1-3 cells thin It contains type-A synoviocyte (phagocytic), type-B synoviocytes (producing hyaluronic acid) and Type 1 collagen

Question 30

What is in synovial fluid?

Answer 30

Hyaluronic acid

Question 31

What is in articular cartilage?

Answer 31

Type 2 collagen Proteoglycan- mainly aggrecan

Question 32

Describe the synovial membrane in rheumatoid arthritis

Answer 32

Synovium beocmes proliferated mass of tissue (pannus) due to: * Neovascularisation * Lymphangiogenesis * inflammatory cells- B/T cells, plasma cells, mast cells and activated macrophages

Question 33

Why are there so many inflammatory cells in RA?

Answer 33

Due to excess pro-inflammatory cytokine imbalance Mainly due to actions of TNF-alpha Therapy for rheumatoid arthritis can be inhibited by antibodies and fusion proteins.

Question 34

What is TNF-alpha?

Answer 34

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

Question 35

What is TNF alpha inhibition?

Answer 35

TNFα in rheumatoid arthritis validated by the therapeutic success of TNFα inhibition in this condition. TNFα inhibition is achieved through parenteral administration (most commonly sub-cutaneous injection) of antibodies or fusion proteins

Question 36

Describe other biological therapy apart form TNF-alpha blockade

Answer 36

Il-6 and IL-1 can also be blockaded 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

Question 37

What is the management of RA? Describe the three therapies

Answer 37

Multidisciplinary approach – physio, occupational therapy, hydrotherapy, surgery. Medication including: * Drugs – DMARDs – Disease-Modifying Anti-Rheumatic Drugs. Started early in the disease – **joint destruction = inflammation x time**. DMARDs (“steroid-sparing agents”) are safer and more effective in the long term than steroids since they avoid the long-term side-effects of steroids. * Biological therapy. * Glucocorticoid therapy – e.g. prednisolone. · Avoid long-term use due to side effects but useful in the short term for symtpom relief.

Question 38

What are DMARDs?

Answer 38

They are disease-modifying anti-rheumatic drugs. Drugs that induce remission and prevent joint damage- they do not cure. They do this by reducing inflammation in synovium and slowing/ preventing structural joint damage. It has a slow onset

Question 39

Give some examples of DMARDs?

Answer 39

* Methotrexate * Sulphasalazine * Hydrochloroquine Leflunomide, gold and penicillamine (are rarely used) Everything has signifcant side effects so bloods need to be monitored.

Question 40

What are the Rituximab and Infliximab management techniques for RA?

Answer 40

Rituximab & Infliximab are chimeric antibodies with Fab mouse regions and human constant regions. **Adalimumab & Golimumab are full human antibodies.** TNFR-Fc is a fusion protein example of TNF-a. --\>Etanercept.

Question 41

What are the side effects/ cons of biological treatment?

Answer 41

These treatments (including the ones above) are very expensive and limited by NICE. o Biological therapy involves all the antibody treatments. o Methotrexate (not biological therapy) is used first and then if this is ineffective, biological therapy is used. **Side effects** from biological therapy include an increased infection risk chance. o TNF-a inhibition =increased susceptibility to mycobacterial infections (screen patients for TB). o B-cell depletion=(can) to hepatitis B reactivation (so screen patients for Hep B). o B-cell depletion =(can) to JC virus infection and progressive multifocal leukoencephalopathy (PML).