MANAGEMENT OF MANAGEMENT OF RHEUMATOID ARTHRITIS RHEUMATOID ARTHRITIS

Dr.Harmanjit SinghDr.Harmanjit Singh

Department of PharmacologyDepartment of Pharmacology

Govt Medical College,Patiala.Govt Medical College,Patiala.

INTRODUCTION INTRODUCTION

RA is chronic multisystem disease of RA is chronic multisystem disease of unknown cause.unknown cause.

Characteristic feature is persistent Characteristic feature is persistent inflammatory synovitis.inflammatory synovitis.

Usually involve peripheral joints in Usually involve peripheral joints in symmetric distribution.symmetric distribution.

Joint changes probably represent Joint changes probably represent autoimmune reaction.autoimmune reaction.

Etiology:Etiology: Cause is unknown .Cause is unknown . Family studies indicate genetic Family studies indicate genetic

predisposition.predisposition.

HLA DR4, Dw16, DR10, DR9, DR3 HLA DR4, Dw16, DR10, DR9, DR3 associated with rheumatoid arthritis.associated with rheumatoid arthritis.

HLADR5, DR7, DR2 may protect HLADR5, DR7, DR2 may protect against rheumatoid arthritis ( Frequency against rheumatoid arthritis ( Frequency less).less).

.. May be manifestation of response to May be manifestation of response to infection by mycoplasma, EBV, CMV, infection by mycoplasma, EBV, CMV, Parvovirus & rubella virus. Parvovirus & rubella virus.

.Cigarette smoking – triggering factor..Cigarette smoking – triggering factor.

PathologyPathology : : Hyperplasia & hypertrophy of synovial cells.Hyperplasia & hypertrophy of synovial cells. Infiltration with mononuclear cells, Infiltration with mononuclear cells,

macrophages.macrophages. Production of IL-1, IL-6 TNF alpha, PGE2, Production of IL-1, IL-6 TNF alpha, PGE2,

Leukotriene B4.Leukotriene B4. TNF alpha TNF alpha : proliferation of inflammatory : proliferation of inflammatory

cellscells IL-1 IL-1 : cartilage proteoglycan resorption, : cartilage proteoglycan resorption,

bone erosion,destructive aspect of RAbone erosion,destructive aspect of RA IL-6 IL-6 : mediates IL-1 & TNF alpha actions: mediates IL-1 & TNF alpha actions

stimulates B cellsstimulates B cells

Diagnosis of rheumatoid arthritisDiagnosis of rheumatoid arthritis

Morning stiffness 1h

Three or more joints involved

Arthritis of hand joints

Symmetric arthritis

Rheumatoid nodules ( over bony prominence , extensor surfaces)

Rheumatoid factor (positive < 5% normal subjects)

Radiographic changes (must show erosion/decalcification)

Present for 6wk

Any 4 of the following must be present to allow diagnosis of RA (Patients with 2 or more clinical diagnoses are not excluded)

RA- joint involvementRA- joint involvement

Extraarticular Extraarticular

manifestationsmanifestations

PericarditisPericarditis

Interstitial lung diseaseInterstitial lung disease

Felty’s syndromeFelty’s syndrome

VasculitisVasculitis

NeuropathyNeuropathy

INVESTIGATIONS INVESTIGATIONS Rheumatoid FactorRheumatoid Factor..  : +ve : +ve In about 80% of casesIn about 80% of cases

- Also present in about 5% of normal individuals - Also present in about 5% of normal individuals

- when it appears in patients with arthritic pain on - when it appears in patients with arthritic pain on both sides of the body, it is a strong indicator of both sides of the body, it is a strong indicator of RA. RA.

ESR.ESR.  The higher the ESR the greater the   The higher the ESR the greater the inflammation., help determine how active the inflammation., help determine how active the condition is.condition is.

C-Reactive ProteinC-Reactive Protein.. High levels of C-reactive  High levels of C-reactive protein (CRP) are also indicators of active protein (CRP) are also indicators of active inflammation..inflammation..

Anti-CCP Antibody TestAnti-CCP Antibody Test.. The presence of  The presence of antibodies to cyclic citrullinated peptides (CCP) antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop. can identify RA years before symptoms develop.

Tests for AnemiaTests for Anemia..  normocytic normochromic   normocytic normochromic

IMAGING TECHNIQES IMAGING TECHNIQES

X-Rays, Dexa ScansX-Rays, Dexa Scans. . Ultrasound.Ultrasound. Special  Special ultrasound techniques called power Doppler ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA. ultrasound (QUS) may be helpful in RA.

Magnetic Resonance ImagingMagnetic Resonance Imaging.. Specially designed  Specially designed magnetic resonance imaging (MRI) equipment magnetic resonance imaging (MRI) equipment called extremity MRI may be able detect bone called extremity MRI may be able detect bone erosions in the hands of RA patients where x-rays erosions in the hands of RA patients where x-rays cannot. cannot.

Above lab findings plus clinical features are Above lab findings plus clinical features are important to make the diagnosis important to make the diagnosis

Monitoring progressionMonitoring progression   Disease Activity Score of 28 jointsDisease Activity Score of 28 joints (DAS28). It is  (DAS28). It is

widely used as an indicator of RA disease activity widely used as an indicator of RA disease activity and response to treatment The joints included in and response to treatment The joints included in DAS28 are DAS28 are PIPPIP , ,MCP MCP joints,joints,wrists, elbows , shoulders and knees  wrists, elbows , shoulders and knees 

When looking at these joints, both the number of When looking at these joints, both the number of joints with tenderness upon touching (joints with tenderness upon touching (TEN28TEN28) ) and swelling (and swelling (SW28SW28) are counted. ) are counted.

In addition, the  In addition, the  ESRESR is measured. is measured. Score less than 3.2 means pt is inactiveScore less than 3.2 means pt is inactive 3.2-5.1 means moderately active patient 3.2-5.1 means moderately active patient more than 5.1 means pt is activemore than 5.1 means pt is active

Goals of therapy

Alleviate pain

Preservation of function

Control disease activityMaximize

quality of life

Slow progression/rate of joint damage

MANAGEMENT MANAGEMENT

Physical Therapies Physical Therapies Diet Diet Pharmacologic TherapiesPharmacologic Therapies- NSAIDSNSAIDS- GlucocorticoidsGlucocorticoids- DMARDSDMARDS- BiologicsBiologics Surgical treatment Surgical treatment Future trends Future trends

MANAGEMENT MANAGEMENT Physical therapiesPhysical therapies Splinting: prevents unwanted joint movementSplinting: prevents unwanted joint movement Exercise: directed to maintain muscle Exercise: directed to maintain muscle

strength & joint mobility strength & joint mobility

Diet Diet  .Some studies suggest that .Some studies suggest that omega-3 fatty acids omega-3 fatty acids

may reduce rheumatoid arthritis inflammation.may reduce rheumatoid arthritis inflammation.

Some Some Herbal remedies Herbal remedies also found to be usefulalso found to be useful

Pharmacologic measures:Pharmacologic measures:NSAIDSNSAIDSFirst line drugs in mild/early casesFirst line drugs in mild/early casesAfford symptomatic relief in pain , swelling , Afford symptomatic relief in pain , swelling ,

morning stiffnessmorning stiffnessDo not arrest disease processDo not arrest disease processNon selective Cox inhibitorsNon selective Cox inhibitors::Naproxen - 500 mg bd.Naproxen - 500 mg bd.Piroxicam -20 mg qidPiroxicam -20 mg qidNabumetone 1000mg odNabumetone 1000mg odAceclofenac , Etodolac upto 1000 mg/day Aceclofenac , Etodolac upto 1000 mg/day Indomethacin reserve dg when other NSAIDs Indomethacin reserve dg when other NSAIDs

don’t provide reliefdon’t provide reliefAspirin is rarely used nowAspirin is rarely used nowAdverse effectsAdverse effects :G I bleeding, ulcers, :G I bleeding, ulcers,

hepatoxicity, rash.hepatoxicity, rash.

Selective cox-2 inhibitorsSelective cox-2 inhibitors::

Celecoxib100-200mg bd Celecoxib100-200mg bd

Etoricoxib 90 mg od has highest Etoricoxib 90 mg od has highest selectivity ratio for inhibition of cox 2. selectivity ratio for inhibition of cox 2. & has superior efficacy compared with & has superior efficacy compared with 500 mg naproxen bd over 12 weeks500 mg naproxen bd over 12 weeks

Rafecoxib valdecoxib are obsolete now Rafecoxib valdecoxib are obsolete now because of their cardiotoxicity because of their cardiotoxicity

NSAID TherapyNSAID Therapy

DisadvantagesDisadvantages

Does not affect disease Does not affect disease progressionprogression

GI toxicity commonGI toxicity common Renal complications Renal complications

(eg, irreversible renal (eg, irreversible renal insufficiency, papillary insufficiency, papillary necrosis)necrosis)

Hepatic dysfunctionHepatic dysfunction

AdvantagesAdvantages

Effective control of Effective control of inflammation and paininflammation and painEffective reduction in Effective reduction in swellingswellingImproves mobility, Improves mobility, flexibility, range of flexibility, range of motionmotionImprove quality of lifeImprove quality of life

Relatively low-costRelatively low-cost

GLUCOCORTICOIDSGLUCOCORTICOIDS

Second line agentsSecond line agents

Mostly combined with NSAIDSMostly combined with NSAIDS

Pharmacological actionsPharmacological actions

Antiinflammatory & immunosuppressant actionAntiinflammatory & immunosuppressant action

Suppress signs & symptomsSuppress signs & symptoms

Slow appearance of new bone erosionsSlow appearance of new bone erosions

GLUCOCORTICOIDSGLUCOCORTICOIDS

PKsPKs Route:Route:

Oral Oral Intraarticular- transient symptomatic therapy when Intraarticular- transient symptomatic therapy when

systemic therapy fails, don’t repeat before 4-6 systemic therapy fails, don’t repeat before 4-6 monthsmonths

DoseDose Prednisolone- 7.5 mg/d, or equivalentPrednisolone- 7.5 mg/d, or equivalent Reduce dose gradually Reduce dose gradually

GLUCOCORTICOIDS: ADRsGLUCOCORTICOIDS: ADRs

Cushing’s habitusCushing’s habitus

InfectionsInfections

Delayed healingDelayed healing

Peptic ulcersPeptic ulcers

CataractCataract

GlaucomaGlaucoma

Growth retardationGrowth retardation

Muscle weaknessMuscle weakness

Mood changesMood changes

OsteoporosisOsteoporosis

HyperglycemiaHyperglycemia

Corticosteroid TherapyCorticosteroid Therapy

DisadvantagesDisadvantages

Does not conclusively Does not conclusively affect disease progressionaffect disease progression

Tapering and Tapering and discontinuation of use discontinuation of use often unsuccessfuloften unsuccessful

Low doses result in skin Low doses result in skin thinning, ecchymoses, and thinning, ecchymoses, and Cushingoid appearanceCushingoid appearance

Significant cause of Significant cause of steroid-induced osteopeniasteroid-induced osteopenia

AdvantagesAdvantages

Anti-inflammatory and Anti-inflammatory and immunosuppressive immunosuppressive effectseffectsCan be used to bridge Can be used to bridge gap between initiation of gap between initiation of DMARD therapy and DMARD therapy and onset of action.onset of action.Intra-articular injections Intra-articular injections can be used for individual can be used for individual joint flaresjoint flares

Disease modifying anti rheumatic Disease modifying anti rheumatic dgs (DMARDs):dgs (DMARDs):

--Current recommendation is to add DMARDs as soon Current recommendation is to add DMARDs as soon as the diagnosis is confirmedas the diagnosis is confirmed

-Slow acting, take 6wks to 6 months to show the -Slow acting, take 6wks to 6 months to show the effects.effects.

-They modify/ alter disease progression-They modify/ alter disease progression Commonly used DMARDs are -:Commonly used DMARDs are -:

- - MehotrexateMehotrexate

- Sulphasalazine- Sulphasalazine

- Chloroquine & Hydroxychloroquine- Chloroquine & Hydroxychloroquine

- Leflunomide- Leflunomide

- cyclosporine- cyclosporine

- Azathioprine - Azathioprine

Advantages of DMARDs Advantages of DMARDs

Slow disease progressionSlow disease progression Improve functional disabilityImprove functional disability Decrease painDecrease pain Interfere with inflammatory Interfere with inflammatory

processesprocesses Retard development of joint erosionsRetard development of joint erosions

Combination DMARD therapyCombination DMARD therapy MTX + SSZMTX + SSZ MTX + HydroxychloroquineMTX + Hydroxychloroquine MTX + cyclosporineMTX + cyclosporine MTX + LeflunomideMTX + Leflunomide

Excellent safety & improved efficacy over Excellent safety & improved efficacy over MTX aloneMTX alone

Who should be put on combination of Who should be put on combination of DMARDs? DMARDs?

Failure to respond to > one Failure to respond to > one DMARD / partial responseDMARD / partial response

When to change?When to change?

- If response is not adequate / - If response is not adequate / toxicity developstoxicity develops

How to combine two drugs?How to combine two drugs?

'step-up' approach 'step-up' approach : (easier to control ADR, : (easier to control ADR, may use only one drug in those who respond)may use only one drug in those who respond)

consisting of starting the patient on a first consisting of starting the patient on a first DMARD followed by the addition of a second DMARD followed by the addition of a second if there is no adequate responseif there is no adequate response

'step-down' approach 'step-down' approach : (better control in early : (better control in early RA)RA)

in which initial combination therapy is in which initial combination therapy is followed by a reduction of the dose or the followed by a reduction of the dose or the abandonment of one or more of the DMARDs.abandonment of one or more of the DMARDs.

Methotrexate:Methotrexate: Considered first choice to treat RA Considered first choice to treat RA MOA: it probably relates to inhibition of MOA: it probably relates to inhibition of

aminoimidazolecarboxamide ribonucleotide aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase & thymidylate (AICAR) transformylase & thymidylate synthetasesynthetase

It has secondary effects on PMN cells It has secondary effects on PMN cells chemotaxis.chemotaxis.

It has direct inhibitory effects on It has direct inhibitory effects on proliferation and stimulates apoptosis in proliferation and stimulates apoptosis in immune - inflammatory cells immune - inflammatory cells

Orally 70% absorptionOrally 70% absorption Dose 15-25 mg weekly, starting with 7.5 mg Dose 15-25 mg weekly, starting with 7.5 mg

Adverse effects of Methotrexate:Adverse effects of Methotrexate: Nausea, mucosal ulcers.Nausea, mucosal ulcers. Dose related hepatotoxicity.Dose related hepatotoxicity. Leucovorin used to reduce side Leucovorin used to reduce side

effects.effects. Contraindicated in pregnancy.Contraindicated in pregnancy.

Sulfasalazine:Sulfasalazine: It is metabolised to sulfapyridine & It is metabolised to sulfapyridine &

5- aminosalicylic acid. 5- aminosalicylic acid. In treated arthritis patients, IgA & IgM In treated arthritis patients, IgA & IgM

rheumatoid factor production are rheumatoid factor production are decreased.decreased.

Suppression of T cell responses to Suppression of T cell responses to concanavalin (glycoprotein that play concanavalin (glycoprotein that play role in cell cell interaction in role in cell cell interaction in inflammatory cell).inflammatory cell).

Inhibition of in vitro B cell proliferation.Inhibition of in vitro B cell proliferation. Reduces radiologic disease Reduces radiologic disease

progression. progression.

Ad effectsAd effects: N, V: N, V headacheheadache rashrash Hemolytic anaemiaHemolytic anaemia methemoglobinemiamethemoglobinemia NeutropeniaNeutropenia Pulmonary toxicityPulmonary toxicity Reversible infertility only in men.Reversible infertility only in men. Dose : Dose : 40 m40 mg/kg/day

Chloroquine & HydroxychloroquineChloroquine & Hydroxychloroquine

Proposed mech :Proposed mech : Suppresion of T lymphocytes response to Suppresion of T lymphocytes response to

mitogenmitogen Decrease chemotaxisDecrease chemotaxis Stablization of lysosomal enzymesStablization of lysosomal enzymesA/E: - A/E: - N/V, abdominal pain, RashN/V, abdominal pain, Rash Retinitis : More with ChloroquineRetinitis : More with Chloroquine CNS: convulsionsCNS: convulsions Cardiac depression Cardiac depression Dose :Chloroquine : 200 mg/dayDose :Chloroquine : 200 mg/day Hydroxychloroquine : upto 6.4 Hydroxychloroquine : upto 6.4

mg/kg/daymg/kg/day

Leflunomide:Leflunomide: MOA: its active metabolite ( A77-1726) MOA: its active metabolite ( A77-1726)

inhibits inhibits dihydroorotate dehydrogenasedihydroorotate dehydrogenase and causes arrest of dividing T cells and causes arrest of dividing T cells and inhibition of production of and inhibition of production of autoantibodies by B cellsautoantibodies by B cells

in RA it is as effective as MTXin RA it is as effective as MTX Inhibits bony damageInhibits bony damage A/eA/e diarrhoea, Hepatitis (FDA boxed diarrhoea, Hepatitis (FDA boxed

warning), alopecia, wt gain, HTNwarning), alopecia, wt gain, HTN C/I : pregnancy C/I : pregnancy DOSE : 20mg/dayDOSE : 20mg/day

GOLD COMPOUNDSGOLD COMPOUNDSMOA:MOA: Alters morphology & functional capabilities of Alters morphology & functional capabilities of

macrophagesmacrophages Inhibiting monocyte chemotactic factor-1, IL-8, 1Inhibiting monocyte chemotactic factor-1, IL-8, 1ββ & &

VEGFVEGF

AdditionallyAdditionally Alter lysosomal enzyme activityAlter lysosomal enzyme activity Reduce histamine release from mast cells Reduce histamine release from mast cells

Formulations-Formulations- Oral: auranofin (29% elemental gold)Oral: auranofin (29% elemental gold) I/M: aurothiomalate, aurothioglucose (50% elemental I/M: aurothiomalate, aurothioglucose (50% elemental

gold)gold)

GOLD COMPOUNDSGOLD COMPOUNDS

DoseDose : : IM gold: Test dose of 5-25 mg & then 50 mg IM gold: Test dose of 5-25 mg & then 50 mg wkly for 20 wkswkly for 20 wks

Oral gold: 6 mg daily in 1 or 2 dosesOral gold: 6 mg daily in 1 or 2 doses

ADRsADRs :-Pruritic skin rash, eosinophilia,Stomatitis & :-Pruritic skin rash, eosinophilia,Stomatitis &

metallic taste,Aplastic anemia- rare, but fatalmetallic taste,Aplastic anemia- rare, but fatal

Proteinuria (8-10% pts), nephrotic syndromeProteinuria (8-10% pts), nephrotic syndrome

Corneal gold deposition Corneal gold deposition

Nitritoid rxns- sweating, flushing & headache, sp. Nitritoid rxns- sweating, flushing & headache, sp.

with gold thiomalatewith gold thiomalate

Rarely used now because of Questnable efficacy Rarely used now because of Questnable efficacy

and high Toxicity and high Toxicity

D-PENICILLAMINED-PENICILLAMINE A copper chelating agents A copper chelating agents

Gold like action in RAGold like action in RA

Dose: Start with 125-250 mg OD, then 250 mg BDDose: Start with 125-250 mg OD, then 250 mg BD

ADRs : Same as goldADRs : Same as gold

Other: loss of taste, SLE & Myasthenia gravis Other: loss of taste, SLE & Myasthenia gravis

Rarely used because of toxicityRarely used because of toxicity

OTHER drugs approved are Chlorambucil, OTHER drugs approved are Chlorambucil,

Cyclophosphamide , Cyclosporine, AzathioprineCyclophosphamide , Cyclosporine, Azathioprine

Biologic therapies, or biologicsBiologic therapies, or biologics Newer drugs that reduce RA inflammation in a Newer drugs that reduce RA inflammation in a

more highly targeted manner than the DMARDs. more highly targeted manner than the DMARDs. These are used when there is inadequate These are used when there is inadequate response with the DMARDSresponse with the DMARDS

Biologics are made through biotechnology and Biologics are made through biotechnology and target very specific proteins or cells that are target very specific proteins or cells that are involved in the inflammatory process. involved in the inflammatory process.

Biologics have also been shown to help reduce Biologics have also been shown to help reduce the progression of joint damage in RA.the progression of joint damage in RA.

The currently available biologic therapies for RA The currently available biologic therapies for RA must either be injected under the skin must either be injected under the skin [etanercept, adalimumab, anakinra] or infused [etanercept, adalimumab, anakinra] or infused [infliximab, abatacept, and rituxumab]).[infliximab, abatacept, and rituxumab]).

TNFTNFαα inhibitors inhibitors Etanercept:Etanercept: MOA: it is recombinant fusion protein MOA: it is recombinant fusion protein

consisting of two soluble TNF p75 consisting of two soluble TNF p75 receptor moieties linked to Fc portion receptor moieties linked to Fc portion of human IgG1, it binds TNFof human IgG1, it binds TNFαα molecule molecule

It decreases rate of formation of new It decreases rate of formation of new erosionerosion

DOSE: 25 mg twice weekly given s.c.DOSE: 25 mg twice weekly given s.c. A/EA/E

- Opportunistic infections, Activation of - Opportunistic infections, Activation of latent TBlatent TB

AdalimumabAdalimumab MOA: it is fully human IgG1 anti TNF MOA: it is fully human IgG1 anti TNF

monoclonal antibody complexes with monoclonal antibody complexes with soluble TNFsoluble TNFαα and prevents its and prevents its interaction with cell surface receptors interaction with cell surface receptors causing down regulation of causing down regulation of macrophages and Tcell functionmacrophages and Tcell function

DOSE: 40 mg given every 2 weely DOSE: 40 mg given every 2 weely given s.c.given s.c.

Respiratory infection is a common a/eRespiratory infection is a common a/e Comb with MTX to improve responseComb with MTX to improve response

InfliximabInfliximab MOA: it is chimeral IgG1 monoclonal MOA: it is chimeral IgG1 monoclonal

antibody that binds with TNFantibody that binds with TNFαα DOSE: 3-10 mg/kg as an i.v. infusion DOSE: 3-10 mg/kg as an i.v. infusion

every 8 weeklyevery 8 weekly Comb with MTX improves response Comb with MTX improves response

and decreases rate of formtion of new and decreases rate of formtion of new erosions more than MTX aloneerosions more than MTX alone

A/E: URTI, nausea, headache, sinusitis, A/E: URTI, nausea, headache, sinusitis, rash, activation of latent TB rash, activation of latent TB

C/I: multiple sclerosis as demyelinating C/I: multiple sclerosis as demyelinating syndromes have been reported syndromes have been reported

TNf-TNf- blocking agents blocking agents

Drug Primary action ROA Usual dose Half life

Infliximab Chimeric anti TNF- Ab

I/V inj. 3 mg/kg at 0,2,6 wks, then 8 wkly.Gradual ↑ to 10 mg/kg if incomplete response

9 days

Etanercept Soluble TNF fusion protein,Binds TNF-α & β

S/C inj.25 mg twice/wk or50 mg once/wk

4 days

Adalimumab

Human anti- TNF-α Ab

S/C inj. 40 mg every 2nd wk 2 wks

More effective in combination with methotrexate

IL-1 ANTAGONIST Anakinra- It is recombinant human

IL-1 receptor antagonist. Used in cases who have failed on

others drugs. A/e local reaction on s/c inj. & chest

infection Do not use in combination with TNF-Do not use in combination with TNF-

alpha antagonistsalpha antagonists

IL-1R antagonists: ANAKINRAIL-1R antagonists: ANAKINRA

IL-6 BLOCKING AGENT : TOCILIZUMABIL-6 BLOCKING AGENT : TOCILIZUMAB

IL-6 activation leads to systemic IL-6 activation leads to systemic inflammatory manifestations and inflammatory manifestations and abnormal lab findings in patients abnormal lab findings in patients with RA.with RA.

Tocilizumab is a Humanized anti IL-6 Tocilizumab is a Humanized anti IL-6 monoclonal Ab that specifically monoclonal Ab that specifically inhibits the action of 1L-6inhibits the action of 1L-6

It is reserved for Resistant RA It is reserved for Resistant RA

Abatacept:Abatacept: It is recombinant fusion protein.It is recombinant fusion protein. MOA: inhibits activation of T cellMOA: inhibits activation of T cell DOSE: depends on body wt it is DOSE: depends on body wt it is

given as i.v inj.given as i.v inj. <60 kg: 500mg<60 kg: 500mg 60-100 kg: 750 mg60-100 kg: 750 mg >100kg: 1000mg. >100kg: 1000mg.

Used when there is inadequate Used when there is inadequate response to DMARDSresponse to DMARDS

A/e :A/e : Risk of infectionsRisk of infections Hypersensitivity reactionHypersensitivity reaction Unfortunately Unfortunately not all patients not all patients

respond sufficiently to TNF blockade respond sufficiently to TNF blockade and some of the patients become and some of the patients become unresponsive to TNF-blocking agents. unresponsive to TNF-blocking agents.

B CELL DEPLETION THERAPYB CELL DEPLETION THERAPY

Targeting B-lymphocytes in these patients Targeting B-lymphocytes in these patients

has opened a new therapeutic window has opened a new therapeutic window

RituximabRituximab

Chimeric monoclonal Ab, targets CD20 B cellsChimeric monoclonal Ab, targets CD20 B cells

Used in resistant RA .Used in resistant RA .Benefit in treatment of Benefit in treatment of

RA refractory to antiTNF agents RA refractory to antiTNF agents

Combination therapy with methotrexateCombination therapy with methotrexate

Dose: 2 IV infusions 2 wks apart Dose: 2 IV infusions 2 wks apart ADRs: Mild infusion reactions (infrequent)ADRs: Mild infusion reactions (infrequent)

BIOLOGICS : FUNCTION AT A GLANCE

Adverse Effects of BiologicsAdverse Effects of Biologics

Infusion related Infusion related : dyspnoea , chest pain , : dyspnoea , chest pain , rash, hypotension rash, hypotension

Serious InfectionsSerious Infections TB : Activation of latent TBTB : Activation of latent TB Skin and soft tissueSkin and soft tissue

MalignancyMalignancy ? Lymphoma,? Solid Tumors ? Lymphoma,? Solid Tumors OTHERS OTHERS Optic neuritis, demyelination , Cytopenias, Optic neuritis, demyelination , Cytopenias,

Increase LFT, ILD, Vasculitis; Increase LFT, ILD, Vasculitis; Pregnancy: stop before 3 months Pregnancy: stop before 3 months No live vaccines should be givenNo live vaccines should be given

SURGICAL TREATMENT SURGICAL TREATMENT

Reserved for pts with severely damaged Reserved for pts with severely damaged

jointsjoints

IncludesIncludes

Arthroplasty/Total joint replacementArthroplasty/Total joint replacement

Open/arthroscopic synovectomyOpen/arthroscopic synovectomy

Reconstructive hand surgeryReconstructive hand surgery

FUTURE PROSPECTIVES FUTURE PROSPECTIVES compound MOA Development

phase

USA EU

TNF inhibitors

CDP-870 Anti-TNF Ab fragment III III

Pegsunercept Pegylated soluble TNF R type 1

II

ISIS-104838 TNF- antisense inhibitors II

AGIX4207 TNF inhibitor (oral) II II

IL based therapies

Atlizumab Humanized anti-IL6 R monoclonal Ab

II I

HuMAX-IL-15/AMG-714

Anti-IL-15 monoclonal Ab II II

ABT-874/J-695 Anti-IL-12 monoclonal Ab II II

FUTURE PROSPECTIVES FUTURE PROSPECTIVES

Compound MOA Development phase

USA

EU

Cell adhesion molecule inhibitors

Natalizumab Humanized monoclonal Ab II II

Co-stimulation inhs

CTLA4-Ig CD27/B7 pathway inhibitor III

Alefacept CD2 antagonist II

FUTURE PROSPECTIVES FUTURE PROSPECTIVES Compound MOA Development phase

USA

EU

Other therapies

CCI-779/ Temsirolimus Cell cycle inhibitor II

Belimumab Ab against B cell stimulator protein

II

AT-001/dnaJp1 Heat shock derived protein

II

Immunoadsorption Apheresis – new technique used in pts who are not responding to drug therepy

FDA Adds Boxed Warning To Leflunomide FDA Adds Boxed Warning To Leflunomide For Severe Liver InjuryFor Severe Liver Injury

July 13, 2010 — The rheumatoid arthritis July 13, 2010 — The rheumatoid arthritis drug leflunomide has received a boxed drug leflunomide has received a boxed warning about the risk for severe liver warning about the risk for severe liver injury.injury.

The FDA identified 49 cases of severe liver The FDA identified 49 cases of severe liver injury associated with the drug, including injury associated with the drug, including 14 cases of fatal liver failure.14 cases of fatal liver failure.

Summary Summary Rheumatoid arthritis is a common autoimmune Rheumatoid arthritis is a common autoimmune

disease that can lead to serious functional limitations, disease that can lead to serious functional limitations, joint destruction, extra-articular disease, poor quality joint destruction, extra-articular disease, poor quality of life, and premature deathof life, and premature death

Early recognition of arthritis and speedy referral to a Early recognition of arthritis and speedy referral to a rheumatologist are essentialrheumatologist are essential

Treatment should start early and aggressively to Treatment should start early and aggressively to prevent functional limitations and structural damageprevent functional limitations and structural damage

Innovations in treatment and monitoring have resulted Innovations in treatment and monitoring have resulted in patients achieving early and sustained clinical and in patients achieving early and sustained clinical and radiographic remissionradiographic remission

Methotrexate is the first line drug, but in high risk Methotrexate is the first line drug, but in high risk patients early combination of methotrexate with patients early combination of methotrexate with prednisone or a tumour necrosis factor inhibitor prednisone or a tumour necrosis factor inhibitor improves outcomesimproves outcomes

Thanks……Thanks……