Dr. Ankur Nandan VarshneyDr. Ankur Nandan VarshneyInstitute of Medical SciencesInstitute of Medical Sciences

Banaras Hindu UniversityBanaras Hindu University

Rheumatoid ArthritisRheumatoid Arthritis Diagnosis and Current Management Diagnosis and Current Management

Introduction Introduction

Commonest inflammatory joint disease seen in clinical Commonest inflammatory joint disease seen in clinical

practice affecting approx 1% of population.practice affecting approx 1% of population.

Chronic multisystem disease of unknown cause.Chronic multisystem disease of unknown cause.

Characterized by persistent inflammatory synovitis Characterized by persistent inflammatory synovitis

leading to cartilage damage, bone erosions, joint leading to cartilage damage, bone erosions, joint

deformity and disability. deformity and disability.

OnsetOnset Although Rheumatoid arthritis may present at any Although Rheumatoid arthritis may present at any

age, patients most commonly are first affected in the age, patients most commonly are first affected in the

third to sixth third to sixth decades. decades.

Female: male 3:1Female: male 3:1

Initial pattern of joint involvement could be:-Initial pattern of joint involvement could be:-

1)1) Polyarticular : most commonPolyarticular : most common

2)2) OligoarticularOligoarticular

3)3) MonoarticularMonoarticular

Morning joint stiffness > 1 hour Morning joint stiffness > 1 hour and easing with physical activity is and easing with physical activity is

characteristic.characteristic.

Small joints of hand and feet Small joints of hand and feet are typically involved.are typically involved.

Clinical ManifestationsClinical Manifestations

ArticularArticular

Extra-articularExtra-articular

Articular manifestationArticular manifestation

Pain in affected Pain in affected joint aggravated joint aggravated by movemnt is by movemnt is the most common the most common symptom.symptom.

Morning stiffness Morning stiffness ≥1 hr≥1 hr

Joints involved -Joints involved -

Relative incidence of Relative incidence of joint involvement in RAjoint involvement in RA

MCP and PIP joints of hands & MTP of feet 90%MCP and PIP joints of hands & MTP of feet 90% Knees, ankles & wrists- Knees, ankles & wrists-

80%80% Shoulders- Shoulders-

60%60% Elbows- 50%Elbows- 50% TM, Acromio - clavicular & SC joints- TM, Acromio - clavicular & SC joints-

30%30%

Joints involved in RAJoints involved in RA

Don’t forget the Don’t forget the cervical spinecervical spine!! !! Instability at cervical spine can lead to Instability at cervical spine can lead to impingement of the spinal cord. impingement of the spinal cord.

Thoracolumbar, sacroiliac, and distal Thoracolumbar, sacroiliac, and distal interphalangeal joints (DIP)of the hand are interphalangeal joints (DIP)of the hand are NOTNOT involved.involved.

PIP SwellingPIP Swelling

Ulnar Deviation, MCP Swelling, Ulnar Deviation, MCP Swelling, Left Wrist SwellingLeft Wrist Swelling

Extra-articular Extra-articular manifestationsmanifestations Present in 30-40% Present in 30-40%

May occur prior to arthritisMay occur prior to arthritis

Patients that are more likely to get are:Patients that are more likely to get are:

High titres of RF/ anti-CCPHigh titres of RF/ anti-CCP

HLA DR4+HLA DR4+

Male Male

Early onset disabilityEarly onset disability

History of smokingHistory of smoking

Constitutional symptoms Constitutional symptoms ( most ( most common)common)

Rheumatoid nodulesRheumatoid nodules(30%)(30%) HematologicalHematological--

normocytic normochromic anemianormocytic normochromic anemia leucocytosis /leucopenialeucocytosis /leucopenia thrombocytosisthrombocytosis

Felty’s syndrome-Felty’s syndrome- Chronic nodular Rheumatoid ArthritisChronic nodular Rheumatoid Arthritis SpleenomegalySpleenomegaly NeutropeniaNeutropenia

Extraarticular Extraarticular InvolvementInvolvement

RespiratoryRespiratory- pleural effusion, pneumonitis - pleural effusion, pneumonitis , pleuro-pulmonary nodules, ILD, pleuro-pulmonary nodules, ILD

CVSCVS-asymptomatic pericarditis , -asymptomatic pericarditis , pericardial effusion, cardiomyopathy pericardial effusion, cardiomyopathy

Rheumatoid vasculitisRheumatoid vasculitis- mononeuritis - mononeuritis multiplex, cutaneous ulceration, digital multiplex, cutaneous ulceration, digital gangrene, visceral infarction gangrene, visceral infarction

CNSCNS- peripheral neuropathy, cord-- peripheral neuropathy, cord-compression from atlantoaxial/midcervical compression from atlantoaxial/midcervical spine subluxation, entrapment spine subluxation, entrapment neuropathiesneuropathies

EYEEYE- kerato cunjunctivitis sicca, - kerato cunjunctivitis sicca, episcleritis, scleritisepiscleritis, scleritis

Rheumatoid noduleRheumatoid nodule

Laboratory investigations Laboratory investigations in RAin RA

CBC- TLC, DLC, Hb, ESR & GBPCBC- TLC, DLC, Hb, ESR & GBP

Acute phase reactantsAcute phase reactants

Rheumatoid Factor (RF)Rheumatoid Factor (RF)

Anti- CCP antibodiesAnti- CCP antibodies

Rheumatoid Factor (RF)Rheumatoid Factor (RF) Antibodies that recognize Fc portion of IgGAntibodies that recognize Fc portion of IgG

Can be IgM , IgG , IgACan be IgM , IgG , IgA

85% of patients with RA over the first 2 years become RF+85% of patients with RA over the first 2 years become RF+

• A negative RF may be repeated 4-6 monthly for the first two year of A negative RF may be repeated 4-6 monthly for the first two year of

disease, since some patients may take 18-24 months to become disease, since some patients may take 18-24 months to become

seropositive.seropositive.

• PROGNISTIC VALUEPROGNISTIC VALUE- Patients with high titres of RF, in general, - Patients with high titres of RF, in general,

tend to have POOR PROGNOSIS, MORE EXTRA ARTICULAR tend to have POOR PROGNOSIS, MORE EXTRA ARTICULAR

MANIFESTATION.MANIFESTATION.

Causes of positive test for Causes of positive test for RFRF

Rheumatoid arthritisRheumatoid arthritis Sjogrens syndromeSjogrens syndrome Vasculitis such as polyarteritis nodosaVasculitis such as polyarteritis nodosa SarcoidosisSarcoidosis Systemic lupus erythematosusSystemic lupus erythematosus CryoglobulinemiaCryoglobulinemia Chronic liver diseaseChronic liver disease Infections- tuberculosis , bacterial endocarditis, Infections- tuberculosis , bacterial endocarditis,

infectious mononucleosis, leprosy, syphilis, infectious mononucleosis, leprosy, syphilis, leishmaniasis.leishmaniasis.

MalignanciesMalignancies Old age(5% women aged above 60)Old age(5% women aged above 60)

Anti-CCPAnti-CCP IgG against synovial membrane IgG against synovial membrane

peptides damaged via inflammationpeptides damaged via inflammation Sensitivity (65%) & Specificity (95%)Sensitivity (65%) & Specificity (95%) Both diagnostic & prognostic Both diagnostic & prognostic

valuevalue Predictive of Erosive DiseasePredictive of Erosive Disease

Disease severityDisease severity Radiologic progressionRadiologic progression Poor functional outcomesPoor functional outcomes

Acute Phase Reactants Acute Phase Reactants Positive acute phase reactants () Negative acute phase reactants ()

Mild elevations

– Ceruloplasmin

– Complement C3 & C4

Moderate elevations

– Haptoglobulin

– Fibrinogen (ESR)

– 1 – acid glycoprotein

– 1 – proteinase inhibitor

Marked elevations

– C-reactive protein (CRP)

– Serum amyloid A protein

– Albumin

– Transferrin

Elevated APRs( ESR, CRP )Elevated APRs( ESR, CRP ) ThrombocytosisThrombocytosis LeukocytosisLeukocytosis ANAANA

30-40%30-40% Inflammatory synovial fluidInflammatory synovial fluid HypoalbuminemiaHypoalbuminemia

Radiographic FeaturesRadiographic Features Peri-articular osteopeniaPeri-articular osteopenia Uniform symmetric joint space narrowingUniform symmetric joint space narrowing Marginal subchondral erosionsMarginal subchondral erosions Joint Subluxations Joint Subluxations Joint destructionJoint destruction CollapseCollapse

Ultrasound Ultrasound detects early soft tissue lesions.detects early soft tissue lesions. MRI MRI has greatest sensitivity to detect synovitis has greatest sensitivity to detect synovitis

and marrow changes.and marrow changes.

Diagnostic Diagnostic CriteriasCriterias

ACR Criteria (1987)ACR Criteria (1987) 1.Morning Stiffness ≥1 hour1.Morning Stiffness ≥1 hour

2.Arthritis of ≥ 3 joints observed by physician 2.Arthritis of ≥ 3 joints observed by physician simulteneously-simulteneously-

Rt/Lt-PIP, MCP,wrist, elbow, Rt/Lt-PIP, MCP,wrist, elbow, knee, ankle, MTPknee, ankle, MTP

3.Arthritis of hand joints-PIP,MCP,wrist3.Arthritis of hand joints-PIP,MCP,wrist

4. Symmetric arthritis4. Symmetric arthritis 5. Rheumatoid nodules5. Rheumatoid nodules 6. Positive Rheumatoid Factor6. Positive Rheumatoid Factor 7. Radiographic Erosions or periarticular 7. Radiographic Erosions or periarticular osteopenia in hand or osteopenia in hand or

wrist jointswrist joints

Criteria 1-4 must be present for ≥6 wksCriteria 1-4 must be present for ≥6 wks Must have ≥4 criteria to meet diagnosis of RAMust have ≥4 criteria to meet diagnosis of RA

2010 ACR/EULAR Classification Criteria2010 ACR/EULAR Classification Criteria a score of ≥6/10 is needed for classification of a patient as having definite RAa score of ≥6/10 is needed for classification of a patient as having definite RA A. Joint involvement A. Joint involvement

SCORESCORE 1 large joint 01 large joint 0 2−10 large joints 1 2−10 large joints 1

1−3 small joints 1−3 small joints (with or without involvement of large joints) 2(with or without involvement of large joints) 2

4−10 small joints (with or without involvement of large joints) 34−10 small joints (with or without involvement of large joints) 3 >10 joints (at least 1 small joint)†† 5>10 joints (at least 1 small joint)†† 5 B. Serology B. Serology (at least 1 test result is needed for classification(at least 1 test result is needed for classification)) Negative RF Negative RF and negative ACPA 0and negative ACPA 0 Low-positive RF Low-positive RF or low-positive ACPA 2or low-positive ACPA 2 High-positive RF High-positive RF or high-positive ACP 3or high-positive ACP 3

C. Acute-phase reactants C. Acute-phase reactants (at least 1 test result is needed for classification(at least 1 test result is needed for classification)) Normal CRP Normal CRP and normal ESR 0and normal ESR 0 Abnormal CRP Abnormal CRP or normal ESR 1or normal ESR 1

D. Duration of symptomsD. Duration of symptoms <6 weeks 0<6 weeks 0 ≥≥6 weeks 1 6 weeks 1

ManagementManagement

Goals of managementGoals of management

Focused on relieving pain Focused on relieving pain Preventing damage/disabilityPreventing damage/disability Patient education about the diseasePatient education about the disease Physical Therapy for stretching and range of motion Physical Therapy for stretching and range of motion

exercisesexercises Occupational Therapy for splints and adaptive devicesOccupational Therapy for splints and adaptive devices Treatment should be started early and Treatment should be started early and

should be individualised .should be individualised . EARLY AGGRESSIVE TREATEMNTEARLY AGGRESSIVE TREATEMNT

Treatment modalities Treatment modalities for RAfor RA

NSAIDSNSAIDS SteroidsSteroids DMARDsDMARDs Immunosuppressive therapyImmunosuppressive therapy Biological therapiesBiological therapies SurgerySurgery

NSAIDSNSAIDSNon-Steroidal anti-inflammatories Non-Steroidal anti-inflammatories

(NSAIDS) / Coxibs for symptom control(NSAIDS) / Coxibs for symptom control

1)1) Reduce pain and swelling by inhibiting COXReduce pain and swelling by inhibiting COX

2)2) Do not alter course of the disease. Do not alter course of the disease.

3)3) Chronic use should be minimised.Chronic use should be minimised.

4)4) Most common side effect related to GI tract.Most common side effect related to GI tract.

Corticosteroids in Corticosteroids in RARA

Corticosteroids , both systemic and intra-Corticosteroids , both systemic and intra-articular are important adjuncts in articular are important adjuncts in management of RA.management of RA.

Indications for systemic steroids are:-Indications for systemic steroids are:-1.1. For treatment of rheumatoid flares.For treatment of rheumatoid flares.2.2. For extra-articular RA like rheumatoid For extra-articular RA like rheumatoid

vasculitis and interstitial lung disease.vasculitis and interstitial lung disease.3.3. As As bridge therapy bridge therapy for 6-8 weeks before the for 6-8 weeks before the

action of DMARDs begin.action of DMARDs begin.4.4. Maintainence dose of 10mg or less of Maintainence dose of 10mg or less of

predinisolone daily in patients with active RA.predinisolone daily in patients with active RA.5.5. Sometimes in pregnancy when other Sometimes in pregnancy when other

DMARDs cannot be used. DMARDs cannot be used.

Disease Modifying Anti-rheumatic AgentsDisease Modifying Anti-rheumatic Agents

Drugs that actually alter the disease course .Drugs that actually alter the disease course .

Should be used as soon as diagnosis is made.Should be used as soon as diagnosis is made.

Appearance of benefit delayed for weeks to Appearance of benefit delayed for weeks to months.months.

NSAIDS must be continued with them until true NSAIDS must be continued with them until true remission is achieved .remission is achieved .

Induction of true remission is unusual .Induction of true remission is unusual .

DMARDsDMARDsCommonly used Less commonly

usedMethotrexate Chloroquine

Hydroxychloroquine Gold(parenteral &oral)

Sulphasalazine CyclosporineA

Leflunomide D-penicillamine/bucillamine

Minocycline/Doxycycline Levamisole

Azathioprine,cyclophosphamide, chlorambucil

Clinical information about Clinical information about DMARDsDMARDs

NAME DOSE SIDE EFFECTS

MONITORING

ONSET OF ACTION

1) Hydroxycloroquine

200mg twice daily x 3 months, then once daily

Skin pigmentation , retinopahy ,nausea, psychosis, myopathy

Fundoscopy& perimetry yearly

2-4 months

2) Methotrexate

7.5-25 mg once a week orally,s/c or i/m

GI upset,hepatotoxicity,Bone marrow suppression, pulmonary fibrosis

Blood counts,LFT 6-8 weekly,Chest x-ray annually, urea/creatinine 3 monthly;Liver biopsy

1-2 months

Clinical information about Clinical information about DMARDs contnd..DMARDs contnd..

NAME DOSE SIDE EFFECTS

MONITORING

ONSET OF ACTION

3)Sulphasala-

2gm daily p.o Rash, myelosuppression, may reduce sperm count

Blood counts ,LFT 6-8 weekly

1-2 months

4)Leflunomide

Loading 100 mg daily x 3 days, then 10-20 mg daily p.o

Nausea,diarrhoea,alopecia, hepatotoxicity

LFT 6-8 weekly

1-2 months

zine

When to start DMARDs?When to start DMARDs?

DMARDs are indicated in all patients with DMARDs are indicated in all patients with RA who continue to have active disease even RA who continue to have active disease even after 3 months of NSAIDS use.after 3 months of NSAIDS use.

The period of 3 months is arbitary & has been The period of 3 months is arbitary & has been chosen since a small percentage of patients chosen since a small percentage of patients may go in spontaneous remission.may go in spontaneous remission.

The vast majority , however , need DMARDs The vast majority , however , need DMARDs and many rheumatologists start DMARDs and many rheumatologists start DMARDs from from Day Day 1.1.

How to select How to select DMARDs?DMARDs?

There are no strict guidelines about There are no strict guidelines about which DMARDs to start first in an which DMARDs to start first in an individual.individual.

Methotrexate has rapid onset of action Methotrexate has rapid onset of action than other DMARD.than other DMARD.

Taking in account patient tolerance, cost Taking in account patient tolerance, cost considerations and ease of once weekly considerations and ease of once weekly oral administration oral administration METHOTREXATEMETHOTREXATE is is the the DMARD of choiceDMARD of choice, most widely , most widely prescribed in the world.prescribed in the world.

Should DMARDs be used Should DMARDs be used singly or in combination?singly or in combination?

Since single DMARD therapy (in conjunction Since single DMARD therapy (in conjunction with NSAIDS) is often only modestly effective , with NSAIDS) is often only modestly effective , combination therapy has an inherent appeal.combination therapy has an inherent appeal.

DMARD combination is specially effective if DMARD combination is specially effective if they include they include methotrexate methotrexate as an anchor drug.as an anchor drug.

Combination of methotrexate with Combination of methotrexate with leflunamide leflunamide are synergestic since there are synergestic since there mode of action is different.mode of action is different.

Limitations of conventional Limitations of conventional DMARDsDMARDs

1)1) The onset of action takes several months.The onset of action takes several months.

2)2) The remission induced in many cases is The remission induced in many cases is partial.partial.

3)3) There may be substantial toxicity which There may be substantial toxicity which requires careful monitoring.requires careful monitoring.

4)4) DMARDs have a tendency to lose DMARDs have a tendency to lose effectiveness with time-(slip out).effectiveness with time-(slip out).

These drawbacks have made researchers These drawbacks have made researchers look for alternative treatment strategies for look for alternative treatment strategies for RA- RA- The Biologic Response Modifiers.The Biologic Response Modifiers.

ImmunosuppresiveImmunosuppresive therapy therapy

Agent Usual dose/route Side effects

Azathioprine 50-150 mg orally GI side effects , myelosuppression, infection,

Cyclosporin A 3-5 mg/kg/day Nephrotoxic , hypertension , hyperkalemia

Cyclophosphamide

50 -150 mg orally Myelosuppression , gonadal toxicity ,hemorrhagic cystitis , bladder cancer

..

BIOLOGICS IN RABIOLOGICS IN RA Cytokines such as TNF-Cytokines such as TNF-αα ,IL-1,IL-10 etc. ,IL-1,IL-10 etc.

are key mediators of immune function in are key mediators of immune function in RA and have been major targets of RA and have been major targets of therapeutic manipulations in RA.therapeutic manipulations in RA.

Of the various cytokines,TNF-Of the various cytokines,TNF-αα has has attaracted maximum attention.attaracted maximum attention.

Various biologicals approved in RA are:-Various biologicals approved in RA are:-1)1) Anti TNF agents : Anti TNF agents : Infliximab Etanercept Infliximab Etanercept

AdalimumabAdalimumab

2)2) IL-1 receptor antagonist : IL-1 receptor antagonist : AnakinraAnakinra

3)3) IL-6 receptor antagonist : IL-6 receptor antagonist : TocilizumabTocilizumab

4)4) Anti CD20 antibody : Anti CD20 antibody : RituximabRituximab

5)5) T cell costimulatory inhibitor : T cell costimulatory inhibitor : AbataceptAbatacept

Agent Usual dose/route Side effects Contraindications

Infliximab(Anti-TNF)

3 mg/kg i.v infusion at wks 0,2 and 6 followed by maintainence dosing every 8 wksHas to be combined with MTX.

Infusion reactions, increased risk of infection, reactivation of TB ,etc

Active infections,uncontrolled DM,surgery(with hold for 2 wks post op)

Etanercept(Anti-TNF)

Active infections,uncontrolled DM,surgery(with hold for 2 wks post op)

Adalimumab(Anti-TNF)

40 mg s/c every 2 wks(fornightly)May be given with MTX or as monotherapy

Same as that of infliximab

Active infections

.25 mg s/c twice a wkMay be given with MTX or as monotherapy.

Injection site reaction,URTI , reactivation of TB,development of ANA,exacerbation of demyelenating disease.

Abatacept(CTLA-4-IgG1 Fusion protien)Co-stimulation inhibitor

10 mg/ kg body wt.At 0, 2 , 4 wks & then 4wkly

Infections, infusion reactions

Active infectionTBConcomittant with other anti-TNF-α

Rituximab(Anti CD20)

1000 mg iv at 0, 2, 24 wks

Infusion reactionsInfections

Same as above

Tocilizumab( Anti IL-6)

4-8 mg/kg8 mg/kg iv monthly

Infections, infusion reactions,dyslipidemia

Active infections

Agent Usual dose/route

Side effects

.

Anakinra

100 mg s/c once dailyMay be given with MTX or as monotherapy.

Injection site pain,infections,neutropenia

Active infections

Contraindications

(Anti-IL-1)

2012 ACR Update2012 ACR Update

How to monitor Tt in How to monitor Tt in RA?RA?

Disease activity is assesed by several Disease activity is assesed by several parameters…parameters…

duration of morning stiffness,tender joint duration of morning stiffness,tender joint count,swollen joint count,observer global count,swollen joint count,observer global assessment,patient global assessment,visual assessment,patient global assessment,visual analogue scale for pain,health assessment analogue scale for pain,health assessment questionnaire,ESR,NSAID pill count,DAS score questionnaire,ESR,NSAID pill count,DAS score etc..etc..

• Patient on MTX,SSZ or leflunamide show clinical Patient on MTX,SSZ or leflunamide show clinical improvement in 6-8 wks.improvement in 6-8 wks.

• Patient should be observed for 6 months before Patient should be observed for 6 months before declaring a DMARD ineffective. declaring a DMARD ineffective.

How long should Tt. be How long should Tt. be continued?continued?

Once remission is achieved , maintenance dose Once remission is achieved , maintenance dose for long period is recommended.for long period is recommended.

Relapse occurs in 3-5 months (1-2 months in case Relapse occurs in 3-5 months (1-2 months in case of MTX) if drug is discontinued in most instances.of MTX) if drug is discontinued in most instances.

DMARDs are discontinued by patients because of DMARDs are discontinued by patients because of toxicitytoxicity or or secondary failuresecondary failure(common after 1-2 (common after 1-2 yrs) and such patients might have to shift over yrs) and such patients might have to shift over different DMARDs over 5-10 yrs.different DMARDs over 5-10 yrs.

Disease flare may require escalation of DMARD Disease flare may require escalation of DMARD dose with short course of steroids. dose with short course of steroids.

Surgical Surgical ApproachesApproaches

Synovectomy is ordinarily not recommended for Synovectomy is ordinarily not recommended for patients with rheumatoid arthritis, primarily because patients with rheumatoid arthritis, primarily because relief is only transient.relief is only transient.

However, an exception is synovectomy of the wrist, However, an exception is synovectomy of the wrist, which is recommended if intense synovitis is persistent which is recommended if intense synovitis is persistent despite medical treatment over 6 to 12 months. despite medical treatment over 6 to 12 months. Persistent synovitis involving the dorsal compartments Persistent synovitis involving the dorsal compartments of the wrist can lead to extensor tendon sheath rupture of the wrist can lead to extensor tendon sheath rupture resulting in severe disability of hand function.resulting in severe disability of hand function.

Total joint arthroplasties , particularly of the knee, hip, Total joint arthroplasties , particularly of the knee, hip, wrist, and elbow, are highly successful.wrist, and elbow, are highly successful.

Other operations include release of nerve entrapments Other operations include release of nerve entrapments (e.g., carpal tunnel syndrome), arthroscopic (e.g., carpal tunnel syndrome), arthroscopic procedures, and, occasionally, removal of a procedures, and, occasionally, removal of a symptomatic rheumatoid nodule.symptomatic rheumatoid nodule.

Thank you.