Block E - IP lecture 2 Flashcards
what do 70% of evidence show for RA ?
70% of patients show evidence of joint damage within 2 years of diagnosis
what does delays in treatment result in ?
Delays in treatment can result in long-term joint damage,
what does early intervention beneficial ?
Good evidence that early, intensive treatment increases chances of halting or slowing disease progression (KEY INTERVENTION)
what are RA treatments ?
Non-steroidal anti-inflammatory drugs (NSAIDs)
Disease modifying anti-rheumatic drugs (DMARDs)
Glucocorticoids such as Classical DMARDs , Biologics , JAK inhibitors
methotrexate ?
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
phase 1 ?
Phase I –conventional synthetic DMARDs and glucocorticoids – short term and low dose
phase II
Phase II – change to a 2nd csDMARD and add in biologics – more expensive therapy
phase III
Phase III - Replace bDMARD with an alternative, or a JAK inhibitor.
name some NSAIDs ?
NSAIDs - 24 in BNF
aspirin
indomethacin
ibuprofen
diclofenac
fenbufen
sulindac
COX 1 ?
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
COX 2 ?
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
how do NSAIs work ?
‘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
other mechanims of action - NSAIDs ?
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
theraputic effects of NSAIDs ?
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
adverse effects of NSAIDs ?
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
imbalance hypothesis ?
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.
what factors dictate what combinations of drugs are used in RA ?
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
DMARDs ?
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.
anti-inflammatory corticosteroids ?
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.
mechanism of action glucocovrticosteroids ?
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).
Annexin-1 inhibit ?
Annexin-1 inhibits the prostaglandin pathway , directly inhibiting PLA2 which turns off leukotrienes and prostaglandin production.
other actions of annexin-1
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
why do glucocorticosteroids inhibit many synthesis of inflammatory mediators ?
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
GC and NFkB pathway ?
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.
adverse effects of glucocorticoids ?
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
