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Rheumatoid Arthritis

M Handel

1st Feb 2012

Rheumatoid Arthritis is a multi-system autoimmune disease of unknown cause characterized by inflammatory changes in the joints

Rheumatoid Arthritis is a multi-system autoimmune disease of unknown cause characterized by inflammatory changes in the joints

Definition of the ProblemDefinition of the Problem

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Features of Rheumatoid Arthritis

• Prevalence of approximately 1% in adult population

• Age of onset usually between 30 – 50 years

• Two- to three-fold more common in women

• Chronic, progressive and disabling

• Higher mortality rates– Shortens life span by 3 to 18 years

Koopman WJ, et al. Arthritis & Allied Conditions. 13th ed. 1997.

FUSIFORM SWELLING

MCP & PIP SWELLING

Hammer Toe Deformities

MTP Erosive Disease

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Potential Pathogenic Pathway in RA

Initiating Event

Synovitis Pannus

Clinical Symptoms

X-rayChanges

Joint Space Narrowing (JSN)

Pain and Stiffness

Swelling

Joint Erosions (JE)

Adapted from: Kirwan JR. Rheum Dis Clin North Am. 2001;27:389.

QoL Change

Pain Structural Damage

Inflammation

8Immune-Mediated Inflammatory Process of RA

Initiation

Perpetuation/Regulation

Inflammation/Joint Destruction

IL-1TNF-IL-6IL-8

IL-10TGF-

IL-2IFN-TNF-IL-4

iNOS

B cellsSynoviocytes

Adhesion moleculeactivation

Immunoglobulins MetalloproteinasesLymphocytes, PMNs,

macrophages

TCR

CD4+

T cell

CD4APC

MHC

Ag

APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor;TGF = transforming growth factor; iNOS = inducible nitric oxide synthase; PMNs = polymorphonuclear cells

Moreland LW, et al. Arthritis Rheum. 1997;40:397-409.

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Feldmann M, et al. Ann Rev of Immunol. 1996;14:397-440.

The Pathogenesis of Rheumatoid Arthritis

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RA Synovium

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RA Synovium

Rosenberg A. In: Cotran RS et al, eds. Robbins Pathologic Basis of Disease. 6th ed. Philadelphia, PA: WB Saunders; 1999:1215.

12Inflamed synovium invading and destroying cartilage and bone

Clinical Course of RAClinical Course of RA

Guerne PA and Weisman MH. Am J Med 1992;16:451-460; Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911“Kelley's Textbook of Rheumatology”, 2008; “Eular Compendium on Rheumatic Diseases”, Ed. Bijlsma JWJ, 2009

91%

78 %

64 %

65 %

50 %

43 %

38 %

17 %

Joint involvement in RA • Main presenting symptoms:– Swelling of the joint and/or

joint margins– Joint tenderness– Systemic malaise– Loss of energy– Severe morning stiffness

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Clinical Course of RA

• Clinical course of RA is highly variable– From mild arthritis– To rapidly progressive multisystem inflammation

With profound morbidity & mortality

• Rate of disease progression 1. Variable presentation

periods of increasing disease activity (early years)

relentless linear progression aggressive and malignant without remission

2. But always progress with irreversible destruction at all phase of disease

Lee DM and Weinblatt E. The Lancet 2001; 358 : 903-911

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Puffy, hands, early arthritis

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Nodular, erosive rheumatoid arthritis

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Joint Destruction and disability in RA

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Progression of RA joint damage

Inte

nd

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ub

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lo

ca

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ev

iew

pri

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l u

se Relationship Between Inflammation,

Radiographic Progression and Disability S

ever

ity

(Arb

itra

ry U

nit

s)

0

Duration of Disease (years)

5 10 15 20 25 30

InflammationDisabilityRadiographs

“In early RA irreversible damage is seen in 60% of patients within the first 2 years of diagnosis.”

Kirwan J. Rheum 1999;26:720. Saleem et al. Clin Exp Rheum 2006;24:S33. Illustration source unknown.

EXTRA-ARTICULAR MANIFESTATIONSEXTRA-ARTICULAR MANIFESTATIONS

Skin -NodulesSkin -Nodules

Heart – PericarditisHeart – PericarditisLungs – Pulmonary Nodules, EffusionsLungs – Pulmonary Nodules, Effusions

Neurologic – Neuritis, Stroke

Neurologic – Neuritis, Stroke

Vascular – VasculitisVascular – Vasculitis

Ocular – EpiscleritisOcular – Episcleritis

Rheumatoid NoduleRheumatoid Nodule

EpiscleritisEpiscleritis

Scleromalacia PerforansScleromalacia Perforans

Periungual Infarcts and Digital Gangrene Associated with Severe Rheumatoid Vasculitis.

Periungual Infarcts and Digital Gangrene Associated with Severe Rheumatoid Vasculitis.

Atlanto axial subluxationAtlanto axial subluxation

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Rheumatoid Arthritis

Classification

Arnett FC et al. Arthritis Rheum. 1988:31:315-324.

*Must be present for at least 6 weeks.

1987 ACR Classification Criteria for RAAt least 4 of the following criteria must be met:

• AM stiffness lasting > 1 hour*

• Swelling of 3 joints*

• Swelling of hand joints*

• Symmetric joint involvement*

• Radiographic changes (erosion or bony decalcification)

• Presence of rheumatoid nodules

• Rheumatoid factor in serum

Aletaha et al. Ann Rheum Dis 2010;69:1580-1588

2010 ACR Classification Criteria for RA

Joint involvement One large joint 0

2-10 large joints 1

1-3 small joints* 2

4-10 small joints* 3

>10 joints (at least one small joint) 5

Serology# RF- and ACPA- 0

Low RF+ or low ACPA+ 2

High RF+ or high ACPA+ 3

Acute-phase reactants# Normal CRP and normal ESR 0

Abnormal CRP or abnormal ESR 1

Duration of symptoms <6 weeks 0

≥6 weeks 1

*With or without involvement of large joints. # at least one test result needed for classification . ACPA: Anti-citrullinated protein/peptide antibodies; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate

Synovitis plus score of ≥6/10 needed for the classification of definite RA

Tree Algorithm to Classify Definite RA or to Exclude its Current Presence

Aletaha et al. Ann Rheum Dis 2010;69:1580-1588APR: acute-phase response; Serology+: low-positive for RF or ACPA; serology++: high-positive for RF or ACPA;serology+/++: serology either + or ++

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Rheumatoid Arthritis

Disease assessment tools

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Measuring Treatment Outcomes: Common Clinical Trial Endpoints

Requirements

Improvement in Signs/Symptoms

Prevention of Structural Damage

Prevention of Disability

Trial Duration

6 mo 1 y 2-5 y

Validated Measure

• ACR 20 (or other composite endpoint)

• Larsen

• Sharp scores

• HAQ

• SF-36

Other • Pain, tenderness, swelling

• Global assessments

• ACR core set

• Response over time preferred

• Prevention of new erosions

• Maintenance of erosion-free state

“Patients should not worsen on

these measures over the

duration of the trial”

FDA, Center for Drug Evaluation and Research. Guidance for Industry.http://www.fda.gov/cder/guidance/1203fnl.htm. February 1999.

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Definition of ACR 20, 50, or 70• Measures response to treatment in a clinical trial:

– Is the patient an ACR 20 responder or not

• A 20%, 50%, or 70% reduction in – the number of swollen jointsand– the number of tender joints and – the same degree of improvement in

at least 3 of 5 other variables: • pain• degree of disability according to the HAQ• patient’s global assessment• physician’s global assessment• erythrocyte sedimentation (ESR)/ C-reactive protein (CRP)

level

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Disease Activity Score (DAS) and Definition of Response

Improvement in DAS or DAS28 from Baseline

DAS 28 at Endpoint1.2

(clinically significant)

0.6 and 1.2

0.6(within error)

3.2(low activity) Good

None

3.2 and 5.1(moderate activity) Moderate

5.1(high activity)

den Broeder, A. et al., Rheumatology. 2002; 41:638-42.

• Continuous variable: – Patient’s disease activity is described on a scale of 1 to 10 using a

composite index• Composite Index incorporating:

– ESR– Number of Swollen joints (SJC) (1-28)– Number of Tender joints (TJC) (1-28)– Assessment of patient’s general health (VAS 1-100)

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Health Assessment Questionnaire (HAQ)

Buchbinder R, et al. Arthritis Rheum. 1995;38:1568–1580; Sullivan FM, et al. Ann Rheum Dis. 1987;46:598–600;Kosinski M, et al. Arthritis Rheum. 2000;43:1478–1487.

Widely accepted, validated, rheumatology-specific instrumentto assess physical function in RA

· 20 questions covering eight types of activities- Dressing and grooming, arising, eating, walking, hygiene,

reaching, gripping, activities of daily living- A mean decrease of at least 0.22 in HAQ score is considered a

minimum clinically important difference (MCID)

HAQ Disability Index (HAQ-DI)· Scores the worst items within each of the eight scales· Based on use of aids and devices

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= Joint narrowing

Schema of Radiographic Joint Evaluation

20 joints evaluated

6 joints evaluated

Modified van der Heijde-Sharp Scoring Method (vdHSS)

Range: 0 – 528

Erosions

6 joints evaluated

20 joints evaluated

Van der Heijde D, et al. Ann Rheum Dis. 2005;64(Suppl II):ii61-ii64.

35VdHSS: Joint Erosions Scored 0 – 5 and Joint Space Narrowing Scored 0 – 4

1 54320

1 4320

ER

OS

ION

SN

AR

RO

WIN

G

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Continuation of DMARDs

Pincus T et al, J Rheumatol 19:1885–1894, 1992

100

80

60

40

20

0

0 12 24 36 48 60

Parenteral gold (269)

Oral gold (84)

Azathioprine (56)

Methotrexate (253)*

HCQ (228)

D-Pen (193)

Est

imat

ed c

on

tin

uat

ion

(%

)

Months

(P < 0.001)

(P < 0.001)

MTX vs

all other drugs

Oral gold vsall other drugs

*Numbers represent courses of therapy