What is Rheumatology?• Rheumatology is the medical specialty concerned with causes, pathology, diagnosis and treatment of disease

affecting the joints, muscles and connective tissue.• Many of these conditions have a degenerative, inflammatory or autoimmune basis, and are chronic and

progressive.• Most are complex systemic diseases

What conditions does it include? • More than 150 diagnoses in rheumatology – more common diseases are RA, OA, osteoporosis and gout.

They fall into categories including:• Arthropathies eg RA, OA • Myopathies eg Fibromyalgia• Vasculitis eg Bechet’s Syndrome• Musculoskeletal & CT eg RA, SLE

What are the aims of treatment?• Control symptoms – relief of pain, stiffness and joint swelling • Impede progression of disease – prevent deformities and disability• Induce remission - should always be the goal of the treatment of RA can be achieved in up to 40% of cases. • Maintain and restore function - not only joints but also morale, health and well being • Prevent complications – including side effects

Reduce onset of co-morbidities - anxiety, depression, cardiovascular disease

RHEUMATOID ARTHRITISCharacteristics of RA

• Autoimmune disease - Pathophysiology not completely understood. Abnormal immune response possibly consequence of several genetic and environmental factors.

• Inflammatory disorder - -abnormal inflammatory response of synovial membrane → synovitis • Chronic -long-term condition but get remission and also disease flares • Progressive - inflammation → erosion and destruction of joint → deformity • Systemic - also affects skin, eyes, nerves, mouth, lungs and cardiovascular system• Significant morbidity and mortality

Morbidity & Mortality • Life expectancy in patients with RA is ↓ by 5-10 years – may be lower in patients who respond to therapy• Mortality possibly associated with CV disease – in RA patients see accelerated atherosclerosis, high BP from

drugs and inability to exercise, also ↑ risk stroke .• Inflammation of pericardium & myocardium → can progress on to heart failure• Other factors that ↑mortality risk: infections, renal disease, GI bleeding & osteoporosis – may be secondary

effects from drug treatment • Study: RA may have become milder over the past decades but the risk of CV death in patients with RA

continues to be 60% higher than in the general population.• Morbidity: Adversely impacts QOL – estimation that 25% stop work or have decreased work capacity within

5 years of diagnosis (Aust 2005)

Who gets RA?• Common – world wide prevalence approx 1% & in Aust figure close to 2%• Onset peaks between ages 35 and 64 - - overall incidence > in those aged ≥65 years but not a disease

associated with old age. Spectrum of ages from young to very old

• More common in females than males (2-3 x) - women also have more persistent synovitis and more progressively erosive disease than men

• Women post pregnancy - postpartum period highest risk time for developing first symptoms• Genetic factors - between 15% and 70% of the risk of developing rheumatoid arthritis may be due to genetic

factors, but high risk genes alone don’t seem to cause RA• Environmental factors eg infection, smoking, obesity, blood transfusions and viral infections• Other factors include lower socioeconomic status, lower education levels, lower psychosocial wellbeing,

smoking associated with higher incidence and more severe disease

Pathophysiology of RA • Not well understood1 Lymphocyte mediated inflammatory disease – involves T and B lymphocytes, antigen-presenting cells (eg,

activated B lymphocytes, macrophages, dendritic cells), and numerous cytokines.2 Stimulating antigens → abnormal inflammatory response - Stimulating antigens lead to proliferation

inflammatory mediators and an abnormal inflammatory response ie increased blood flow → heat & redness3 Inflammatory mediators (cytokines)TNF-α, IL-1, IL-64 ↑ cell population → new blood vessels 5 Synovial membrane hypertrophies → synovial pannus - Synovial pannus is rich in inflammatory cytokines and

destructive enzymes that degrade both bone and cartilage. Continual cycle develops - Proliferation of synovial membrane → more synovial fluid → swelling and pain. Bone destruction or erosion → joint space narrowing seen in x-rays

6 Cytokine rich synovial fluid → damage to adjacent supporting structures - Ligaments and tendons damaged → further joint weakening

7 Unopposed inflammation → systemic disease - This unopposed cumulative inflammatory activity is the proposed basis for the widespread systemic manifestations of the disease.

Clinical presentation or RA 1 Joints → swollen, painful, morning stiffness, warmth and redness – caused by inflamed synovial membrane2 Small joints of hands and feet – MCP, PIP, wrist, MTP - Also knees, shoulders, ankles, elbows, hips, spine –

less often at presentation but more likely as disease progresses 3 Symmetry – bilateral joints affected4 Multiple joints - 3 or more affected simultaneously5 Non-specific systemic symptoms - weakness, fatigue, malaise, weight loss, low grade fever6 Signs on X-ray and MRI - MRI more sensitive, can show early signs of joint damage – although erosion and

deformity are generally late symptoms that therapy is trying to prevent Biochemical markers – ESR, CRP, RhF, Anti-CCP, ANA - Biochemical markers are not specific for RA but do lend weight to the diagnosis

Biochemical Markers • ESR and CRP – generally low specificity for RA. Inflammatory markers • RhF - in 60-80% of patients with RA, in 5% without RA - positive may indicate more severe disease • Anti-CCP (anti-cyclic citrullinated peptide) – newer, more specific for RA, good early indicator, high levels

more aggressive disease ANA (Anti nuclear antibodies) not usually present in RA – may help with differential diagnosis eg SLE

Reasons to Refer • Early diagnosis and management results in better outcomes

Previous therapy aims were palliation with supportive analgesic treatment initially and then NSAID’s to treat pain. Now the aim is to treat more aggressively to achieve early induction of disease remission and prevent joint damage

• Refer patients with: two or more swollen joints and/or, morning stiffness for > 30minutes and involvement of MCP or MTP joints for evaluation by a Rheumatologist

• Refer within 6 weeks There is substantial evidence that in RA joint destruction begins within a few weeks of symptom onset and that early treatment decreases the rate of disease progressionAggressive and early therapy is critical to improving long term outcomes by minimising joint damage and associated pain and disability.

Diagnosis of RA• Can be difficult as not all symptoms and signs present initially • May develop insidiously over the course of weeks to months – Some more dramatic onset of symptoms

Chart American College of Rheumatology (ACR) Classification – 4 criteria present 1-4 (*) must be present

Treatment of RA involves a multidisciplinary approach.• Includes - Rheumatologist, GP, nurses, podiatrists, occupational therapists, physiotherapists and pharmacists

for a coordinated approach • Also optimal care of patients with rheumatoid arthritis (RA) requires an integrated approach of

pharmacologic and non-pharmacologic therapies.• Pharmacologic includes drugs to manage the disease and also drugs for management of co-morbidities, such

as CV disease and depressionNon pharmacologic therapies important to total management.

Non Pharmacologic Therapies• Exercise - Patients often fear exercise. Better outcome if they engage in both aerobic and strengthening

exercises on a regular basis.• Education - Arthritis Australia• Diet: not strong evidence, acceptance that healthy weight and BMI reduces mechanical stress and CV

disease• Footcare - Annual foot assessment and reviews so early detection and interventions can be made if

necessaryMassage, hydrotherapy, splints, living aids - designed to maintain function and independence

Omega 3 Fatty Acid Supplements • Fish oils may be of benefit (omega-3 fatty acid) – there is some evidence • May reduce production of pro-inflammatory mediators and also ↓ BP, and improve arterial compliance and

↓ raised triglycerides • Reduce pain, morning stiffness, number of affected joints and ↓ NSAID use • Evidence for high dose and as fish oil may take up to 3 months for maximal effectiveness, it should initially

be administered in combination with analgesics. High dose required (up to 12 capsule or 15ml of fish oil liquid – 2.7g omega-3 daily)

• Avoid reflux by taking immediately before main meal• Improve palatability take with fruit or veg juice • Gamma linoleic acid (GLA) less evidenceThere is evidence that fish oil may be of some benefit in RA

Analgesics in RA • Manage pain & inflammation - but are never the sole treatment as they do not stop disease progression.

Paracetamol• Paracetamol remains analgesic of choice due to safety profile but NSAIDs often used as few people are

adequately controlled by paracetmol

• In late disease where inflammation is no longer prominent and pain is due to structural joint damage it may be appropriate to substitute paracetamol for NSAIDs

NSAIDs (conventional and COX-2 selective) • Higher risk of side effects than paracetamol• Clinical response and toxicities to NSAIDS differ greatly among individuals • Generally indicated for early management as bridging therapy whilst awaiting the effects of DMARDs or

during disease flares• To limit toxicity use lowest dose for shortest period

OpiodsOpioids are sometimes necessary to manage more severe pain eg oxycodone, morphine and transdermal fentanyl

What do they do? • Rapidly and effectively control joint inflammation. Anti-inflammatory, immunosuppressant and disease

modifyingThree main uses

• Bridging therapy until DMARD effective - short term therapy for rapid disease control while less toxic DMARD takes effect (DMARDs have slow onset which may take 6 weeks to 6 months). Useful when starting or ↑ dose of a DMARD. Once DMARD takes effect the corticosteroid can be omitted.

• Acute flares – Can be treated with oral, intra-articular or depot IM injections of corticosteroids. Dose is variable. Can use short term pulse therapy to suppress an active flare at any stage in disease

• If oral therapy is used for a period > than 2 to 3 weeks the corticosteroid dose needs to be tapered to ↓ the chance of rebound flare or precipitation of an adrenal crisis.

• Long term therapy– used in patients who cannot tolerate NSAIDs or where the use of DMARDs has been unsuccessful or poorly tolerated. A long term dose of prednisone or prednisolone (with or occasionally without a DMARD ) may provide disease control

What dose?• Oral treatment or intra-articular injection• Betamethasone (Celestone), methylprednisolone (Depo-Medrol), triamcinolone (Kenacort A)• Triamcinolone is least soluble and provides longest duration of relief from symptoms• Can also see depot IM injections or intravenous therapy • Dosing:

Short term 0.1-1.0mg/kg/day up to 50mg/dayLong term doses 5-10mg daily. Doses higher than 15 mg daily should be avoided if possible.IA injections ≤ 4 per joint in 12 month period

• See short term and long term side effects with corticosteroidsShort term

• GI upset – take in morning with food to minimise • BP/diabetes – monitor• Euphoria – also other mood changes• Insomnia – take in morning to minimise sleep distruption – coincide with body’s early morning natural

cortisol release. Long term Weight gainSkin atrophyBruisingOsteoporosisCataracts Hyperglycaemia

Hypertension ↑ risk of infectionPeptic ulcer disease Cushingoid features Fluid retentionPremature atherosclerosisCNS – confusion, delerium

DMARDs• Methotrexate and leflunomide most common• Cyclophosphamide, chlorambucil and cyclosporin are effective in treatment of severe, progressive RA but

carry risk of potentially serious toxicity.These drugs are usually limited to patients with progressive RA unresponsive to more conservative management or for potentially life threatening complications of RA

bDMARDs• Should be considered for the treatment of rheumatoid arthritis if remission is not achieved with the

appropriate use of DMARDsAre becoming increasingly popular and more being released onto the market and onto PBS

When to use?• Initiate therapy for ALL patients within 3 months ideally• Slow onset → bridging therapy - Should see a response at 12 weeks but due to slow onset may need

bridging therapyWhy use? (see graph)Illustrates the effect early treatment with DMARDs vs late treatment. In early treatment disease activity is lower overall for the course of the disease. Joint deterioration is largely avoided and early treatment gives the best chance of remission.First line therapy?

• Methotrexate (MTX) is first line therapy is Aust -– depending on severity of disease can use sulfasalazine, hydroxychloroquine or leflunomide instead of or in combination with MTX

Monotherapy or combination therapy? • Good evidence to suggest combination therapy is superior to monotherapy for patients who have recent

onset disease and those not adequately controlled on a single DMARD• Change in practice – previously DMARDs were sequentially substituted now tendency to combine• Optimum combination of DMARDs and bDMARDs not yet elucidated. Can use triple therapy of DMARDs• If remission not achieved or significant disease activity persists after trialing non biologic DMARDs →

Rheumatologist for assessment for bDMARD therapy. • Generally monotherapy with nonbiologic is considered appropriate for patients with low disease activity and

no features of poor prognosis• Biologic DMARDs as initial therapy in Aust restricted by PBS - PBS restrictions require patient to have failed

nonbiologic therapies before progressing to biologic therapy.Ongoing treatment

• Once disease control achieved → lowest effective dose to maintain control• Most patients on DMARDs indefinitely (expectation)• Rare to achieve permanent remission• If therapy ceased can be more difficult to control if recurs• Need to assess disease-specific outcomes – treat to target

Illustrates the effect early treatment with DMARDs vs late treatment.• In early treatment disease activity is lower overall for the course of the disease. Joint deterioration is largely

avoided and early treatment gives the best chance of remission. My story

• Post partum presentation • Dismissed as “pain after pregnancy” ? “perhaps she is depressed and not coping”• Finally diagnosed via MRI – widespread inflammation although symptoms mainly hands and feet • By the time referred to Rheumatologist → remission, no treatment commenced • Second flare – analgesics and NSAIDs unsuccessful, returned to Dr and then Rheumatologist and MTX

commenced with prednisolone bridging therapy.Picture was used to show Rheumatologist swelling that had been apparent for months.

Gold standard in RA • MTX not only slows radiographic progression of disease but also is associated with a reduction in long term

mortality.How it works?

• Not fully understood how MTX works in RA – cytotoxic high doses but RA dose relatively lower• Folic acid antagonist – cytotoxic, immunosuppressive and anti-inflammatory actions

Dose?• Dosage 7.5 – 25mg once a week. Dose can be given orally, SC or IM injection • 6-8 weeks before full benefit seen • Can divide oral weekly dose into 2 or 3 doses 12 hours apart if GI upset

Folic acid used in conjuction • Give with folic acid 5mg once or twice a week (not same day as MTX) Folic acid doses can vary 5-27.5mg per

week • Folic acid → ↓GI upset, somatitis, abn LFTs, toxicity, alopecia

Adverse effects:• Mild toxicity common(~60%) adverse effects usually minor but 30% discontinue after 5 years • Disease flare for a day or two following each dose• Nausea often occurs the day after the dose is taken.• Nausea and mouth ulcers common but ↓ with continued use and folic acid use• Hair loss is reversible - Also fatigue, depression, diarrhoea, rash

Major toxicities are myelosuppression, abnormal LFTs, hepatotoxicity, nephrotoxicity, and rarelylung toxicity.

• Myelosuppression/anaemias – symptoms to watch for - mouth ulcers, lethargy, sore throat, fever, bruising. ↑ risk if advanced age, reduced renal function, high MTX dose or combination with other anti-folate drugs

• Mild transaminase elevations common - progression to fibrosis/cirrhosis is rare but ↑ with alcohol• Pneumonitis and fibrosis occurs most common early in treatment (3-7%) – serious side effect. Possibly ↑ in

patients who smoke. Can be delayed and can even develop up to 4 weeks after therapy discontinued. Most frequent symptoms are non-productive cough, dyspnoea and fever. Mortality from this 10-25%

Monitoring: • Chest x-ray at baseline :FBC, LFT’s, Cr monthly for 6 months then every 1-2 months

Interactions:• Anti-folate drugs (trimethoprim & phenytion) → increased risk of haematological toxicity • Dose reduction in mild renal impairment – contraindicated in moderate to severe renal impairment• Hepatotoxicity is potentially ↑ by co-administration of azathioprine, sulfasalazine or leflunomide

MTX concentrations are ↑ if given concurrently with probenecid, penicillins, aspirin or other NSAIDs.

How do they work?• Pro-inflammatory cytokines, particularly tumour necrosis factor (TNF) alpha and interleukin-1 (IL-1), play a

major part in the pathophysiology of RA• Biological drugs directed against TNF alpha and IL-1 have been developed for the treatment of RA and other

inflammatory disordersWhat is their place in therapy? Limitations on Use?

• These drugs are most efficacious in RA when given in combination with MTX.• Widespread use limited by cost and availability (on PBS) and side effects?• BUT Can alter disease in previously difficult to treat patients – currently the most potent inhibitors of

radiologically measured joint damage.• More bDMARDs are in the experimental or clinical trial stage and becoming available on the PBS

Dosing?• Not oral – Subcutaneous injection or IV infusions • TNF inhibitors, effect is usually apparent within 2 to 4 weeks.• Not all patients respond and it is unclear why

Adverse Effects: risk of severe infection, also ↑ risk lymphoma, reactivation of latent TB and inactive Hep B, thrombocytopenia and Multiple sclerosis, exacerbate CCF Before commencement screen for TB, HBV and HCVReactions related to administration Monitor: FBC and LFTs every 3 to 6 months

Case Study• Illustrates the complexity of controlling aggessive disease and dealing with resultant side effects from drug

treatment• Many drugs to control disease progression and pain (many tried along the way also) – • Many drugs to control systemic manifestations of RA • Many drugs to control side effects of medications

Tricyclic antidepressants may be of use if other medications provide insufficient pain relief for pain persisting beyond 2 to 3 weeks, and particularly when pain is interfering with sleep.

OSTEOARTHRITIS

Characteristics of OA• Most common musculoskeletal condition. - 1.5 million Australians• Debate about pathophysiology • Uncommon before the age of 40 but then ↑ significantly with age. > 50% in those aged over 65 years• Most commonly affected joints include the hands (particularly the distal interphalangeal joints (DIP) and the

first carpometacarpal joints (CMC)), cervical spine, lumbar spine, knees and hips. • OA no longer just considered a disease of wear and tear. Biomechanical forces are involved but also some

inflammatory, biochemical and immunologic components• Affects cartilage, subchondral bone, ligaments, capsule, synovial membrane and periarticular muscles

Clinical Presentation• Pain is primary symptom – acute and chronic.• Pain is described as a deep aching pain that is not well localised. Acute pain is due to the inflammatory

process and chronic pain is due to peripheral and central sensitisation that occurs due to persistent pain stimulus.

• Pain exacerbated by activity – as disease progresses can get pain at rest.• Stiffness can be severe but transient – often occurs after brief rest periods but <30minutes after rising• Joint enlargement & deformity – bony proliferations (osteophytes) → joint enlargement and deformity• Loss of function - range of movement restricted, reduced mobility. Can be very variable e.g. impairment with

insignificant pain • Overall: limitations to ADL, ↓ independence, ↓ social interactions, decline in well being • X-ray - - radiological changes not necessary for diagnosis – little relationship between radiological changes,

pain & disabilityLab testing not useful for diagnosis as OA primarily non-inflammatory arthritis, ESR and CRP expected to be normal

Who gets OA?• Depends on joint vunerability and joint loading• Risk factors include:• age• gender• genetics• Nutrition• injury• occupational overuse,• muscle weakness• bone density• Malalignment• proprioceptive deficiencies• obesity• sport activities• Management of patients with OA should include an assessment for risk factors. Some risk factors for OA

such as age, female gender and family history - not reversible but obesity, injury, malalignment, and occupational overuse - potentially modifiable..

• Age – by age 65 - 80% show radiographic changes although not all report symptoms • Gender – females > risk than males (except < 50years more prominent in males)• Genetics – Children of parents with early onset OA are at ↑ risk of developing OA• Nutrition – Low serum Vit D → ↑ risk of disease progression but not of developing OA, also proposed that

antioxidants (eg vit C) protect against tissue damage eg cartilage and thus OA• Previous injuries - fractures or tearing of ligaments → more susceptible to OA• Occupational overuse - repetitive tasks, heavy lifting, kneeling, squatting → knee and hip OA; tasks repetitive

pincer grip → higher rate OA in distal interphalageal joints • Muscle weakness - in muscles bridging a joint is a result of OA but also can ↑ OA risk• Osteoporosis - Inverse relationship with OA and Osteoporosis – high BMD → ↑ hip, hand and knee OA • Malalignment → stress on focal areas of cartilage which then break down eg bowlegged• Proprioceptive deficiencies → perception (awareness) of joint position & movement. Critical to joint stability.

Seems to ↓ with age and sedentary lifestyle • Obesity – strong association with OA of knee and less so with hip. Overloading the weight bearing joints can

lead to cartilage breakdown and failure of ligament and other structural support. But also see more OA in the hands of obese people – suggests some metabolic component due to excess adipose tissue

• Sports – high intensity, direct joint impact (contact), twisting movements (eg baseball & elbows), playing surfaces (eg soccer & knees). Moderate regular running appears to have low if any risk.

Comparison of OA and RA

Very important to understand differences

Pathophysiology• Historically considered to be a non-inflammatory degenerative disease of ‘wear and tear’, it is now

understood that OA results from a combination of factors, including joint integrity, genetic predisposition, local inflammation, mechanical forces, and cellular and biochemical processes.

• Pathophysiology on X-ray

• Clearly shows the “bone rubbing on bone” due to thinned cartilage that is characteristic of OA as opposed to the swollen synovitis seen in RA

Treatment of OA Aims

• Patient education & self management • Pain control• Improved function and ↓disability• Altering disease process and its consequences

Management strategies• Education – Arthritis Australia (website), Pharmacy self care • Exercise & physiotherapy - Physical exercise that is light to moderate in intensity and consists of resistance

training, aerobic exercise and flexibility exercises should be recommended. Focus on strengthening muscles across the affected joint, improving range of motion, improving aerobic capacity and endurance, all of which contribute to improving physical functioning and pain reduction. Low impact exercises eg water aerobics and water resistance training may be better tolerated by patients as there is reduced stress due to buoyancy * remember to consider co-morbidities when recommending exercise

• Weight reduction - A weight loss of around 5kg over 10 years can ↓ odds of developing OA by >50%• Hot & cold packs - Thermotherapy evidence (esp heat) is limited• TENS - can be beneficial depending on device and wave forms used, also need adequate duration eg 4 weeks • Acupuncture - theoretically endogenous opioid pathways are triggered to produce analgesia• Aids and devices – Independent Living Centre - OT or physio may recommend appropriate aids and devices

Magnetic devices - weak evidence for use of magnetic bracelets to treat hip and knee OA and little evidence for other devices. Caution: possible interference with pacemakers and other medical devices; avoid placement near transdermal medication due to potential to ↑ blood flow and alter release rates.

Drug therapy in OA • Non pharmacological approaches constitute the basis of OA therapy but pharmacological therapy has an

important adjunctive role • No drugs available which reverse or alter structural or biochemical changes associated with OA• Pharmacological therapy targeted at symptom control ie pain relief

Supplements in OA • Although evidence may be lacking they should not be immediately deemed inappropriate as use

demonstrates an active participation by patients in the management of their disease• The rationale for the use of glucosamine sulfate is based on animal models of OA in which there is

normalisation of cartilage metabolism, some anti-inflammatory properties, and a rebuilding of experimentally damaged cartilage.

• Studies are inconsistent. Recent Cochrane review – only 1 brand benefit over placebo Rotta brand• Also studies with sulfate and not hydrochloride• Long-term effectiveness and toxicity of glucosamine in OA is yet to be established.

• Suggest trial medication for 2 to 3 months to evaluate - Dose 1500mg daily (usu 500mg tds) • No evidence combination with chondroitin better

Caution: shellfish allergies, monitor INR (possible effects), concern glucose control unsubstantiated but recommend diabetics monitor

Paracetamol in OA Place in therapy

• Treatment of choice, mild – moderate, persistent pain • Paracetamol has analgesic and antipyretic actions in the central nervous system• Mechanism of action not fully understood- analgesia probably results from inhibition of prostaglandin

synthesis centrally. The lack of inhibition peripherally explains the lack of anti-inflammatory action.Paracetamol dosing

• Immediate release tablets: 1-2 x 500mg every 4 to 6 hours; max 8 tablets (4g) in a day • Modified release tablets: 2 x 665mg every 6 to 8 hours; max 6 tablets (3990mg) in a day• Dosing should be by the clock rather than as needed• Need to consider precautions• Need to consider all sources of paracetamol (eg OTC preparations)

Expectation• Rapid absorption – peak conc 10-60 minutes, analgesia - 30minutes after admin, short duration – 4-6 hours

thus need adequate dosing• Many people who report no success with paracetamol may use inadequate dosing.

Metabolism & Caution• Metabolised in liver – conjugated to inactive metabolites and excreted in urine • A small proportion is metabolised to a hepatotoxic metabolite Normally this is inactivated via conjugation

with glutathione however in patients with depleted glutathione stores (eg starvation or excessive dosing) or hepatic or renal dysfunction the risk of paracetamol toxicity is increased. Thus caution – renal or hepatic dysfunction

Hepatotoxicity rare with therapeutic doses but ↑ with poor nutrition, fasting or chronic alcohol abuse.

NSAIDs in OA Place in therapy/Action

• Analgesic, antipyretic - Anti inflammatory - several days dosing • No NSAID more effective than another - patient variability seen • No NSAID is considered safe • Paracetamol first line • Concurrent paracetamol to ↓ NSAID dose• Intermittent use of NSAIDs – for exacerbations • Choose NSAID with short half-life for use in the elderly, and in patients with renal impairment

Dosing• Onset of action / effect 30 – 60 min• Diverse group of drugs• Must dose constantly at least several days -Prn not significant anti-inflammatory action

Maximal analgesia and anti-inflammatory effects are usually seen within 2 weeks

How do NSAIDs work?• All NSAIDs exhibit their main effect by inhibiting cyclooxygenase (Cox) → reducing pro-inflammatory

prostaglandin synthesis centrally and peripherally • There are two Cox isoforms

• Cox 1 inhibition is associated with reduced synthesis of thromboxane A2, inhibition of platelet aggregation and gastrointestinal toxicity

• Cox2 inhibition is associated with reduced pain and inflammation, reduced prostacyclin synthesis (and so reduced anti-thrombotic activity) and increased risk of serious cardiovascular events. (NB the experience with Vioxx® withdrawn in 2004)

• Reduction in glomerular filtration rate and renal blood flow occurs with both Cox 1 and Cox 2 • All NSAIDs currently available in Australia are non selective inhibitors of Cox1 and Cox2

Adverse Effects Gastrointestinal toxicity

• Upper abdominal pain or discomfort – reported in up to 50% of NSAID users• A minority → serious GI complications eg peptic ulceration, occult bleeding or perforation• Symptom analysis cannot reliably distinguish NSAID-related dyspepsia from ulcer pain• Many problems clinically silent until complications such as bleeding, anaemia or perforation occur.• Risk of a serious GI adverse event varies between drugs and is also dose-related. NSAIDs with longer half-life

- more likely → serious GI complications.• Risk is also related to patient-specific risk factors eg age (>65 years), co-morbidity, past ulcer disease,

smoking and concomitant medication (eg antiplatelet agents, anticoagulants and corticosteroids). • H. pylori infection combined with NSAID use increases the risk of ulcer disease 60-fold. • Gastroprotective strategies only considered for patients already at risk of ulcer complications• Although concurrent low dose asprin ↑ risk of GI ulcer should not stop low dose aspirin treatment when

using an NSAID as NSAID antiplatelet effect is unreliable• Can use PPIs or double dose H2 antagonists. Mistoprostol 800mcg daily shown to ↓ ulcer complications but

intolerable diarrhoea and nausea. Cox-2 selective (eg celecoxib) may cause fewer ulcer complications than non selective but risk of CV events may be greater

• Enteric coated and rectal formulations do not ↓risk of GI ulceration Renal impairment - NSAIDs in patients with existing renal impairment may worsen renal function and → acute renal failure Oedema - can occur with NSAIDs

• Cardiac disease - All NSAIDs can worsen existing cardiac disease eg by ↑ BP and ↓ renal functio. Heart failure can be exacerbated

Bronchospasm - Watch for wheezing and shortness or breath. If a patient has aspirin-induced asthma and great need for an NSAID they may be able to tolerate a selective Cox2 inhibitor *first dose under medical supervision

Opiods in OA Place in therapy

• Increasingly being prescribed for chronic non-cancer pain • Treatment of severe pain – when paracetamol & NSAIDs insufficient, joint surgery is contraindicated or

delayed• A major aim of their use is to relieve pain to an extent that allows increased mobility and participation in

normal activities of daily livingHow do they work?

• Diminish both the sensation and the response to pain• Mimic endogenous opioids by activating one or more subtypes of opioid receptors (mu, kappa, delta) at

supraspinal, spinal and peripheral sites• Some pure agonists, some mixed agonist-antagonist, some partial agonists• Partial agonist – ceiling response – ie an ↑ in dose does not produced an ↑response

Which one?• Weak opioids are less effective than strong opioids but have the same adverse effects. • Long acting agents used regularly are preferred over short acting agents used “prn”

• Codeine - weak opioid of choice• Morphine – strong opioid of choice• Oral route should be used whenever possible

Precautions• Need a stable patient – assess psychological stability of the patient• No contraindications eg severe COPD

How to implement use?• Accurate diagnosis – commencement of opioids should be done as part of an overall pain management

strategy, involves consultation with the rheumatologist or pain specialist. Need to assess the underlying cause of the pain

• Informed consent from patient – discussion risks and benefits• Limits on prescribing established - Limiting prescriptions and dispensing of opioids to certain doctor(s) and

pharmacy • Trial period and reassessment plan - trial period of 4 to 6 weeks, tapering and cessation of the drug if

adverse effects outweigh the therapeutic benefits, or treatment goals have not been reached.

Other Options in OA Topical treatments

• Several topical NSAID preparations are available in Australia, including diclofenac , ibuprofen, ketoprofen and piroxicam.

• The topical analgesic capsaicin is available as a cream and rubefacients containing methyl salicylate are also available.

• In patients with multiple, large joint involvement, topical NSAIDs are expensive and relatively impractical.Intrarticular Injections

• Indicated for acutely painful, swollen jointsViscosupplementation

• Hyaluronans that are available in Australia are marketed only for knee OA: (Synvisc® and Fermathron®).SurgeryNot just replacements (arthroplasty) also arthroscopic lavage and debridement (joint irrigated with sizeable volume of physiological saline); tidal irrigation (similar to lavage but local anaesthesia only), osteotomy (remove section of bone near joint with or without realignment)

GOUT

What is gout? • Acute inflammatory arthritis caused by uric acid crystal deposition in the joint• Usually sudden onset - Max pain occurs within 6 to 12 hours. Urate crystal formation however occurs slowly

(weeks to months) and does not produce symptoms.The inflammatory system largely (but not completely) ignores the crystals most of the time, but eventually an inflammatory response occurs resulting in an attack of gout.

• Tendency to recur (intercritical gout) - Most untreated patients will have a second attack within 2 years• Underlying metabolic disorder – hyperuricaemia. Often at the time of the attack uric acid levels can be

misleadingly “normal”. Also interesting is that not all people with hyperuricaemia will develop gout. Can get asymptomatic hyperuricaemia.

• Commonly occurs in the big toe - May affect other joints such as heels, ankles, knees, fingers, wrists and elbows

• Kidney involvement - The two major manifestations are nephrolithiasis and chronic urate nephropathy

Who gets gout?• Gout mainly affects middle aged men but:• For a given concentration of hyperuricaemia, men and women have = risk of gout. However, men have ↑

concentrations of uric acid and therefore a ↑ prevalence of gout, whereas pre-menopausal women and children have ↓ concentrations and therefore a ↓ prevalence of gout

• There is a gradually increasing prevalence in both men and women in older age groups. Women usually develop gout after menopause.

• Peak incidence of first acute attack 40 -60 years • Table includes other risk factors• Interestingly some reports suggest that diuretics do not actually increase the risk of gout. Indications to

prescribe diuretics (hypertension and cardiovascular diseases) are themselves associated with gout. Conditions such as hypertension and CV diseases are also associated with higher uric acid serum concentrations.

Dietary risk factors for gout• Dietary changes can help ↓ uric acid levels in the blood. Since purine chemicals are converted by the body

into uric acid, purine-rich foods are avoided. Examples of foods rich in purines include shellfish and organ meats such as liver, brains, kidneys, and sweetbreads.

• Researchers have reported, in general, that meat or seafood consumption ↑ risk of gout attacks, while dairy food consumption seemed to ↓ the risk.

• Protein intake or purine-rich vegetable consumption was not associated with an ↑risk of gout.• Total alcohol intake was strongly associated with an ↑risk of gout (beer and liquor were particularly strong

factors). Consumption of sugar sweetened soft drinks and fructose is strongly associated with an ↑ risk of gout in men.

Pathophysiology of gout• Hyperuricaemia – high conc ↑ likelihood gout• Hyperuricaemia due to : overproduction or underexcretion • Although hyperuricaemia required for crystal formation - not the full explanation. Urate crystals form in only

certain locations, and not at all in most people with hyperuricaemia. Various biological substances, such as IgG, influence the nucleation and growth of urate crystals. The balance between inhibitors and promoters of crystal formation probably plays a major role in determining if and where urate crystals form

• Crystals form initially within joints (synovium) and subsequently in other connective tissue sites such as bones, skin and tendons.

• Urate crystals cause release of inflammatory mediators and phagocytes; influx of neutrophils → synovitis • Intense joint inflammation occurs as white blood cells engulf the uric acid crystals and chemical messengers

of inflammation are released, causing pain, heat, and redness of the joint tissues.Chronic gout

• Chronic gout → cytokine driven synovial proliferation, cartilage loss and bone erosion• Chronic gout can lead to the development of solid urate deposits (tophi) • Tophi occur in connective tissues such as the upper extremity on the fingers, nodes over the olecranon bursa

(bony tip of elbow) or ear.• These tophi may ulcerate or get infected.

Hyperuricaemia causes • Increased production:

• 10% of hyperuricaemia

• Genetic disorders /hereditary• Conditions with: ↑ cell turnover eg psoriasis, Paget’s disease, ↑nucleoprotein turnover eg

lymphomas, leukaemia, haemolytic anaemia • Decreased secretion:

• > 90% hyperuricaemia • ↓ renal excretion due to drugs and diseases

Lowering uric acid • Vitamin C has a uricosuric effect ↓ serum uric acid levels• Vitamin C also significantly ↑ glomerular filtration rate • Research shows – (In men) the risk for gout appears to decrease as vitamin C intake increases.• Coffee: • Long-term coffee consumption is associated with a lower risk of gout.

Caffeine is a methyl xanthine and may be a competitive inhibitor of xanthine oxidase. It may therefore exert a preventive effect similar to allopurinol.

Classifications of gout• Primary: inborn/inherited defects affecting purine metabolism or renal function• Secondary: to certain acquired diseases, drugs and lifestyle factors• Acute : First attack usually 1 joint (often big toe), can be severe and lasts 2 days -2 weeks (if untreated).

Often also fever and malaise. Chronic: Eventually, recurrent attacks may fail to resolve completely → a crippling destructive arthritis. Can see tophi at this stage

Diagnosis of gout• Serum uric acid levels (may be in normal range in acute attack) • Female……0.15–0.40 mmol/L (APF 21 ref ranges)

Male……… 0.20–0.45 mmol/L• Aspiration of affected joint to detect crystals • Consider secondary causes • Consider differential diagnoses eg septic arthritis, pseudogout,

Calcium pyrophosphate deposition disease (pseudogout)

Acute gout treatment goalsShort term:

• Stop the acute inflammation of joints• Provide rapid pain relief

Long term:• Prevent further attacks (if possible)• Prevent future complications (tophi , destructive arthritis, renal stones)• Deal with any associated medical conditions such as alcoholism, hyperlipidaemia, hypertension, obesity, and

glucose intolerance/insulin resistanceHow to treat acute gout?

• May subside spontaneously in < 1 week but patient usually seeks treatment• Non pharmacological treatments – rest, ice, lifestyle changes, ↑ water • NSAID’s (except aspirin) treatment of choice - Need to avoid aspirin as an analgesic during acute attacks as it

can prolong and worsen attacks due to effects on plasma urate concentration. However do not stop low dose aspirin

• Use full doses and continue for 1 week after attack settled

• Allopurinol: NOT to commence during an acute attack but continue for patients already on allopurinol while having an acute attac

Intercritical gout• Intercritical gout is given to the asymptomatic interval between (even severe) recurrent attacks of acute gout• Eventually attacks become more frequent and polyarticular

Important to initiate urate lowering therapy at this time and educate patients to make lifestyle changes

Drug therapy in acute gout• Indomethacin: 50 mg orally, 3 x daily if tolerated, until symptoms abate (up to 5 days) and then reduce the

dose to 25 mg orally 3 x daily until the attack has abated and then cease (eTG))*• Consider GI toxicity risk and renal function• Corticosteroids: often preferred treatment in patients with complex medical problems where NSAIDs

contraindicated. 20-25mg mane tapered over 2-3 weeks • Colchicine: 0.5 mg orally, given 6- to 8-hourly until the attack has abated and then cease. (NB max dose) *

eTG • Reserved for acute gout when NSAIDs and corticosteroids (oral and IA) contraindicated or inappropriate

Revised dosing for colchicine in acute gout• Vomiting and diarrhoea commonly occur when colchicine is dosed at 1 hour or 2 hour intervals for acute

gout.• Recent evidence that low dose colchicine effective when prescribed within 12 hours of onset of gout flare

New dose (as per AMH) – 1mg initially followed by 500mcg one hour later (maximum 1.5mg per course. Do not repeat the course within 3 days.

Colchicine in goutAnti-inflammatory

• No effect on uric acid production or excretion, no analgesic activity. Narrow therapeutic index

• Potential for toxicity and drug interactions – 2nd line – can get accumulation• Colchicine metabolised by CYP3A4.• Combination with drugs similarly metabolised may ↑ colchicine concentration and hence toxicty. Eg

azithromycin,diltiazem,cyclosporin,erythromycin, ketoconazole, verapamil • Interactions more likely to occur in renal impairment • Fatal reactions with clarimthromycin – AVOID combination

Commence within 24 hours• Less effective once an attack has persisted for a few days (within 24 hours best)

Contraindicated• Contraindicated if Crcl < 30mL/min and patients with CVD or hepatic impairment.

Adverse drug reactionsADRs - diarrhoea, abdominal discomfort, nausea, vomiting , myopathy, bone marrow toxicty and peripheral neuropathy. Not well tolerated by older patients & renal impairment.

Drug therapy in intercritical gout• Maintenance drug therapy should be considered if a 2nd attack occurs with 1 year.• For most people with occasional attacks of gout, the risk of preventive drug treatment probably outweighs

the benefits.• Treating acute attacks early with appropriate medications and reducing risk factors may be sufficient if

attacks are infrequent.Urate lowering therapy

• Allopurinol: 50 mg orally, daily for the first week, increasing by 50 mg weekly to a maximum of 300 mg daily AND

• Colchicine: 0.5 mg orally, 3 times daily for the introductory period until after the target dose for allopurinol is reached AND/OR

Indomethacin:25 mg orally, twice daily (or a similar NSAID in the appropriate dose e.g. Naproxen)

How does it work?• Xanthine oxidase inhibitor → lowers plasma and urinary urate concentrations. Active metabolite also inhibits

xanthine oxidase and also renally excretedPrevents gout

• Drug of choice for preventing gout. Allopurinol is not indicated to treat asymptomatic hyperuricaemia• Allopurinol prophylaxis a life-long commitment

MUST NOT be started during an acute attack • Allopurinol should not be started during acute gout, due to the potential for worsening the arthritis;

however, if the patient is taking allopurinol, it should always be continued during an acute attack.Adverse drug reactions

• see next page Counselling points

• Take this medicine shortly after food to reduce the possibility of stomach upset.• If you develop a rash, swollen lips or mouth, persistent fever or sore throat, stop taking allopurinol and tell

your doctor immediately.• Make sure that you drink lots of fluids during treatment to prevent kidney stones.• This medicine may make you feel dizzy or drowsy; do not drive or operate machinery if you are affected.

Adverse drug reactions • rash, nausea, vomiting, diarrhoea, taste disturbances, abdominal pain, headache, drowsiness, vertigo,

arthralgia and (rarely) severe hypersensitivity reactions • A significant portion of patients are unable to tolerate allopurinol, and fatal hypersensitivity reactions have

occurred. • Minor hypersensitivity reactions to allopurinol (pruritus and dermatitis) occur in about 2% of patients,

usually after 3 weeks of treatment. • A more severe reaction can occur, and may be life-threatening. Allopurinol hypersensitivity syndrome

presents with fever, eosinophilia, dermatitis, hepatic dysfunction, renal failure and vasculitis.• ↓ doses in renal impairment (Max dose when CrCl is 30 mL/min is 100mg daily)

PicturedMost cases of toxic epidermal necrolysis (TEN) are drug induced, typically occurring within the first 8 weeks of therapy. It is a potentially life threatening condition.

Drugs in chronic gout• Chronic gout is usually difficult to treat. There is no asymptomatic period in which to commence urate-

lowering therapy. • The patient may be unwilling to take allopurinol because of previous experience of having had acute attacks

precipitated by its inappropriate use without colchicine or NSAID cover. • It is usually vital to resolve the inflammation if possible, before very slowly introducing allopurinol with

accompanying NSAID and/or colchicine. • The dose of allopurinol can be titrated up to achieve a serum urate concentration less than 0.36 mmol/L.

Beware failure to achieve normal uric acid concentrations may indicate poor compliance. Doses can go higher than 300mg daily if necessary but should be divided into 2 doses.

• Probenecid is used infrequently and renal impairment limits its usefulness (< effective if CrCl <50ml/min and probably ineffective if CrCl<30ml/min).

• It is occassionally used by specialists when allopurinol alone is inadequate for tophaceous disease.Patients need to drink >2L of water during the first few months of treatment to ↓ risk of uric acid kidney stones