Block E - IP lecture 2

Question 1

what do 70% of evidence show for RA ?

Answer 1

70% of patients show evidence of joint damage within 2 years of diagnosis

Question 2

what does delays in treatment result in ?

Answer 2

Delays in treatment can result in long-term joint damage,

Question 3

what does early intervention beneficial ?

Answer 3

Good evidence that early, intensive treatment increases chances of halting or slowing disease progression (KEY INTERVENTION)

Question 4

what are RA treatments ?

Answer 4

Non-steroidal anti-inflammatory drugs (NSAIDs)

Disease modifying anti-rheumatic drugs (DMARDs)

Glucocorticoids such as Classical DMARDs , Biologics , JAK inhibitors

Question 5

methotrexate ?

Answer 5

Methotrexate is a common first line treatment unless there are undesirable effects then leflunomide or sulfasalazine is used instead and glucocorticoids are added in.

When a patient fails to respond to treatment, then they are moved onto the next phase

Question 6

phase 1 ?

Answer 6

Phase I –conventional synthetic DMARDs and glucocorticoids – short term and low dose

Question 7

phase II

Answer 7

Phase II – change to a 2nd csDMARD and add in biologics – more expensive therapy

Question 8

phase III

Answer 8

Phase III - Replace bDMARD with an alternative, or a JAK inhibitor.

Question 9

name some NSAIDs ?

Answer 9

NSAIDs - 24 in BNF

aspirin

indomethacin

ibuprofen

diclofenac

fenbufen

sulindac

Question 10

COX 1 ?

Answer 10

COX-1

constitutive

involved in normal physiology e.g. early stages of inflammation in the endothelium

found in blood vessels and other cell types

calcium dependent enzyme and makes moderate amount of PGE2

Question 11

COX 2 ?

Answer 11

COX-2

inducible

Induced/upregulated in chronically inflamed tissue

Upregulated by cytokines such as TNF alpha and IL-1

Calcium independent

Produced a lot of PGE2

Question 12

how do NSAIs work ?

Answer 12

‘Classical’ NSAIDs are non-selective inhibiting both COX-1 and COX-2 with most showing some moderate (naproxen, indomethacin) or marked (flurbiprofen) preference for COX-1,

In RA NSAIDs especially inhibit COX2 found in the joints

COX-2 selective inhibitors include celecoxib, rofecoxib,eterocoxib,

Although all NSAIDs inhibit COX, other actions may also contribute to their anti-inflammatory actions

Question 13

other mechanims of action - NSAIDs ?

Answer 13

Aspirin triggers formation of lipoxins – aspirin-triggered lipoxin (ATL) - and resolvins via COX-2 and produces more anti-inflammatory effects.

acetylates COX-2 – acetylated COX-2 converts eicosapentanoic acid (EPA) to 18R-HEPE which is then converted by 5-LOX to resolvin E1 which resolves inflammation

Indomethacin and diclofenac inhibit degradation of resolvins/lipoxins

Question 14

theraputic effects of NSAIDs ?

Answer 14

Reduce pain – very effective analgesics

Reduce inflammation – pain, vasodilatation, increased vascular permeability – swelling reduced

Reduce morning joint stiffness

Antipyretic – reduce fever

Effectively reduce symptoms but do not modify underlying disease process

Question 15

adverse effects of NSAIDs ?

Answer 15

g.i. tract (peptic ulcer disease)

Kidney (PGs contribute to renal blood flow, reduced PGs – reduced blood flow – renal insufficiency in susceptible patients)

Lung (Aspirin induced Asthma – 20% of population, severe bronchospasm)

cardiovascular system (increased risk of MI & stroke) especially with COX2 inhibitors

Question 16

imbalance hypothesis ?

Answer 16

COX2 selective inhibitors leads to this theory , COX1 is active in endothelial cells and platelets while COX2 is strongly active in endothelial cells under certain conditions with the ability to produce lots of Prostaglandin ( vasodilator and anti-thrombotic-prevent platelet aggregation). However, COX2 selective inhibitors prevent the production of prostaglandins, therefore increasing the risk of MI in RA patients.

Therefore, when prescribing COX2 selective inhibitors, you need to weigh up the pain management and potential risk of MI in RA patients.

Question 17

what factors dictate what combinations of drugs are used in RA ?

Answer 17

Disease progression (severity and rate of joint damage),

How well the patient responds to a chosen DMARD,

Patient becomes refractory to a DMARD,

Other underlying health conditions and the severity of side effects.

The cost of treatment

Question 18

DMARDs ?

Answer 18

Traditionally a host of different drugs some used for many decades. Older DMARDs include methotrexate which was discovered in 1914.For some the mechanism of action is unknown or just being discovered especially for older DMARDs. Some mechanisms are already known (steroids). Problems with adverse reactions, side effects and non-responders.

A range of DMARDs - infliximab, cyclosporin, sulphasalazine, leflunomide, methotrexate, corticosteroids and IL-1 receptor antagonists. These slow down the progression of disease by slowing joint damage. These were all superior to placebo in reducing erosions in RA , effectiveness is not related to pharmacological properties but instead the management of pain. Anti-malarials appear to be less effective,The drugs are slow in onset often requiring enzymes and NSAIDs are needed to control pain.

Question 19

anti-inflammatory corticosteroids ?

Answer 19

Suppress all actions of the inflammatory response such as;

Reduce vascular permeability

Inhibit adhesion molecule expression – this is what causes WBC migration into joints

Inhibit fibroblast activity

Inhibit WBC accumulation/activity

Inhibit COX-2 and cytokine production such as IL-1 / IL-6

Used less frequently due to their side effects, particularly effective during the early stages of disease.

Question 20

mechanism of action glucocovrticosteroids ?

Answer 20

Act intracellularly

Modify transcription either by – this is a genomic effect

Induction of anti inflammatory molecules

Repression of pro inflammatory molecules

Increasing interest in non-genomic effects mediated by membrane-bound receptors (e.g. immunosuppression of T-cells)

GC act intracellularly they are lipid soluble so they can bypass the phospholipid bilayer to enter the cell, they bind to intracellular receptor called GR-α in the cytosol. The receptor is then translocated by chaperone proteins to enter the nucleus, here they bind to specific sections of DNA, called glucocorticoid responsive elements (GRE). This binding triggers the induction of transcription to produce anti-inflammatory mediators, they produce annexin-1(lipocortin).

Question 21

Annexin-1 inhibit ?

Answer 21

Annexin-1 inhibits the prostaglandin pathway , directly inhibiting PLA2 which turns off leukotrienes and prostaglandin production.

Question 22

other actions of annexin-1

Answer 22

Inhibits neutrophil accumulation – involved in acute inflammation

Inhibits monocyte-macrophage accumulation in joints due to inhibition of adhesion molecules

Inhibits macrophage phagocytosis

Inhibits production of cytokines by macrophages

Question 23

why do glucocorticosteroids inhibit many synthesis of inflammatory mediators ?

Answer 23

This is due to gene suppression

arachidonic acid metabolites

nitric oxide (via iNOS)

inflammatory cytokines (e.g. TNFa, IL-1, IL-8, IL-12)

Chemokines (CXCL)

adhesion molecules

Question 24

GC and NFkB pathway ?

Answer 24

GC work by binding to GRE and inhibiting gene transcription. The GR-α complex inhibits NFkB pathway , a key transcriptional pathway for pro inflammatory genes.

Question 25

adverse effects of glucocorticoids ?

Answer 25

Glucocorticoids have severe significant side effects which prohibit long-term use , they are normally used in a short term treatment and at a low dose.

Multi-systemic metabolic effects, such as –

GI tract bleeding

Osteoporosis

Ulcer formation