TREATMENT OF RHEUMATOID ARTHRITIS

(RA)

Pravin Wahane

B.J.G.M.C. Pune

INTRODUCTION

• Chronic, systemic, inflammatory, autoimmune

• Primary target is the synovial tissue

• Characterized by joint erosions and destruction

EPIDEMIOLOGY

• Commonest inflammatory joint disease seen in practice

• Affects around .8% of world’s and about 1% of Indian population

• Commoner in women by a ratio of 3:1

• Usually starts in 3rd to 5th decade of life

• Associated mortality

AETIOLOGY

• Multifactorial

• Genetic predisposition and shared epitope hypothesis

• Role of infections

• Molecular mimicry

TREATMENT PARADIGMS

PAST

PRESENT

FUTURE

Traditional pyramidal approach;Go slow, go low(empirical)

Early and universal use of DMARDs (Disease modifying anti rheumatic drugs) often in combination (evidence based)

DMARDs + Biological agents(mechanism based)

IMPORTANCE OF EARLY DIAGNOSIS AND

TREATMENT

• Joint damage is an early phenomenon

• It is largely irreversible

• Duration of the disease is inversely proportional to outcome and response

ACR CRITERIA FOR DIAGNOSIS OF

RHEUMATOID ARTHRITIS• Morning stiffness(lasting at least 1 hour)• Arthritis in 3 or more joint areas (soft tissue

swelling or effusion observed by physician)• Arthritis of hand joints(wrist,PIP,MCP joints)• Symmetric arthritis• Rheumatoid nodules• Rheumatoid factors in serum• Radiological changes(erosions or periarticular

bony calcifications on hand and wrist radiographs)

OTHER AIDS TO DIAGNOSIS

• Elevated levels of serum rheumatoid factors

• Radiographic changes

• Serum antibodies like antibodies to CCP

SEVERITY ASSESSMENT

• Duration of morning stiffness

• Tender and swollen joint count

• Observer and patient assessment

• VAS for pain

• Disease activity score (DAS)

SEVERITY ASSESSMENTDAS

• Most widely employed

• Requires 28 tender joint count, 28 swollen joint count, ESR and general health assessment by the patient

• Can range from 0-9.4

• Remission

• Meaningful change

POOR PROGNOSTIC FACTORS

• High tender/swollen joint count

• Early age of onset

• High titres of RF, ESR and CRP

• Erosions on hand X-rays

• Presence of CCP antibodies

MEASUREMENTS OF RESPONSE

ACR 20 Response :

A decrease of at least 20% in both the number of tender and swollen joints along with 20% reductionin at least three of the following:

Patient,s assessment of disease status Patient,s assessment of pain Patient,s assessment of physical function Physician,s assessment of disease status C-reactive protein level

CLASSIFICATION OF DRUGS

• NSAIDs ( Non steroidal antiinflammatory drugs)

• Corticosteroids

• DMARDs

• Biological response modifiers (BRMs)

BROAD ALGORITHM

Diagnosis establishmentAssessment of baseline disease activity and damage

Prognosis estimation

NSAIDsDMARD as per severity

Consider local or systemic corticosteroids

Response-continue No responseAdd Methotrexate if not already usedParenteral MTX if oral MTX used

Response- continue

No response Add other DMARDs Add BRMs

NSAIDs IN RA

• Integral part of initial therapy

• Buy time and offer symptomatic benefit

• ‘Adjuncts to’ and not ‘substitutes for’ DMARDs

NSAIDs IN RA

• Combination of NSAIDs

• Adverse effects

• COX-2 inhibitors

• Measures to control adverse effects

CORTICOSTEROIDS IN RA

• Retard the rate of joint destruction and relieve synovitis in low doses

• Mild disease modifying potential

• Adverse effects and their prevention

CORTICOSTEROIDS IN RA

• Bridge therapy for 8-12 weeks

• Treatment of rheumatic flares

• For rheumatic vasculitis and interstitial lung disease

• Intra-articularly in recalcitrant joints

DMARDs IN RA

• Step up approach

• Step down approach

• Saw tooth approach

• Parallel approach

DMARDs IN RA

FREQUENTLY USED

• Methotrexate• Hydroxychloroquine• Sulphasalazine• Leflunomide

INFREQUENTLY USED

• Chloroquine• Gold• Cyclosporin A• Levamisole• D-penicillamine• Minocycline

METHOTREXATE

• Anchor of treatment

• Acts by inhibiting dihydrofolate reductase, thymidylate synthetase and aminoimidazolecarboxamide

• Most economical, best tolerated and with highest rate of retention

METHOTREXATE

• Initial and maintenance dose

• Duration of treatment

• Treatment failure

METHOTREXATE

• Adverse effects

• Their prevention

• Contraindication

HYDROXYCHLOROQUINE

• Suggested mechanisms involve suppression of T lymphocyte responses to mitogens, reduced chemotaxis, free radical trapping

• Extensively bound to tissues specially to melanin containing ones

• Place in treatment of RA

HYDROXYCHLOROQUINE

• Usual dosage

• Adverse effects

SULFASALAZINE

• Sulfapyridine is the active moiety

• Acts by inhibition of proinflammatory cytokines and transcription factors

• Usually used as an add on drug

• Also useful in juvenile arthritis and ankylosing spondylitis

SULFASALAZINE

• Adverse effects

• Use in pregnancy

LEFLUNOMIDE

• New DMARD

• Isoxazole derivative

• Acts by competitive inhibition of Dihydroorotate dehydrogenase

LEFLUNOMIDEDihydroorotate Orotate Uridine

monophosphate

Go G1 S G2 M

Early signalsIL2, NFATCa influx

Sensors of Ribon. Levels p53, cyclin D & E

+

_

OTHER ACTIONS

• Inhibition of Tyrosine kinase

• Inhibition of NF-kB dependant transcription

• Reduction in levels of IL-6, matrix metalloproteinases and prostaglandin E

PROPERTIES

• Prodrug

• Highly protein bound with long t ½

• Undergoes extensive enterohepatic circulation

• Inhibits CYP2C9

USE IN RA• Found to be as efficacious as Sulfasalazine and MTX

• Slows radiographic progression as compared to placebo

• Alternative agent in face of MTX intolerance in the dose of 20 mg/day

• Combination of MTX and Leflunomide

PREGNANCY PROTOCOL

• Leflunomide in fetopathic and teratogenic

• Should be discontinued before pregnancy

• Emergency drug washout with oral Cholestyramine 8gm thrice daily for 11 days

ADVERSE EFFECTS

• Reversible elevation in liver enzymes in 2-4% of patients

• Risk of severe liver injury is small and acceptable

• Weight loss• Diarrhea• Alopecia• Hypertension • others

COMBINATION OF DMARDs

• Better than monotherapy in inducing remission

• Cost effective in long term

• Not necessarily more toxic

• MTX +Leflunomide

• MTX+Sulfasalazine +Hydroxychloroquine

DMARDs IN SPECIAL SITUATIONS

Contraindicated Indicated

Pregnancy MTX, Leflunomide Sulfasalazine,Steroids HCQS, NSAIDs

Lactation do

Cyclosporin

do

Gold salts

Liver disease

MTX, Leflunomide, NSAIDs, Sulfasalazine

HCQS and Gold salts

Renal disease

NSAIDs, MTX- dose

Gold

HCQS, Sulafasalazine

Lung disease MTX - caution Leflunomide, HCQS and Sulfasalazine

BRMs IN RA• Integration of molecular biology with bedside medicine

• Genetically engineered products

• Modulate a specific aspect of underlying autoimmune process

• Therapeutic effect involves downregulation of proinflammatory cytokines and occupancy of their receptors

BRMs IN RA

• Soluble TNF α receptor – Etanercept

• Anti TNF α antibodies - Infliximab,

Adalimumab

• IL1 receptor antagonist – Anakinra

ETANERCEPT

• Soluble TNF receptor fusion protein

• Composed of soluble ligand binding portion of type2 TNF receptor linked to Fc portion of human IgG

• Has affinity with both TNF α and β and binds to them before they can bind to their receptors

ETANERCEPT

• Given by SC route

• Dosage

• Bioavailability-60%

• t ½ - 50 hrs

ETANERCEPT IN RA

• Better and faster ACR response rates as compared to placebo

• Rapidity is dose dependent

• Beneficial in patients who have an inadequate response to MTX

• Approved for use as monotherapy

INFLIXIMAB

• Chimeric IgG anti-TNF-α antibody

• Binds to both soluble and membrane bound TNF-α

• First anti-TNF-α agent used

INFLIXIMAB- EFFECTS

• Reduces serum conc. of IL6

• Reduces serum conc. of ICAM-1 and E selectin

• Reduces vascular endothelial growth factor

• Increases expression of TNF receptors

INFLIXIMAB

• Half life about 9 days• 3 mg/kg by IV infusion at 0, 2 and 6 weeks

followed by every 8 weeks• Single IV dose confers rapid improvement • Has been found to be effective as compared to

placebo but monotherapy associated with loss of efficacy

• Can only be used in combination with MTX• Other uses

ADALIMUMAB

• Recombinant human IgG monoclonal anti-TNF-α antibody (1330 amino acids)

• Not only causes impaired cytokine binding but also lyses cells expressing surface TNF-α

ADALIMUMAB

• Given by SC route . Dose 40 mg SC weekly

• t ½ 2 weeks

• Bioavailability 64%

ADALIMUMAB IN RA

• Has shown better ACR response rates as compared to placebo

• Appears to have additive effect with MTX

• Inhibits progression of structural joint damage

• Dose adjustment with MTX

ADRs OF TNF ANTAGONISTS

INFECTIONS

• Definite risk of opportunistic infections such as tuberculosis and histoplasmosis

• Max risk with Infliximab

• Tuberculosis occurs due to reactivation of old latent infection

• Occurs within first 2-5 months of therapy

• Importance of screening procedures

MALIGNANT DISEASES

• Increased incidence of lymphoma but causal association lacking

• No evidence of any other malignancy

INJECTION SITE AND INFUSION REACTIONS

• Minor redness and itching for few days after receiving Etanercept and Adalimumab

• Headache and nausea after Infliximab

• Urticaria and anaphylaxis in 2% patients after Infliximab

IMMUNE RESPONSES

• Etanercept is least immunogenic and antibodies found only in 3% patients

• Human chimeric antibodies develop in a majority of patients taking Infliximab

• Combination with MTX blunts the autoimmune response

• Antibodies to Adalimumab found in 12% patients receiving monotherapy but only in 1% of those receiving MTX combinatuion

DEMYELINATING SYNDROMES

• Reports of exacerbation of quiescent multiple sclerosis in patients taking Etanercept and Infliximab

• Causal relationship not established

IL-1 AND RECEPTOR ANTAGONISTS

• Role of IL-1 in immune and inflammatory process

• IL-1 receptor antagonist(IL-1Ra)

• Dynamic balance

ANAKINRA

• It is recombinant IL-1Ra

• Binds competitively to IL-R type 1

• Given 100 mg/day SC

• Bioavailability-95% ; t ½ 4-6 hrs

• Elimination by renal clearance

ANAKINRA

• Has been found to be effective as compared to placebo both in monotherapy and combination with MTX

• Slows the rate of joint damage

• Useful in patients who have no response or fail to tolerate DMARDs and other BRMs

ANAKINRA

• Theoritical possibility of synergistic action with TNF antagonists but not substantiated by studies

• Well tolerated with MTX but a small fraction can develop reversible neutropenia

• Contraindicated in presence of active infections

• Daily injections have limited its role

BRMs IN RA

• Indicated in resistant RA with active disease (DAS >5.1)• Defined as failure of response to at least 2 DMARDs

( one should be MTX) used in optimal doses for at least 6 months

• Generally have rapid onset of response• Should be withdrawan in case of advent of adverse

effects or lack of effect(DAS improvement <1.2 at >3 months)

• Major deterrent to their use is cost

INITIAL TREATMENTOral MTX 7.5-15mg per week +/- 5-7.5 mg Prednisone per day

5 mg increments in dose every month to a max of 20-30 mg per week

Switch to subcutaneous injections

DMARD combination

New concept- Induction therapy with Etanercept which has been found to rapidly suppress disease activity

ESTABLISHED RAMaximal MTX dose

Add Sulfasalazine, Hydroxychloroquine or both but not Cyclosporin

2-3 months

3 months

Add Leflunomide to MTX

TNF inhibitors

1 year after diagnosis

COEXISTING ILLNESSES

• Infections

• Osteoporosis

• Cardiovascular disease

INFECTIONS

• Doubling of the risk of infection and degree of increase correlates with severity

• Possible role of corticosteroids and TNF inhibitors

• Regular Influenza and Pneumococcal vaccination ( start before DMARD)

• Prescreen and follow up for TB

OSTEOPOROSIS

• Incidence of osteoporosis is doubled

• Base line bone density studies

• Bisphosphonate therapy

FUTURE STRATEGIES

• B cell depletion therapy using Rituximab

• Inhibition of IL-6

• Inhibition of IL-18

• Costimulation block

RITUXIMAB

• Chimeric monoclonal IgG anti CD20 antibody

• Has shown significant efficacy comparable to TNF inhibitors

RITUXIMAB-DOSAGE

• Given by slow infusion

• Two doses of 1 gm each 1 week apart

• Methyl Prednisolone as premedication on the day of dosing

• Effects last at least 6 weeks

• Monotherapy in RF +ve patients

• No benefit of combining with MTX

ADVERSE EFFECTS

• Pricking sensation in the throat at the time of first infusion

• Increased risk of lower airway infections

• Transfusion reactions

IL-6

• Pleiotropic cytokine, glycoprotein in nature

• Various names

• Produced by a variety of immunocytes and mesenchymal cells

• Binds to cell surface or soluble receptor

• IL-6/IL-6R complex binds to gp 130 on cell surface and leads to effects

FUNCTIONS OF IL-6

• Stimulation of B cells

• Proliferation and differentiation of T cells

• Differentiation of osteoclasts and increased proteoglycan breakdown

• Pyrogenic and weight loss

• Paradoxically suppresses IL-1 and TNF-α

IL-6 IN RA

• Implicated in joint damage and systemic manifestations of disease

• IL-6 knockout mice

• Results of SC IL-6

ANTAGONISTS OF IL-6•In animal models•In human studies Rapid improvement with 10 days treatment in initial studies (10 mg/kg IV OD)

In subsequent studies, found to be effective after 1 wk and sustained effect till 8 wks

Optimum dose- 8 mg/kg

Combination with MTX found to be better than monotherapy with either drug

INTERLEUKIN - 18• Belongs to IL1 superfamily

• Major function is induction of INF-γ

• Also induces T- helper cells as also other inflammatory cytokines

• Increased levels are seen in patients of RA

• IL-18BP is produced endogenously and counters IL-18

ROLE OF IL-18 AND ITS ANTIBODY

Antimurine IL-18 antibody Suppresses swelling by 60% and reduces TNFα and IL-1 levels when given to Rabbits with Streptococcal cell wall induced arthritis

IL-18 when given to Mice immunized with type II collagen, increases the erosive and inflammatory component of arthritis

ROLE OF IL-18BP

Reduces the clinical severity of the disease in Mice having CIA and causes a reduction in the levels of circulating cartilage matrix protein

Murine IL-18BP fused with Fc portion of murine IgGHas been found to reduce histological severity

COSTIMULATION BLOCKERS

• Requirement of dual signal for T-cell activation

• CTLA4 – constitutively expressed protein on T cell surface

CTLA4-Ig

• It is a soluble antigen immunoglobulin fusion protein

• Consists of extracellular domain of human CTLA4 and Fc portion of human IgG

CTLA4-Ig IN RA

• Found to induce long term graft survival in rodent models

• In phase-II trails – combination of CTLA4Ig and MTX compared with MTX monotherapy

• Combination showed ACR 20 response in 60% patients as compared to 35.3% in monotherapy group

OTHER AGENTS

• Pegylated soluble TNF-α receptor antagonist

• Agents that trap cytokines

• Interleukin 15 blockers

• Agents that prevent the cleavage of human compliment component C5

• Agents that inhibit adhesion molecules