RHEUMATOID ARTHRITIS

What Is RA?

Auto immune disease that causes chronic inflammation of the jointsAttacks the synovial membrane , resulting in inflammation, swelling & damage No cureAffects smaller joints first : wrists, hands, ankles, feetAlternate between periods of increased inflammation (flare) & periods of remissionIs a progressive illness that has potential joint destruction & functional disabilityChronic inflammation leads to destruction of cartilage, bone, and ligaments causing deformation of joint

RISK FACTORS OF RAWomen are 2-3 times more likely to develop RAUsually occurs between age 40-60 but can also occur in older adults & childrenFamily history : increased riskSmoking : increased risk

Tests & Diagnosis of RA(1) Presence of Rheumatoid factor (RF)- not very specific antibody- found in 10% of healthy population - can be negative in early stage of RA

Presence of Anti-citrullinated Peptide Antibodies (ACPAs) more specific than RF rarely positive if RA not present

(3) Elevated Erythrocyte Sedimentation Rate (ESR)

(4) Radiological changes in joints- ultrasound & MRI can detect bone damage in patients with normal X-ray

SIGNS & SYMPTOMSJoint painJoint swellingJoint that are tender to touchRed & puffy handsFirm bumps of tissue under the skin on arms (rheumatoid nodules)FatigueMorning stiffness that last at least 30 minutesFeverWeight lossInflammation usually in a symmetrical pattern

Diagnostic CriteriaAmerican College of Rheumatology has defined thefollowing criteria for RA at least 4 of theseMorning stiffness of 1 hour most mornings- at least 6/52Arthritis & soft tissue swelling at least 6/52Arthritis of hand joints- at least 6/52Symmetrical arthritis- at least 6/52Subcutaneous nodulesRF at a level about 95th percentileRadiological changes suggestive of joint erosion

PATHOPHYSIOLOGY OF RARA occurs when white blood cells move from the blood stream into the membranes that surround the joints (synovium)Migration of these white blood cells cause inflammation & release proteins that over months or years cause synovium to thickenThese proteins can also damage the cartilage, bone, tendon & ligaments near the jointOver time the joint loses its shape & alignment & eventually destroyed

CAUSES OF RACause of RA unknownInfectious agents such as viruses, bacteria and fungi have been suspected but not provenMaybe genetically inheritedCertain infections or factors in the environment might trigger the activation of the immune system then attack the bodys own tissue initially against soft tissues and later against cartilage & bone

Common Complications of RAPeripheral neuropathy & carpel tunnel syndrome-resulting from nerve damage- Sx include tingling,numbness or burningScleritis- inflammation of blood vessels in schlera (white part of eye) can damage eye & impair visionInfections due partly to use of immune-suppessing drugsGI problems- often a s/e of medicationsOsteoporosis more common in RAHeart disease RA affect blood vessels - coronary dxExtrmeme dryness of eyes & mouthShorten life span 5-10 yearsLymphoma & other cancer - risk

GOALS OF TREATMENT OF RAGoal is to reduce joint inflammation & painNo known cureMaximise joint functionPrevent joint destruction & deformity

TREATMENT OF RA1ST LINE 1) NSAIDs 2) corticocteroids2ND LINE Disease modifying anti- rheumatic drugs (DMARDs)Biologic Response Modifiers

NSAIDsThese agents reduce acute inflammation thereby decreasing pain & improving functionThey DO NOT change the course of the disease of RA or prevent joint destructionMOA inhibit generation of prostaglandins by blocking cyclooxgenase enzymes; COX-1 & COX-2COX-1 found in most tissues, esp platelets, gastric mucosa, renal vasculatureCOX -2 induced at sites of inflammationProstaglandins are mediators of inflammation & painProstaglandins also have important roles in maintenance of normal body functions including protection from stomach acid, maintenance of kidney blood flow, aggregation of platelets and vascular function

NSAID contd.NSAIDs can be divided into 2 groups1) Non selective inhibitors-block COX-1 & COX-22) Selective COX-2 inhibitorsCOX -2 selective inhibitors selectively block prostaglandins generated via COX-2 which have prominent role in inflammationA higher dose is often required to reduce inflammationLower dosage can initially be used if inflammation is mild, in elderly patients or patients have other risk factorsIf a drug is ineffective after a 4-week trial or is not tolerated , another NSAID can be initiatedNo one NSAID is more superior than another

Examples of NSAIDsCelecoxib ( Celebrex ) COX-2 selectiveDiclofenac ( Voltaren )Etoricoxib ( Arcoxia ) COX-2 selectiveIbuprofen ( Nurofen )Indomethacin ( Indocid )Ketoprofen ( Orudis )Mefenemic acid ( Ponstan )Meloxicam ( Mobic ) COX-2 selectiveNaproxen ( Naprosyn )Piroxicam ( Feldene )

SIDE EFFCTS OF NSAIDsMost common toxicity of NSAIDs is GI disturbance burning, belching or irritation, erosion or ulceration of the lining of stomach which can result in bleedingCo-administration of medication such as proton-pump inhibitor such as omeprazole ( Losec), lansoprazole (Prevacid), esomeprazole (Nexium) and a medication that provides back protective prostaglandin called misoprostol (cytotec) can reduce GI bleeding

SIDE EFFCTS OF NSAIDs contd.COX-2 selective inhibitor exhibit safer GI profiles than non selective NSAIDsBecause prostaglandin regulate blood flow in kidneys & maintain glomerular filtration, NSAIDs can impair renal function leading to salt retention, edema, BPPatients at high risk are those with peptic ulcers, fluid imbalances, compromised kidney function (e.g. heart failure, diuretic use, dehydration & renal insufficiency)Selective COX-2 inhibitors may CV risk Rofecoxib(Vioxx) and Valdecoxib(Bextra) was banned due to heart attack & stroke in pt

NSAIDs Potential interactionsPharmacokinetic Interactions - involve absorption, distribution, eliminationPharmacodynamic Interactions - involve drug effects and/or toxicity

Pharmacokinetic InteractionDecreased Absorption Of NSAIDsSucralfate coat stomach to protect from bleeding/ulcerH2-blockers/ antacids - stomach acidBile acid sequestrants bind to bile acid and prevent manufacture of cholesterol may bind to NSAIDs

Pharmacokinetic Interaction contd.

Protein Binding

Most NSAIDs are greater than 95% protein- boundPotential for drug-drug interaction via competition for protein binding sites with - warfarin - aspirin - digoxin

Pharmacokinetic Interaction contd.Warfarin InteractionNSAIDs plasma levels of free warfarin - bleeding

Aspirin Protein BindingAspirin plasma levels of NSAIDsSome NSAIDs potentiate anti-platelet activity of aspirin

Digoxin Protein BindingDigoxin is highly protein-bound & easily displaced by other drugsIndomethacin can plasma level of digoxin to a toxic levelPt on digoxin should avoid indomethacin

Pharmacokinetic Interaction contd.P450 InteractionsMost P450 interactions involve changing the metabolism of NSAIDs Fluconazole enzyme inhibitor - celecoxib plasma concentration - ibuprofen plasma conc - potential for excessive NSAIDs levels that could lead to nephrotoxicity & cardiovascular eventsRifampicin it induces liver enzymes - significantly plasma levels of celecoxib - pt may not have adequate pain control

Warfarin is an anticoagulant metabolised by liver enzymes - competition for metabolism lead to level of warfarin leads to excessive bleeding

Pharmacokinetic Interaction contd.Renal EliminationProbenecid renal reabsorption of NSAIDs - plasma level of NSAIDs - may lead to effects of probenacid

Methotrexate & Lithium - renal elimination in the presence of NSAIDs toxicity

Pharmacodynamic InteractionsEffects on other drugs due to inhibition of prostaglandins adverse effects e.g. - Bleeding - GI toxicity - Nephrotoxicity

Pharmacodynamic Interactions- contdInhibition of Renal ProstaglandinsLoss of BP control with beta-blockers, ACE inhibitors, diuretics

Increased Risk of Nephrotoxicity withCyclosporinMTXAminoglycosidesTriamtereneThese drugs can cause kidney damage on their own

Pharmacodynamic Interactions- contdIncrease GI bleeding with - Salicylates - Anticoagulants - Antidepressants

NSAIDS CONTRAINDICATIONSGI BleedingGI ulcerationPt with renal impairmentThrombocytopenia & coagulation abnormalitiesPt on anticoagulantsPt with heart failureChildren with a tendency to asthmaChildren receiving regular asthma medication

CORTICOSTEROIDS

E.g. are prednisolone , methyprednisoloneThey have both anti-inflammatory & immunoregulatory activityCan be given orally, IV, IM or injected directly into the joint (intra-articular) Useful in early disease as temporary adjunctive therapy while waiting for DMARDs to workAlso useful in chronic adjunct therapy in pt with severe dx that is not well controlled on NSAIDs & DMARDs

CORTICOSTEROIDS-contd

Usually low dose oral prednisolone is given ( 5-10mg daily) Occasionally given at high dose to give immediate effect & the dose is reduced gradually (tapered) over few weeks or monthsOnce started corticisteroids therapy may be difficult to discontinueMust not be stopped abruptly this will lead to severe side effects or orsening of RA- taper the dose slowly over days or weeks to less than 10mg dailyOnce a day dosing of prednisolone is associated with fewer side effectsSome may tolerate EOD dosing which may S/E

CORTICOSTEROIDS CONT.Bisphosphonates such as alendronate (Fosamax) are recommended to prevent / treat osteoporosis in addition to calcium & vit D supplementsHigh doses of prednisolone are rarely necessary unless there is a life-threatening complicationGenerally steroids are given in the morning upon waking to mimic the bodys own steroid surgeUse of corticosteroids as the sole therapeutic agent should be avoidedIntra-articular corticosteroids (e.g. Triamcinolone or methyprednisolone ) are effective for controlling a local flare

CORTICOSTEROIDS CONT.SIDE EFFECTS esp. given in high doses for long periods of time include:Wt gainCushingoid appearance (facial puffiness, redness of cheeks & buffalo hump over the neck) BP blood sugar risk of cataractsMuscle wastingDestruction of large joint e.g. hips (osteoporosis) risk of infection

DMARDsSuppress the bodys overactive immune and/or inflammatory systemsImprove symptoms of active RA & improve radiographic outcomeSlow acting take effects over weeksChoice of DMARDs depend on a no. of factors incl. the stage & severity of the joint condition, possible side effectsIndication for DMARDs is presence of erosions or joint space narrowing on x-rays

DMARDs- contdDMARDs have been found both to produce durable symptomatic remissions & delay or halt progressionThis is important as such damage is usually irreversiblePermanent damage of the joints can occur at a very early stageNowadays started early in the disease soon after diagnosisDMARDs can suppress the ability of the immune system to fight infections-watch out for signs of infections e.g. fever, cough or sore throat

METHOTRXATE1ST line DMARD for pt with RARelatively rapid onset of action 6-8 weeksIt reduces inflammation & decrease bone damageUsually taken ONCE PER WEEK or by injectionUsually started at a low dose (

METHOTRXATE contdAdverse effects of MTXCommon side effects include upset stomach & sore mouth, mild alopeciaGI upset ( nausea & diarrhoea can be lessen when taken at night)MTX interfere with bone marrows production of blood cells leads to fever, infections, swollen lymph nodes & bleedingLiver & lung damage can occur even at low doseAlcohol consumption during therapy with MTX can risk of liver damage- limit to no more than 2/week

METHOTREXATE contdMonitoring required chest x-ray before starting treatmentBlood tests every 4-8 weeksSupplement of folic acid 1mg daily or folinic acid 5mg weekly can reduce risks of certain S/E such as upset stomach, sore mouth & abnormal liver functionMTX not safe during pregnancy women taking it must use a reliable method of birth controlWomen on MTX should discontinue this drug & allow one full menstrual cycle to pass before attempting to conceiveMen on MTX should wait at least 3 months before their partners attempting to conceive

SULFASALAZINE(Salazopyrin)mechanism of action unknownMaybe used in combination with other DMARDs if not responsive to one medicationTaken orally twice daily with foodUsually start at a low dose (500mg/day) and increase slowly to 2000-3000mg/day) to minimise side effectsTake 6 weeks 3 months to see effects

SULFASALAZINE- side effectsS/E include changes in blood counts, nausea & vomiting, sensitivity to sunlight, skin rash, headachesPatient with G6PD deficiency maybe predisposed to red blood cells hemolysis & anemiaPeople allergic to sulfa drugs may have cross allergySulfasalazine is yellow/orange colour patient may notice their urine , tears & sweat develop an orange tingeAdequate fluid intake is importantSulfasalazine is a preferred agent to MTX in pt with liver disease or who have Hep B or CSafe for use in pregnancy- passes into breast milk so C/I for nursing mums

HYDROXYCHLOROQUINE(Plaquenil)Can be used early in the course of RAOften use in combination with other DMARDsCan be combined with steroids to the amount of steroid neededUsually taken orally once dailyUsual dose 400mg/day taken once a day or bd . 600mg/day is sometimes usedTake 2-4 months to take effect

HYDROXYCHLOROQUINESide-effects & Special PrecautionsProlonged therapy esp. at high dose may increase risk of damage to retina- most important S/EAn eye exam is recommended before starting treatment & every 6 -12 months thereafterUse in pregnancy is controversialSafe to use when breastfeedingPt with underlying retinopathies or risk may not be a good candidate for hydroxychloroquineOther common S/E : skin rashes, GI effects, hair loss, sensitivity to sunlight

LEFLUNOMIDE (Arava)inhibits production of inflammatory cells to reduce inflammationOften used alone but can be used in combination with MTX for people who have not responded adequately to MTX aloneTaken orally 10-20 mg once dailyOnset of action relatively rapid within 4-8 weeks

LEFLUNOMIDE- contdSide-effects & Special PrecautionsS/E rash, temporary hair loss, liver damage, nausea, diarrheoa, wt loss & abd painMonthly liver function test is recommended for the 1st 6-12 months of treatment & followed by longer intervalsNot safe for use in pregnancyWomen on leflunomide should stop it for at least 2 years before trying to conceiveCaution should be used when adm to pt with renal or hepatic dx, heavy alcohol use or immunosuppression

CYCLOSPORIN(Neoral)inhibit T-lymphocytes, a cell that contributes to inflammationConcern about long term safety & its association with kidney disease & high BPUsually taken orally twice dailyS/E high BP , swelling, kidney damage, increase hair growth, nausea, diarrhoea & heartburnPt must have BP & kidney function monitored regularlyEffect on pregnancy not known

AZATHIOPRINE(Imuran)Generally reserved for pt who have not responded to other treatmentsIt inhibits lymphocyte proliferation & secretion of certain cytokinesDose 1-3mg/kg daily (withdraw if no effect after 3 months)Most common S/E nausea, vomiting, appetite, liver function abnormalities, low white blood cell counts & infectionTaken orally once dailyComplete blood count & liver function test is recommendedAvoid AZA during pregnancyMen on AZA advised to stop 3 months before trying to conceive

INTRAMUSCULAR GOLD

Gold is effective in the treatment of RA when given intramuscularly e.g. Sodium AurothiomalateMost often used until 1990s now replaced by MTX & other DMARDsRarely use now due to numerous S/E, monitoring requirements(blood & urine tests), limited efficacy & very slow onset of actionAn oral gold compound (Auronofin) is also available but with low efficacyOnset of action 4-6 monthsS/E in 35% pt, leading to discontinuation Most common S/E rash, ulceration of mouth ,tongue & pharynx, proteinuria that can progress to kidney failure, hematuria

PENICILLAMINE(Artamin)mode of action uncertainSuppression of RA may result from marked reduction in concentrations of immunoglobulin (IgM) rheumatoid factorSingle daily dose of 125-250mg usually is used to initiate therapyDosage can be increased at intervals of 1-3 months to a range of 500-750mg/day

PENICILLAMINE - contdSide-effects40% of pt develop severe adverse effects which include nephropathy, blood discrasias, skin reactionsLess serious S/E nausea, vomiting, diarrhoea, dyspepsia, anorexia & transient loss of taste for sweet & saltShould be given on an EMPTY stomach to avoid interference by metals in foodContraindication include pregnancy or presence of renal insufficiency

Adverse Effect of DMARDs - summaryLiver & bone marrow toxicity - (MTX, SSZ, Leflunomide, Gold cpds, Penicillamine)Renal toxicity (Cyclosporin, Parenteral gold salts, Penicillamine)Pneumonitis (MTX)Allergic skin reactions (Gold cpds, SSZ)Autoimmunity (Penicillamine, SSZ)Infections ( Azathioprine, Cyclosporin)Retinal toxicity (Hydroxychloroquine)

BIOLOGIC RESPONSE MODIFIERSthese agents block the actions of substances naturally produced by the immune system such as tumour necrosis factor or interleukin-1(which are involved in the abnormal immune reaction associated with RA)They do not cure the disease but slow down RA & can lead to remissionOften used in combination with one or more DMARDsThey are expensive & long term effects are still under studyHave to be under specialist supervisionMay tske weeks or months to show effectsE.g. are Etarnercept. Infliximab, Adalimumab , Anakinra

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