Lecture 8: Rheumatoid arthritis

Question 1

Describe RA

Answer 1

Chronic, progressive, systemic autoimmune disease
- causes inflammation in the joints (especially in hands, wrists and feet) that often present symmetrically
- primarily located in the lining of the joint

Question 2

True or false: RA and OA are both located in joints, are chronic and progressive with no cure?

Answer 2

True

Question 3

What is the difference in the initial location of joint damage in OA and RA?

Answer 3

OA = cartilage (erosion of the articular cartilage)
RA = inflammation of the synovial membrane (eventually extends to damage to cartilage and bone erosion) –> as RA progresses the damage to cartilage results in OA

Question 4

How do pro-inflammatory cytokines IL-1 and TNF-alpha affect the endothelium?

Answer 4

exposure of endothelium to Il-! or TNF-alpha alters the phenotype of the endothelial cells where they express more adhesins (selectins and integrins) that promote attachment of leukocytes to the endothelium

Question 5

What are the symptoms of RA?

Answer 5

No obvious distinctive feature that is diagnostic in the early stages but people start to experience:
- simultaneous symmetrical joint swelling (often slow progression but can be rapid) - difficulty using their hands
- morning joint stiffness that alleviates as they move around
- elevated temperature, unplanned weight loss, fatigue, skin nodules

–> all associated with other conditions - taken together they indicate RA but diagnosis can be challenging

Question 6

How is RA diagnosed?

Answer 6

• initially diagnosed based on symptoms

biochemical test: Rheumatoid factor (RF) positive in about 80% of RA sufferers

X-ray - later stages show joint erosion

Question 7

What is rheumatoid factor and how can it be used in the diagnosis of RA?

Answer 7

RF is a group of autoantibodies to the Fc portion of the IgG (test for the presence of autoantibodies)
- majority of people with RA are positive for RF but can also be found in unaffected people and people with other unrelated autoimmune conditions

Question 8

True or false: RF levels are correlated with disease severity?

Answer 8

True

Question 9

Why is it difficult to diagnose early stages using RF?

Answer 9

levels correlate with disease severity so may be relatively low in early stages where disease is less severe

Question 10

What are the predominant joint affected in the hands in RA?

Answer 10

PIPs (proximal interphalangeal joint)
DIPs (distal interphalangeal joint)

Question 11

How does RA progress?

Answer 11

Synoviocytes lining the synovial membrane become hypertrophic and hyperplastic resulting in growths that extend into the synovial space
- angiogenesis supplies synoviocytes with pro-inflammatory mediators = promotes process
- infiltration of synovial space/fluid with immune cells (B and T-lymphocytes, neutrophils)
- aggressive growth of synoviocytes creating mass of tissue inside the joint results in degradation of cartilage, menisci and bone

Question 12

What are synoviocytes?

Answer 12

fibroblast-like cells that line the synovial membrane

Question 13

How can RA affect peoples quality of life?

Answer 13

pain with movement
- results in sedentary lifestyle - elevated co-morbidity incidence - cardiovascular complications for example

Question 14

How does RA cause bone destruction?

Answer 14

Osteoclasts and osteoblasts involved in bone remodelling
- in RA, reduction in osteoblast or activation in osteoclast
–> increase in cytokines that can activate osteoclasts and proteases (MMPs and aggrecanase) contribute to bone erosion by collagen degradation

Question 15

True or false: OA can be caused by RA?

Answer 15

True (RA eventually damages cartilage resulting in OA and may need joint replacement)

Question 16

How can bone erosion affect the joint?

Answer 16

destabilises the joint - not repairable and joint replacement only option for severe erosion

Question 17

Describe the prevalence of RA

Answer 17

• not as common as OA
• gender bias (2-3 times more common in women)
• lower prevalence in some ethnic groups (African American, Chinese, Japanese)
• condition associated with older population (onset commonly between 40-60 years old)

Question 18

True or false: RA and OA can both affect young people?

Answer 18

True but more commonly seen in the older population

Question 19

How does the timescale for the development of RA differ to that of OA?

Answer 19

RA normally develops over several months but can develop over a few weeks and some cases can develop in less than a week

Differs to OA, which is known to often take several years to develop

Question 20

What is the aetiology of RA? Include modifiable and non-modifiable risk factors of RA?

Answer 20

No known cause of RA (like OA)

However a number of factors can increase risk of developing RA:
Non-modifiable risk factors:
- Age
- genetic factor (but needs to have an environmental trigger - pathogen, environmental toxins, diet, drugs)

Modifiable risk factors:
- BMI (adipocytes promote pro-inflammatory response systemically = more adipocytes = more background inflammation)
- smoking (bigger risk factor for males than females)

Question 21

True or false: the development of RA is dependent solely on the environmental factors?

Answer 21

False: environmental factors trigger the development of RA but individuals have to have a genetic predisposition (not all people with the genetic predisposition develop RA so is dependent on environmental trigger)

Question 22

Name three genes shown to be associated with RA?

Answer 22

HLA-DRB1 (encodes part of the HLS/MHC complex)
PTPN22 (protein tyrosine phosphatase, non-receptor type 22)
TRAF1 (encodes factor that interacts with TNF-receptor - upregulation of TNF-alpha receptor activity)

Question 23

What is the HLA-DRB1 gene?

Answer 23

encodes for part of the human leukocyte antigen (HLA) complex involve din distinguishing self from non-self (also referred to as MHC complex)

Question 24

How can RA be treated?

Answer 24

Immunosuppression as second-line approach using drugs such as methotrexate (systemic - helpful for RA but not for long period of time as can have increased disease and cancer)

NSAIDs - usually first-line treat - treat pain - good for shorter term

SADMD (Slow acting disease-modifying drugs) - gold, hydroxychloroquine

corticosteroid injections - potent anti-inflammatory drugs that give effective short term relief from pain

Anti-TNF therapy

Question 25

True or false: there are a wider range of treatment options for RA than OA (why/why not)?

Answer 25

True

why? because RA is an autoimmune disease which more is known about how to treat

Question 26

Give an example of an immunosuppressive drug that can be sued to treat RA

Answer 26

Methotrexate

Question 27

What are the downsides of using corticosteroids injections?

Answer 27

cannot be self-administered

their effectiveness falls away after time leading to patients requiring larger doses and can cause severe reactions when treatment stopped (physiological and phycological dependence)

Question 28

True or false: RA can improve without treatment?

Answer 28

True but not known why

Question 29

What is one treatment option that has shown success in treating RA?

Answer 29

Anti-TNF therapy - often involve use of monoclonal antibodies against TNF-alpha or its receptor
= really effective treatment
- focussed and targeted treatment

Question 30

What are the downsides of anti-TNF therapy?

Answer 30

Expensive
Regular injections

Question 31

Give one example of a drug used in anti-TNF therapy for treatment of RA

Answer 31

Infliximab