Rheumatoid arthritis management

RHEUMATOID ARTHRITIS

MANAGEMENT


MANAGEMENT

Dr.S.AISHWARYA

DR .AUGUSTIN JACOB LANDRÉ-BEAUVAIS DOCUMENTED FIRST CASE OF R.A.

DOROTHY MARY HODGKIN

PETER PAUL RUBENS

ALFRED BARING GARROD

CHRISTIAAN BERNARD

SUFFERED FROM R.A.


Chronic inflammatory autoimmune and systemic disease.

Target tissue is SYNOVIAL TISSUE.

PREVALENCE -0.8% adult population worldwide.

Age 4th -5th decades (80% 35-50 yrs ).

GENARAL PRINCIPLES

Pain relief

Reduce inflammation

Protection of articular surfaces

Maintenance of function

Control of systemic involvement

MANAGEMENT OF R.A.

Medications are divided into three main classes

1.NSAIDs

2.corticosteroids

3.DMARDs

4.BIOLOGICS

5.Surgery

OUTLINE OF CURRENT MANAGEMENT OF RA Non biologics

biologics

CURRENT THERAPEUTIC APPROACH IS EARLY AGGRESSIVE INTERVENTION.

DMARDS

METHOTREXATE;HYDROXYCHLOROQUINE;SALFASALAZINE;LEFLUNAMIDE .

other DMARDS

GOLD;CYCLOSPORINE-A;

AZATHIOPRINE;CYCLOPHOSPHAMIDE;

CHLORAMBUCIL;

D-PENICILLAMINE;

MINOCYCLINE ,DOXYCYCLINE.

TYPES OF COMBINATION THERAPYOF DMARDSSTEP –UP

TICORA trial-SSZ ESCALATING MTX ,HCQ if it fails cycloph and MTX NEXT LEF ,INJ GOLD

STEP-DOWN: 3or 4DMARDS deescalated to 1 DMARD

COBRA trial –SSZ+MTX+prednisolone only SSZ

PARALLEL :multiple DMARDS continued on long term basis

FINRACO TRIAL –SSZ+MTX+HCQ+low dose prednisolone for 2yrs

DISEASE ACTIVITY SCORE (DAS) Is a composite score

Tender and swollen joint count

ESR

PATIENT global assessment of disease activity using a 100 mm visual analogue scale.

Assessess suitability for biological therapies and response to treatment.

DAS28 = 0.56 (number of tender joints )+ 0.28 (number of swollen joints ) + 0.70 In (ESR)+0.014 global assessment in mm

METHOTREXATE gold std of treatment

7.5 to 25 mg orally, IM, or SC per week given at least 3-6 months

One to two months

Nausea, diarrhea; fatigue; mouth ulcers; rash, alopecia; abnormal LFTsRare: low WBC and platelets; pneumonitis; sepsis; liver disease; Epstein-Barr virus–related lymphoma; nodulosis

CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed; liver biopsy if no resolution on discontinuation.

Rapid onset (six to 10 weeks); tends to produce more sustained results over time than other DMARDs and lowers all-cause mortality; can be used when cause of polyarthritis uncertain; often combined with newer DMARDs.

HYDROXYCHLOROQUINE (PLAQUENIL) 200 to 400 mg orally per day(6.5mg/kg)

Immunomodulatory effect

Two to six months

Nausea; headachesRare: abdominal pain; myopathy; retinal toxicity

Eye examinations every 12 months in patients older than 40 years and those with previous eye disease

In combination with MTX ,SSZ,corticosteroids.

SULFASALAZINE(AZULFIDINE)

2 to 3 g orally per day in divided doses

48 (14 to 31)

One to three months

Nausea, diarrhea; headache; mouth ulcers; rash, alopecia; contact lens staining; reversible oligospermia; abnormal LFTsRare: leukopenia

CBC every two to four weeks for three months, then every three months

Rapid onset (eight to 13 weeks); enteric, coated forms available; can be used when diagnosis uncertain; modest effects compared with other medications.

LEFLUNOMIDE (ARAVA) (100 mg orally per day for three days loading dose

earlier) 10 to 20 mg orally per day

Four to 12 weeks (tending toward four)

Nausea, diarrhea; rash; alopecia; highly teratogenic, even after discontinuationRare: leukopenia; hepatitis; thrombocytopenia

Hepatitis B and C serology in high-risk patients; CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed.

Inhibits pyrimidine synthesis and may suppress T-cell activation;

LEF toxicity ;cholestyramine 8gms -11days or activated charcoal 50gm qid-11days

AZATHIOPRINE (IMURAN)

50 to 150 mg orally per d

Two to three months

NauseaRare: leukopenia; sepsis; lymphoma

CBC every one to two weeks until dose is stable, then every one to three months

Has greater toxicity and is used less commonly than other DMARDs

CYCLOSPORINE (GENGRAF, NEORAL, GENERIC) 2.5 to 5 mg per kgorally per day

Two to four months

Nausea; paresthesias, tremor; headaches; gingival hypertrophy; hypertrichosisRare: hypertension; renal disease; sepsis

Creatinine every two weeks until dose is stable, then monthly; consider CBC, LFTs, and potassium level tests

Significant clinical benefit up to one year; adverse effects limit use.

D-PENICILLAMINE

D-Penicillamine (Cuprimine)

250 to 750 mg orally per day

Three to six months

Nausea; loss of taste; rash; reversible platelet decreaseRare: proteinuria; late autoimmune disease

CBC and urinary protein by dipstick every two weeks until dose is stable, then every one to three months

Used less commonly than other DMARDs.

AURANOFIN

Auranofin (Ridaura)

3 mg orally twice per day or 6 mg orally per day

Four to six months

ADV :DiarrheaRare: leukopenia

Monitor ---CBC and urine protein (by dipstick) every one to three months

Has modest effects compared with other DMARDs.

IM GOLD

Gold sodium thiomalate (Myochrysine)Aurothioglucose (Solganal)

25 to 50 mg IM every two to four weeks

Six to eight weeks

Mouth ulcers; rash; vasomotor symptoms after injectionRare: leukopenia; thrombocytopenia; proteinuria; colitis

CBC and urinary protein by dipstick every two weeks until dose is stable, then with each injection

Has significant withdrawal rate in trials because of toxicity.

MINOCYCLINE (MINOCIN)

100 mg orally twice per day

One to three months

Dizziness; skin pigmentation

None needed

Effective in combination with prednisone for management of new-onset rheumatoid arthritis.

GUIDELINES FOR USE OF BIOLOGICS Must have failed to response with atleast two

DMARDs including MTx (20-25mg/wk)

Must have ACTIVE disease.

Have no major infections in the preceding six months.

Have no malignancies

Non pregnant,non breast feeding women

INFLIXIMAB Infliximab (Remicade)

3 mg per kg IV at weeks zero, 2, and 6, then every eight weeks

A few days to four months

Infusion reactions; increased infection risk, including TB reactivationRare: demyelinating disorders

Monitor for TB, histoplasmosis, and other infections; CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.

A chimeric(mouse and human) monoclonal antibody to TNF-3; reduces disease activity with acceptable safety.

Always used n conjunction w MTX 10-25mg/wk

Chimeric monoclonal antibody against TNFα

Monoclonal antibody against TNFα

ETARNERCEPT

Etanercept (Enbrel)

25 mg SC twice per week or 50 mg SC per

A few days to 12 weeks

Contraindicated in infection; mild injection site reactionsRare: demyelination

CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.

Combination fusion protein of TNF receptor and portion of IgG1; inhibits TNF-3; slows joint damage.

ADALIMUMAB

DMARDs for Treatment of Rheumatoid Arthritis

Adalimumab (Humira)

40 mg SC every two weeks

A few days to four months

Adv reactions :Infusion reactions; increased infection risk, including TB reactivationRare: demyelinating disorders

Monitor for TB, histoplasmosis, and other infections; CBC and ALT at baseline and monthly until dose is stable; may continue every two to three months thereafter.

Recombinant monoclonal antibody to TNF-3; shown to reduce disease activity with acceptable safety.

Recombinant TNFα Soluble Receptor

ANAKINRA

100 to 150 mg SCper day

Within 12 weeks; lasting effects by 24 weeks

ADV REACTIONS :Infections and decreased neutrophil counts; headaches, dizziness; nauseaRare: hypersensitivity

MONITOR :CBC at baseline, monthly for three months, then every three months

Interleukin-1 receptor antagonist; used when treatment with another DMARD has failed.

TNFα and it’s Receptor

TOCLIZUMAB

First IL-6receptor inhibiting monoclonal antibody.

Dose :8mg/kg i.v. every 4wks given as i. v. infusion over an hour.

Moderate to severe RA

CONTRA INDICATIONS :infusion reactions,active infections.

RITUXIMAB(ANTI CD20 THERAPY) Genetically engineered human mouse chimeric

monoclonal antibody.

CD 20 antagonist and B cell ACTION depletor

Dose:1000mg /infusion on days 1 and 15(over sevaeral hrs ) with 100mg i.v. methyl prednisolone.

Contraindications :hypersensitivity,active infection,severe HF.

ABATACEPT (T CELLS CTLV-4 IG) Prevents co-stimulatory binding of CD28 on

naïve T-cells and attenuating T-cell function.

Dose:10mg/kg i.v. every 2wkly for 3 doses ,followed by every 4wkly.

Contraindications: hypersensitivity,active infections,COPD.

ADVERSE REACTIONS OF BRMS

1.injection site/infusion reactions

2.infections (activation of latent TB or new TB)

3.neutropenia,aplastic anemia

4.mild reversible lupus like syndrome

5.CCF

6.malignancy

7.ANA postivity

8.demyelinating neurological diseases

PARADIGM SHIFT

1.early use of DMARDs --initiated early within 3months-3yrs.

-- to avail window of oppurtunity,replacing’ Go low,go slow.

--’inverting pyramid’ concept

2.REMISSION :instead of relief.

3.MTX :anchor drug -as monotherapy or combination therapy.

CONTD….

4.Combination therapy—DMARD combination

triple therapy-of MTX+SSZ+HCQ

MTX+biologicals --better outcome

5.Reappraisal of glucocorticoids :low dose+DMARDS

6.Evolution of strategy trials :like COBRA,CAMERA,FINRACO,TICORA.

Sub group of Best trails.

WHEN TO START DMARD THERAPY

Before onset of erosion by US/MRI

Within 3-6 months

WHO TO TREAT?

Consider DMARD therapy for all patients with early inflammatory polyarthritis where persistent disease is likely

Most important determinant of chronicity is disease duration > 12 weeks.

WHOM TO TREAT WITH DMARDS? Early n severe synovitis

Strogly +ve ACPA and RF

Extra articular features

Joint erosion –US/MRI

Functional impairment

Lower educational status

HOW TO INITIATE DMARD THERAPY?

SSZ,HCQ -in mild cases

MTX,LEF OR cyclosporine-in severe cases

MTX +biologicals –very severe cases

IN PREGNANCY DMARDS ?

SSZ ,HCQ are safe

FOLLOW UP?

Every6 wks or earlier.

COMBINATION DMARD THERAPY MTX + SSZ + OH-Chloroquine

O’Dell 1995

MTX + CSA

Tugwell 1995

MTX + Etanercept

MTX + Remicade

MTX + Adalimumab

MTX + Leflunomide

excellent safety & improved efficacy over MTX alone

RATIONALE FOR TNFΑ BLOCKADE Cytokines are small molecules whose

function is to communicate between cells

Tumor necrosis factor α = gatekeeper of inflammatory cascade

Cytokines can be either pro-inflammatory or anti-inflammatory

Mechanisms in Rheumatology ©2001

PROINFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES IN RA

TNF INHIBITORS AND TB Mycobacterium tuberculosis currently infects

approximately one third of the world's population (close to 2 billion people).

Approximately 2 million people die of TB each year and there are 8 million new cases reported annually.

TNF is essential for formation and sustainment of granuloma, which sequester mycobacteria and prevent their dissemination.

The calculated risk ratio of TB in infliximab-treated patients with RA versus patients with RA not exposed to this agent was 19.9 (95% confidence interval [CI], 16.2–24.8) in the year 2000 and 11.7 (95% CI, 9.5–14.6) in the year 2001.

Screening has almost eliminated this increased risk in Spain and Germany

Quality of Life in Rheumatoid Arthritis

SURGERY IN RA

Tenosynovectomy.

Decompression of carpal tunnel

Reconstructive arthroplasty

Corrective artrotomies of matatarsals

Stabilization of cervical spine

Tendon release and transfer

Arthrodesis of ankle

CORTICOSTEROIDS IN RA

ACCORDING TO EULAR COMMITTEE RECOMMONDATIONS

NOMENCLATURE OF CORTICOSTEROID DOSING :

Low dose:<7.5mg prednisolone/day

Medium dose:>7.5 but <30mg /day

High dose:.>30 but <100mg/day

Very high dose:>100mg/day

Pulse therapy:>250mg/day for 1 or few days

CORTICOSTEROIDS

Current indications are---

1.bridge therapy inacute cases

2.acute ocular emergencies

3.rheumatoid vasculitis

4.combin therapy with DMARDs

5.active disease in pregnancy

6.intra articular use in monosynovitis

MODES OF USE OF CS

Oral prednisolone 10mg/d with tapering to 2.5-5mg/d over few months.

Inj.methylprednisolone acetate 80-120mg i.m. every 4 wks for 2-3 months.

Intra articular steroids in monosynovitis

RECENT ADVANCES CS

NOVEL MODIFIED RELEASE( MR) prednisolone formulation given at bedtime -better clinical effects

CAPRA -1(circadian administration ofpradnisolone in RA trail).

SEGRAs :Selective glucocorticoid receptor agonists (NEW CLASS OF STEROIDS)

Compound A(CpdA)

Botschanzev

TARGETS OF TREATMENT IN RA.

Biological agents are divided into --

monoclonal ab

small molecules

MONOCLONAL AB S

FUNCTION BY neutralizing target cytokine/receptor blocking co stimulation moleculescytolysis depletion of target cell molecule or apoptosis.

TNF ALPHA INHIBITORS

Infliximab,etanercept,adalimumab –being used.

Golimumab ;certolizumab likely to be approved

IL -1 INHIBITORS

ANAKINRA

Canakinumab is on clinical trails

IL -6 INHIBITORS

Tocilizumab now approved for the mod to severe RA.

IL-15 INHIBITOR :HUMANISED MONOCLONAL AB AGAINST IL-15(HuMaxIL-15) proved

IL-17 inhibitor :clinical trial in progress.

IL-12/IL-23 inhibitor :ustekinumab –on going trails.

Inhibitors of osteoclastogenesis :Danosumab in phase 3 clnical trail.

Inhibitors of TNF superfamily members :baminercept,belimubab ,atacicept –in trails

Inhibitors of chemokines and angiogenesis :bevacizumab –ab against VEGF.

APOPTOSIS regulators :anti FAS IgM ab under trails.

T-cell inhibitors :alemtuzumab ,keliximab,clinoliximab --discontinued trails due to lymphopenia and skin rash.

B-cell inhibitors :RITUXIMAB approved ;clinical trails in progress by ocrelizumab,ofatumumab.

SMALL MOLECULES

Molecular wts do not exceed 1kDa.

GOAL is to develop orally effective agents and increased selectivity.

INHIBITORS OF

1. intracellular signalling molecules

2. mitogen activated protein (MAP)

3. transcription factors

4. cytokines/chemokines

5. cell surface markers

OTHER TARGET FUTURE RX OF RA Regulatory t cells (treg cells)

Toll like receptors

RNA epigenetic alterations

Gene therapy

UNDER TRIALS.

With the help of these newer drugs,the future may well see rheumatologists talking not about symptomatic relief but potencial cure for RA.

AIM OF MANAGEMENT OF R.A .CASE

THANK YOU

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