Itis
inflammation
Arthro
joint
Osteoarthritis (1)
Osteo - bone
Primary
“Wear and tear”
Related to aging
Secondary
Trauma
Disease or obesity
Pain through inflammation
Rheumatoid arthritis
Rheum - flowing in a stream
Systemic auto-immune disorder
May affect other tissues
Pain through inflammation
Rheumatologists treat a range of other disorders
Osteoarthritis (2)
Disease affecting synovial joints
Characterised by loss of cartilage and bone from articulating surfaces
Alteration in cartilage structure
Why is cartilage degraded?
Upregulation of cytokines?
IL-1β inhibits type II collagen synthesis of hyaline cartilage
Destroy environment surrounding cartilage cells → changes to cartilage structure
Cathepsin-B can cleave aggrecan
↑Matrix metalloproteinases → breakdown of collagen → cartilage degradation
Risk factors
Gender (more common in women) Obesity Age (> 40) Genetic (e.g. collagen gene mutations) Previous joint injury/ disease
Prostaglandins
PGD2/ PGI2 → vasodilation
PGE2 → vasodilation, pyrogenic + (under certain conds.) anti-inflammatory effects
Potentiate effects of histamine, bradykinin
Increased permeability of venules → oedema
Increased sensitivity of C fibres (PAIN!)
COX-1
‘Constitutive’ Expressed in most tissues (inc platelets) Housekeeping’ enzyme Protects GI mucosa Control of renal blood flow Initiation of labour
COX-2
‘Inducible’
Inflammatory cells – induced by injury, infection, cytokines
Prod. inflamm. mediators
COX-3
?
Found in CNS of some species
The NSAIDs
Non-Steroidal Anti-Inflammatory Drugs (~ 50 on global market)
Aspirin
Ibuprofen*
Diclofenac
Meloxicam
Indomethacin
Many are available OTC
Most widely prescribed drugs for arthritis
Diff formulations (e.g. tablets, suspensions, gels, injections)
Actions of NSAIDs
Antipyretic
inhibit actions of PGs on hypothalamus
Analgesic
reduce sensitivity of neurons to bradykinin
effective against pain of muscular/ skeletal origin
Anti-inflammatory
reduce vasodilation and decrease permeability of venules
Other actions of NSAIDs
May scavenge oxygen radicals → ↓ tissue damage
Aspirin – inhibits NFκB expression → ↓ transcription of genes for inflammatory mediators
Celecoxib, diclofenac and ibuprofen - ↓ IL-6 and TNF-α in SF
N.B. only suppress signs + symptoms of inflammation – do not ↓ cytokine rel or ↓ toxins which cause tissue damage in chronic disease.
NSAIDs (contd)
Variation in individual responses/ tolerance to drugs
~ 60% people respond to any NSAID
Others usually respond to certain NSAIDs
Pain relief almost immediate → full analgesic effect within a week (anti-inflamm. effect takes longer)
Problems with NSAIDs
Risk of gastric ulcers
Impair coagulation
Use with caution in elderly (GI bleeding can be serious/ fatal)
Risk of CV events in patients with cardiac disease/ hypertension
May induce asthma attack, angioedema, urticaria or rhinitis
Why the problem?
Many inhibit COX1 as well as COX2
PGs produced by COX1 are involved in many beneficial processes:
Production of GI mucus (protective)
Blocking ↑ risk of ulcer
Cardiovascular function : PGs (e.g. PGI2) inhibit platelet aggregation*
COX also generates TXA2, which promotes platelet aggregation.
Solving the problem
COX1 and COX2 differ in structure Should be possible to produce selective drugs Observed that best tolerated (GI) drugs had some COX2 selectivity E.g. meloxicam But rofecoxib (early COX-2 inhibitor) withdrawn, as some patients died from CV complications (↓ PGI2 → platelet aggregation?)
COX2 Inhibitors
E.g. celecoxib, etoricoxib
Used mainly in patients at high risk of serious GI side effects (but with little CV risk*)
Common side-effects: headache, dizziness, skin rash, peripheral oedema
*i.e. due to possible CV side-effects
An Alternative Strategy
Misoprostol (synthetic PG) Given alongside NSAIDs Preserves mucous lining of GI tract Protects against ulceration Other uses? Side-effects: diarrhoea (can be severe), vaginal bleeding N.B. Precautions in women of childbearing age! Proton Pump Inhibitors (e.g. omeprazole) Reduce acid secretion
Aspirin
Rapidly absorbed in stomach (i.e. weak acid)
Displaces warfarin bound to plasma proteins
i.e. ↑ plasma warfarin + potentiates warfarin’s anticoagulant activity!!
Paracetamol: A Special Case
Paracetamol is NOT an NSAID Why? It has no anti-inflammatory effect But... It is analgesic, antipyretic It suppresses PG production Actions may involve COX, but in CNS (COX3?) May stimulate serotonergic pathways involved in inhibition of pain sensation Often grouped together with NSAIDs
Paracetamol – side effects
Few side-effects Chronic use of large doses → kidney damage Toxic doses (10 – 15g) → potentially fatal liver damage (occurs 24 – 48hr after O.D.)
Osteoarthritis – treatment options
Weight loss Exercise – strengthens core muscles/ improves aerobic fitness Suitable footwear + pacing Joint supports/ braces Thermotherapy/ TENS devices
Drugs used to treat osteoarthritis
Paracetamol – regular dosing ± oral NSAID (with PPI*)
Topical NSAID or capsaicin (esp knee/ hand)
Opioid analgesic – for further relief
Intra-articular corticosteroid injection → temporary benefit
Joint replacement surgery (hip, knee, ankle)
Drugs with potential benefit (1)
Strontium ranelate
promotes osteoblast differentiation/ inhibits osteoclast activity*
reduces pain*
Indicated for prevention of fractures in severe osteoporosis (OP)
BUT
- found to ↑ risk of MI and thrombotic events so use restricted to treatment of severe OP**
Drugs with potential benefit (2)
Glucosamine sulphate
major constituent of ECM
Present in cartilage + synovial fluid
Demonstrated positive effects both in vitro + in vivo (animal models)
Differing results from clinical trials – measured pain and structural improvement
Overall no sig benefit but poss long-term side effects
Not recommended by NICE!
Rheumatoid arthritis
Causes joint inflammation, especially:
Synovial membrane
Tendon sheaths
Bursae*
Leads to proliferation of synovial membrane + erosion of cartilage/ bone
Symptoms: Joints swollen + stiff (morning stiffness > 30 mins), can be painful
Rheumatoid arthritis (contd)
Affects ~ 1% UK population → 1 in 3 likely to develop severe disability
Autoimmune disorder → 2- 4 x more common in women
Most commonly diagnosed between 40 and 60 years of age
Rheumatoid arthritis: Treatment Options
NSAIDs/ opioid analgesics Glucocorticoids Immunosuppressants Disease Modifying Antirheumatic Drugs (DMARDS) Anticytokines
Glucocorticoids
Naturally produced in the body – where?
Used short-term – to manage flare-ups (rapidly reduce inflammation) in patients with recent-onset or established disease
Long-term – if other treatment options failed - must discuss complications
Actions of Adrenal Steroids
Two main types of action: Glucocorticoid metabolic effects anti-inflammatory immunosuppressive
Mineralocorticoid
water & electrolyte balance
Natural steroids
Hydrocortisone/ corticosterone
show both (MC + GC) activities
enzyme in MC-sensitive tissues (e.g. kidney) converts these to MC-inactive compounds – why?
Aldosterone
mineralocorticoid only
Synthetic steroids
Modification of natural steroids gives:
Different split of activities/potencies
Varying duration of action
i.e. useful to be able to manipulate steroid activity according to therapeutic needs
Splitting activities
Modification of natural steroids gives:
Mixed gluco-/ mineralocortiocoid activity
prednisolone, prednisone
Glucocorticoid activity
dexamethasone, betamethasone beclomethasone, budesonide
Mainly mineralocorticoid activity
fludrocortisone
Duration of action of steroids
Short-acting (1 -12 hrs)
Cortisone/ hydrocortisone
Twice daily cream or intra-articular injection
Intermediate-acting (12 – 36 hrs)
Prednisolone
Daily oral or intra-articular injection
Long-acting (36 – 55 hrs)
Dexamethasone
Intra-articular injection every 3 - 21 days
Glucocorticoid actions in R.A.
anti-inflammatory, immunosuppressant actions:
↓ transcription of pro-inflammatory cytokines (e.g. IL-2)
↓ circulating lymphocytes
inhibit phospholipase A2 → ↓ release of arachidonic acid…………….
↑ synthesis of anti-inflamm. proteins (e.g. protease inhibitors)
used for asthma and ARTHRITIS….
beclomethasone, budesonide, prednisolone – stabilise mast cells (so ↓ histamine rel.)
Unwanted effects of oral corticosteroids
Buffalo hump Moon face Hypertension Increased abdominal fat Thinning of skin Increased risk of infection Muscle wasting Poor wound healing Osteoporosis
Methods of reducing side effects
Lower plasma concentrations → fewer side effects
Choose route of admin to achieve this (e.g. topical admin.)
Danger of stopping steroid treatment abruptly
Patients on course of steroid therapy > 1 month must not suddenly stop treatment
Patients on long-term therapy advised to carry card
Disease Modifying Antirheumatoid Drugs (DMARDs)
Drugs with unrelated structures + diff mechanisms of action
Therapy started upon definite diagnosis of R.A. → slow onset of disease
Most important examples:
Sulfasalazine, gold compounds, penicillamine, immunosuppressants (e.g. methotrexate, ciclosporin, azathioprine, leflunomide), anticytokines
Sulfasalazine
Common 1st choice DMARD in UK
Complex of salicylate (NSAID) + sulphonamide (antibiotic)
Thought to act by scavenging free radicals prod by neutrophils
Causes remission in ‘active’ R.A.
Given as enteric-coated tablets (poorly absorbed orally)
Side-effects: GI upset, headache, skin reactions, leukopenia
Penicillamine
Prod by hydrolysis of penicillin
75% patients respond but therapeutic effects take weeks
Thought to ↓ IL-1 generation + ↓ fibroblast proliferation → ↓ immune response
Given orally – peak plasma conc → 1-2 hrs
Side-effects: rashes, stomatitis (40% patients); anorexia, taste disturbance, fever, n & v
Should not be given with gold compds – metal chelator!
Gold compounds (sodium aurothiomalate/ auranofin)
Auranofin (oral) → inhibits induction of IL-1 + TNF-α → ↓ pain + joint swelling
Sodium auranofin – deep i.m. injection
Concentrate in synovial cells, liver cells, kidney tubules, adrenal cortex & macrophages
Effects develop over 3 – 4 months
Side-effects: skin rashes, flu-like symptoms, mouth ulcers, blood disorders (33%)
Serious side-effects: encephalopathy, peripheral neuropathy + hepatitis (10%)
Anti-malarials (chloroquine/ hydroxychloroquine)
↑pH of intracellular vacuoles → interferes with antigen-presenting
Induces apoptosis in T-lymphocytes
Usually used when other treatments fail
Therapeutic effects take a month
~ 50% patients respond
Side-effects: n+v, dizziness, blurring of vision – requires screening
Anticytokine Drugs
Engineered recombinant antibodies → v. expensive!
Use restricted to patients who don’t respond well to other DMARDs
Can be given with methotrexate
E.g. adalimumab, etenercept, infliximab – target TNF; rituximab, abatacept, natalizumab – target leukocyte Rs; tocilizumab - blocks IL-6 Rs → disrupt immune signaling
Anticytokine Drugs (contd)
Proteins – how does this restrict admin?
Given by s.c. or i.v. injection
Some patients do not respond
Side-effects: may develop latent disease (e.g. TB, hep B, herpes zoster, etc) + opportunistic infection; also, nausea, ab pain, worsening heart failure, hypersensitivity
Immunosuppressants
Rheumatoid arthritis is an AUTOIMMUNE disorder
Suppressing the immune system will therefore suppress (but not cure) disease
Ciclosporin
1st discovered in fungus
Potent immunosuppressant but no effect on acute inflammation
Inhibits IL-2 gene transcription → ↓ T cell proliferation
Poorly absorbed orally – special formulations (capsules/ oral solutions)
Accumulates in high conc in tissues (i.e. remains for some time)
Side-effects
Nephrotoxicity*
Hepatotoxicity
Hypertension
Also: nausea/ vomiting, gum hypertrophy, GI problems
Azathioprine
Cytotoxic: interferes with purine metabolism → ↓ DNA synthesis
Depresses cell-mediated + antibody-mediated immune reactions
i.e. targets cells in induction phase of immune response
Main specific effect: suppression of bone marrow – impact of this?
Methotrexate
Folic acid antagonist → inhibits DNA synthesis
Blocks growth and differentiation of rapidly dividing cells – other uses?
Inhibits T cell activation
Patients often continue treatment for > 5 years
Side-effects: possibility of blood dyscrasias (abnormalities) + liver cirrhosis (requires monitoring), folate deficiency – why is this a problem?
Often prescribed with a DMARD
Leflunomide
Specific inhibitor of activated T cells
Well absorbed orally; long t½
Side-effects: diarrhoea, alopecia, ↑ liver enzymes → risk of hepatotoxicity
Cyclophosphamide
Only used when other therapies have failed
Prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein
Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)
Immunosuppressants: general problems
Glucocorticoids + other IS drugs:
Increase risk of infection
Increase risk of cancer
NSAIDs
Aspirin, ibuprofen, meloxicam, celecoxib
Inhibit COX enzyme →
↓ PG prod
Corticosteroids
Prednisolone, dexamethasone, fludrocortisone
Block gene transcription + synthesis of inflammatory proteins, immunosuppressant.
Immunosuppressants
Ciclosporin, azothioprine, methotrexate, leflunomide, cyclophosphamide
Inhibit DNA synthesis or T cell activation.
DMARDS
Sulfasalazine, pencillamine, gold compds, anti-malarials
Diff mechanisms: scavenge free radicals, ↓ IL-1, etc
Anticytokines
Etenercept, infliximab, rituximab, abatacept
Antibodies which bind to specific immune cells cytokines to inhibit immune response.