Pharm: Rheumatoid arthritis

Question 1

What is the radiological manifestation of rheumatoid arthritis?

Answer 1

Severe inflammation in proximal metacarpophalangeal joints with relatively little inflammation of distal interphalangeal joints.

Question 2

What are the therapeutic goals in rheumatoid arthritis?

Answer 2

Preserve function

Prevent pain

Question 3

What happens in rheumatoid arthritis?

Answer 3

Inflammation of synovial membrane takes place and infiltration of the membrane with macrophages, T and B lymphocytes, fibroblasts, and other inflammatory cells.

This disorder is autoimmune and is caused by T-cells reacting to normal tissue being presented by APC and proliferating/being activated and activating some B lymphocytes and macrophages.

Question 4

What drugs are used for rheumatoid arthritis and what is their mechanism of action?

Answer 4

To cancel the effect of T-cell proliferation and function:

Methotrexate

Leflunomide

Glucocorticoids

To counter macrophage function:

TNF-alpha inhibitors

Glucocorticoids

Mode of action uncertain:

Sulfasalazine

Hydroxychloroquine

Question 5

What is the function of TNF-Alpha?

Answer 5

Aggregates as trimers and acts on:

Endothelial cells: Adhesion receptors for leukocytes

Lymphocytes: Activation, proliferation

Macrophages themselves: activation

Antigen presenting cells: Maturation and migration

Some tumour cells: Apoptosis

Question 6

What is the evidence of TNF-alpha inhibitors working to protect from progression of rheumatoid arthritis?

Answer 6

Women who were given TNF-alpha inhibitors had a lower sharps store after 2 years.

Question 7

What types of molecules are used to inhibit action of TNF-alpha?

Answer 7

anti-TNFalpha antibodies

Soluble TNF-receptors

Question 8

What are the anti-TNFalpha antibodies called?

Answer 8

Infliximab (human and mouse sequences are modified to minimise human antigenicity)

Adalimumab (Completely humanised Fab sequence)

Question 9

Why is minimising human antigenicity of antibodies so important?

Answer 9

Prevents the immune system from clearing out the antibodies before they can carry out their function.

Question 10

How are antibody drugs named?

Answer 10

Adalimumab

(Ada) - no origin

(lim) - refers to system it is working on (Immune system)
(u) - Human derived
(mab) - monoclonal antibodies

Question 11

What are the limitations/adverse effects of TNF-alpha use for RA?

Answer 11

Immune suppression:
Increased infection rate, including some infections only seen in immunosuppression.

Particular risk in people with dormant tuberculosis

Increased rate of some malignancies

Another limitation is the cost TNFalpha inhibition can cost 24617$ per year per person!

Question 12

How do glucocorticoids work in protecting against RA?

Answer 12

They suppress lymphocyte and macrophage function.

Question 13

How is dexamethasone different to prednisolone and why is that useful?

Answer 13

Dexamethasone has a Fluoride group which makes it much more potent due to extended half life.

Question 14

How do glucocorticoids work?

Answer 14

They bind to circulating corticosteroid binding globulin in the blood to be transported before entering the cell.

Steroid then binds to a cytosolic receptor which translocates to the nucleus

Steroid-receptor complex binds recognition sequences on promoter of responsive genes stimulating transcription.

Question 15

What do glucocorticoids do?

Answer 15

Suppress inflammation by suppressing the action of:

Macrophages and cytokines including TNFalpha and other proinflammatory functions.

T-lymphocyte recruitment and proliferation

B-lymphocytes from producing antibodies

Question 16

What conditions are glucocorticoids administered for?

Answer 16

Autoimmune diseases

Allograft tolerance

Asthma

Dermatitis

Ulcerative colitis

Inflammatory arthritis and other

Question 17

How are glucocorticoids used?

Answer 17

Sparingly due to the adverse metabolic and mineralocorticoid effects.

Commonly used systemically early in treatment

They are typically injected into joints

Question 18

What does methotrexate do?

Answer 18

It resembles folic acid and inhibits nucleic acid synthesis by inhibiting dihydrofolate reductase (DHFR).

It acts as an antiproliferative drug.

Question 19

What are the risks with using methotrexate?

Answer 19

It’s antiproliferative actions impact bone marrow (neutropaenia, thrombocytopaenia) and gut.(Mouth ulcers and GI upset)

Teratogenic risk (high doses embryotoxic)

Hepatotoxicity and pulmonary fibrosis

MTX is mostly renally excreted so ensure renal function is good.

Question 20

What does leflunomide do?

Answer 20

Blocks dihydroorotate dehydrogenase which is in the pathway of pyrimidine synthesis. This drug is antiproliferative and is presumed to act on T cells.

Question 21

What are the limitations to using leflunomide?

Answer 21

It is a teratogen with long half life. Takes long time before it is harmless in childbearing aged women.

Should be avoided in young women or reliable contraception

It is hepatotoxic

Question 22

How can pain be controlled in RA?

Answer 22

By controlling the prostaglandins being released by macrophages in inflamed tissue.

NSAIDs can do this by blocking prostaglandin synthase/cyclo-oxygenase inhibitors

Question 23

Does inhibiting prostaglandin production reduce progression of the disease?

Answer 23

No it suppresses signs of inflammation and pain but disease still progresses unless treated another way

Question 24

How are the different forms of treatment combined together for treating RA?

Answer 24

MTX or leflunomide

Add hydroxychloroquine, sulfasalazine

Add biological agent like anti-TNF-alpha

Low-dose systemic glucocorticoids commonly used in early phase when pursuing remission

Cyclooxygenase inhibitors (NSAIDs) for analgesia and acute anti-inflammatory action

Question 25

How is RA managed non-pharmacologically?

Answer 25

Protection of joints (splints)

Management of CV risk

General functional support to compensate for disability

Psychological support