Rheumatoid Arthritis Therapeutics

Question 1

What is rheumatoid arthritis ?

Answer 1

This is an autoimmune disease where the body begins to attack the bones causing bone erosion and joint destruction, this autoimmune response can also affect other organs in the body not just the joints and bones.

-inflammation and swelling of the synovial joints due to the immune attack.

At this stage it is not just the joint that is getting eroded it is the bone too.

Question 2

What are the symptoms of RA?

Answer 2

-symptom onset >25 years old

-females more likely

-swollen inflamed synovial membrane due to damage, the tissue thickens in the joints.

-redness

-pain ,cartilage and bone within joint will wear down over time and be attacked by the immune system.

-stiffness, inflamed joints tend to stiffen and are difficult to move correctly.

-inflammation

-morning stiffness lasting longer than 30 minutes.

SYMMETRICAL, both joints will be attacked.

Question 3

What is the pathogensis of RA?

Answer 3

-combination of both environmental and genetic components.
-auto immune disease
-leads to generation of auto antigens (this is something that we are producing in the body e.g. one of our proteins and the immune system reacts.
-our immune systems attack the joints and cartilage in the absence of an infection due to an autoantigen

Question 4

How does genetics play a huge role in rheumatoid arthritis?

Answer 4

-HLA=human leukocyte antigen, this is a complex of genes found on chromosome 6 that regulate the immune system. People have alterations within this gene are more susceptible to RA.

-patients suffering from rheumatoid arthritis are more susceptible to it if there is a genetic alteration in the genes.

-PTP2N22 mutation = this is important as it regulates the activation of inflammatory cells and T cells.

Question 5

What environmental factors play a role in RA?

Answer 5

-smoking
-diet
-obesity
-hormones
-infection from viruses
-TB
-gum disease
-airborne pollutants
-CITRULLINATED PROTEINS (proteins are modified and they look different, thus they are not recognisable by the immune system causing attack) these proteins are citrullinated via a substance called citrulline

Question 6

What are non genetic risk factors off RA?

Answer 6

-smoking
-microbiota
-Female sex
-diet
-ethnic factors

Question 7

What is the citrullination of proteins?

Answer 7

-citrullination is the conversion of arginine to a citrulline group in proteins by an enzyme called peptidyl arginine deminiase(PAD)

If a lot of proteins are being changed to appear foreign then this is called HYPER-CIRTULLINATION. LEADS TOO AUTOANTIGENS BEING FORMED , ALTERED PROTEIN NOW SO THE IMMUNE SYSTEM ATTACKS. The immune system generates anti citrullinated protein antibodies (ACPA) which attack the cirtullination proteins, it recognises any protein with a citrulline group on it.

Question 8

What do the macrophages realease?

Answer 8

They release cytokines:
-TNFa
-IL-1 this is responsible for the inflammatory response
-IL6 this is responsible for the release of osteoclasts to lead to bone destruction.

Question 9

What are cytokines?

Answer 9

These are small secreted proteins that essentially have a specific effect on the interactions and communication between cells.
-they bind to cytokine receptors
-when cytokines are released by cells they trigger processes in other nearby cells
-Regulate the immune system
-activates the immune response

Question 10

How to diagnosis RA?

Answer 10

-family history

-pain history and examination of joints

-blood tests
POSTIVE rheumatoid factor -autoiantibody
POSTIVE anti cyclic citrullinated peptide
High erythrocyte sedimentation
POSTIVE c reactive protein , if these are present it will tell us the patient have RA not OA because these are not present in them

Imaging scan:
X rays
Ultra sounds
Scans

Question 11

Why is RA very serious?

Answer 11

There can be a release of cytokines into the blood where it can go onto to effect the:
-central nervous system
-cardiovascular system
-adipose tissue e.g. insulin resistance
-liver

Question 12

What is RA mainly caused by?

Answer 12

-heart disease
-infection
-GI bleeding

Question 13

What do we give as first line to treat RA for short term and what do they work to do ?

Answer 13

NSAIDs -these are for short term it does not have any effect long term
They work short term to provide immediate pain relief.
-works through cox inhibition enzymes.

Question 14

What are some examples of NSAIDs can you use in RA?

Answer 14

1.diclofenac
2.ibuprofen
3.naproxen
4.piroxicam (gel)

Question 15

What are some adverse effects of NSAIDs?

Answer 15

1.gastric problems

2.headaches

3.hypertension

Question 16

What medications are used as long term treatment in rheumatoid arthritis?

Answer 16

DMARDS (disease modifying anti rheumatic drugs)

Question 17

What are the two different types of DMARDs?

Answer 17

TRADITIONAL DMARDS:
-sulfasalzine
-leflunomide

Immonunosuppresants:
-methotrexate
-azathioprine

Antimalarials:.
Hydroxychloroquine

BIOLOGICAL DMARDS:
-abatacept
-rituximab
-tofacitanib

TNF antagonists:
-inflixaimab

IL6 inhibitor:
-tocilizumab

Question 18

How do DMARDs work?

Answer 18

they work by slowing the progression of RA not just relief
-however it can take two weeks to a month to start posing its effect

Question 19

What is first line in treatment of rheumatoid arthritis?

Answer 19

SULFASALIZINE (aminosalicylates)

Question 20

How does sulfasalazine work?

Answer 20

-It works by inhibiting leukocyte movement- so inhibits the immune system.
- reduces cytokines levels and TNF

Inhibits the inflammatory mediators:
-prostaglandins
-leukotrienes
-platelet activating factors
-clycooxygenase (by blocking this enzyme it blocks the production of prostaglandins and leukotrienes) thus suggests it works as pain relief as well as a DMARD

Question 21

How does methotrexate work?

Answer 21

Suppresses the immune system
-methotrexate essentially blocks the pyrimidine and purine biosynthetic pathway and the proliferation of B cells by interfering with DNA synthesis repair and replication.

-stops/suppresses thymidine synthesis
Overall methotrexate suppresses the immune system by inhibiting DNAS synthesis to stop division and multiplication of immune cells.

Question 22

Who uses methotrexate?

Answer 22

This is an anti folate drug approved for the treatment of rheumatoid arthritis in adults who are intolerant to or that have an insufficient response to 5-ASA (sulfasalazine)

Question 23

What happens when methotrexate increases adenosine levels in the body ?

Answer 23

-stops proliferation of T cells
-changes the vascular permeability of the cells, so harder to get in and out of cells

Question 24

How does leflunomide work?

Answer 24

IMMUNOSUPPRESANT DRUG:
-inhibits the pyrimidine biosynthetic pathway resulting in decreasing DNA and RNA nitrogen containing bases and arresting the B cell and T cell proliferation cycles and production of antibodies
-specifically inhibits the dihydriirate dehydrogenase

Question 25

If methotrexate doesn’t work what do we give?

Answer 25

Leflunomide

Question 26

What else can we use to treat RA and how do they work?

Answer 26

Monoclonal antibodies- these work by binding specifically blocking action.
-monoclonal antibodies therapy targets either TNF or TNFR, this is the key cytokine involved in the inflammatory process.
-multiple monoclonal antibodies are used to block this key pathway
-reduces inflammation
-stop TNF binding to the TNF receptor

E.g. infliximab

Question 27

What are T cell co-stimulation modulators ?

Answer 27

-T cells activation requires recognition of antigen by antigen presenting cells