L11: Arthritis and its treatment

Describe the features of a joint affected by rheumatoid arthritis ?

- Bone and the cartilage are no longer smooth

- The synovial fluid is no longer clear as it contains inflammatory cells

- Growth of synovial membrane which invades the bone

What does RA affect ?

Mainly the joints but sometimes other systems

What does RA lead to ?

Pain and stiffness

Inflammation (swelling )

What does RA lead to?

Joint destruction and systemic lesions

What type of disease is rheumatoid arthritis?

Autoimmune

When does RA typically develop ?

-At 25-50yrs

- Three times more common in females

What age group does osteoarthritis affect ?

Large percentage of people over 60

Describe the features of osteoarthritis?

- Progressive and disabling

- Associated with old injuries

- Cartilage cells change, thins loses elasticity & start to split

- Loses smooth functioning

- Bone loses shape, thickens at ends to produce bony spurs

As the cause of RA is unknown state the types of treatment provided to manage RA ?

- Relief of symptoms

- Conservation and restoration of function in affected joints

- Suppression of active progressive disease

What is the role of TNF alpha in arthritis ?

- Causes proliferation & production of other agents like PGs and other cytokines

- Helps turn the synovial membrane into an inflammatory organ

- Acts in synergy with IL-1 to cause cartilage and bone erosion

What causes the inflammation in RA to be amplified?

Variety of pro-inflammatory cytokines (TNF alpha, IL-1,6,8)

What is the role of prostaglandins at inflammatory sites ?

- Sensitise nerves (hyperalgesic) - amplify the pain produced by other mediators

- Increase blood flow (vasodilate) which increases inflammatory response

- Potentiate oedema formation

Define hyperalgesic ?

An increased sensitivity to feeling pain and extreme response to pain

What are positives and negatives of biologics

Positives

- Decrease the need for surgery

- New drugs that improve patient outcomes

Negatives

- Expensive

How do most non steroidal anti-inflammatory(NSAIDs) drugs work?

By inhibiting COX so inhibiting PG production

What are three words that can be used to describe NSAIDs ?

Analgesic

Anti-inflammatory

Anti-pyretic

What are the different types of NSAIDs ?

Salicylates (Aspirin) Acetic acids (Indomethacin, Diclofenac) Proprionic acids (Ibuprofen, naproxen) Oxicoms (Piroxicam, phenylbutazone) Fenamates (Meclofenamate)

What is the role of COX-1 ?

- Involved in the normal physiology to maintain homeostasis

- E.g in g-i tract PGs are important in maintaining good blood flow which allows for the production of mucus which reduces the risk of ulcers forming

-in vasculature TxA2 stimulates platelets to aggregate (thrombus) and PGI2 inhibits this

Where is COX-1 found ?

Most cells

What is role of COX-2 in the body ?

Releases high level of PGs at inflammatory sites

How is COX-2 induced ?

In inflammatory cells by inflammatory stimuli

Name drugs used for the inhibition of PG generation?

Non-selective inhibitors

- Aspirin, ibuprofen and Indomethacin

COX-2 selective inhibitors

- Celecoxib, Rofecoxib, Meloxiam

What can be used with oral NSAIDs to inhibit gi reflux due to excess acid ?

Proton pump inhibitors (e.g esomeprazole )

What is an expensive alternative to use with oral NSAIDs in patients with cardiovascular risk?

Give a prostaglandin back to the patient = PG analogues e.g misoprostol

When is the use of topical NSAIDs ideal for patients ?

In patients with a cardiovascular risk

(agents like diclofenac - Voltaren Gel, Novartis)

Why will a doctor prescribe DMARDs ?

As the COX-2 inhibitors prevent pain but don't improve the progression of the disease

What is the gold standard DMARD for inflammatory arthritis ?

Methotrexate

What are the benefits of methotrexate ?

- Acceptable safety

- Effective in 30% of the population

- Low cost

- Prevents the use of steroids

- Used in all stages of the disease

- Can be used in all age groups both elderly and very young

What are the negatives of methotrexate ?

- Takes several weeks to work (unlike NSAIDs)

- Works by several mechanisms

What is the mechanisms of action of methotrexate ?

- Reduction of T cell proliferation and inflammatory cytokines by blocking the enz AICAR acetylase leading to adenosine not being metabolised

- Adenosine is anti-inflammatory acts via A2 receptors

- Blocks dihydrofolate reduction

- Inhibition of signalling pathways for inflammation and bone degradation

Why is monitoring of methotrexate essential ?

As there is possibility of developing different problems

Why is it believed the methotrexate is a folate antagonist and not anti-inflammatory ?

Give people folate and still have anti-inflammatory mechanisms occurring

What are the pros of using anti-inflammatory steroids ?

- Several anti-inflammatory activities

- Several effects on immune response

What are the anti-inflammatory activities

of steroids ?

• Inhibit AA release

• Cytokine inhibition

• Down-regulation of adhesion molecules

• Inhibition of enzyme induction (COX, NOS)

What are the effects on immune response of steroids ?

• Inhibition of lymphocyte t-cell proliferation

• Induces apoptosis

What are the side effects of using steroid to treat arthritis ?

- Development of osteoporosis

- Increased risk of infection

- Adrenal atrophy (insufficient adrenal hormone)

How are the side effects of steroid decreased ?

When given locally

- Intra-articular

- Aerosol

- Topically

Name the two groups of Anti-TNF drugs

1) Monoclonal antibody (infliximab, adalimumab)

2) Soluble TNF receptor fusion protein (etamercept)

How do Anti-TNF drugs work ?

They bind to TNF mopping it up preventing

- Pain, stiffness, swelling, tenderness, inflammation, tissue damage, deformities and disability

What type of drug is used if the patient does not respond to both anti-TNF/ methotrexate?

Il-6 blockers (Tocilixumab, RoActemra)

What are the new emerging drug approaches - cytokines ?

- IL-1 antibodies/receptor antagonist (Anakira, Canakinumab)

- IL-6 blocker (Tocilizumab, RoActemra)

- IL-7 receptor antagonist (used in psoriatic arthritis )

How does rituximab (brand name = MabThera) work?

Cell based drug works by removing antibody producing WBCs called B-cells

How does abatacept (Orencia) work ?

Inhibits action of T cells and reduces damaging effects

What are biosimilars?

a biologic medical product that is almost an identical copy of an original product that may manufactured by a different company (Cheaper than the expensive biologics )

Describe the traditional vs modern treatment of RA ?

Traditional treatment = treating the symptoms (pain,swelling), less aggressive and use of NSAIDs

Modern treatment = early aggressive treatment to limit joint destruction, combination therapy, increased use of biologics mostly biosimilars